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Beukelmanetal. Pediatric Rheumatology (2022) 20:113
https://doi.org/10.1186/s12969-022-00768-6
RESEARCH ARTICLE
First-line options forsystemic juvenile
idiopathic arthritis treatment: anobservational
study ofChildhood Arthritis andRheumatology
Research Alliance Consensus Treatment Plans
Timothy Beukelman1* , George Tomlinson2, Peter A. Nigrovic3,4, Anne Dennos5, Vincent Del Gaizo6,
Marian Jelinek6, Mary Ellen Riordan7, Laura E. Schanberg5,8, Shalini Mohan9, Erin Pfeifer9, Yukiko Kimura7 and for
the CARRA FROST Investigators
Abstract
Background: The Childhood Arthritis and Rheumatology Research Alliance (CARRA) developed consensus treatment
plans (CTPs) to compare treatment initiation strategies for systemic juvenile idiopathic arthritis (sJIA). First-line options
for sJIA treatment (FROST) was a prospective observational study to assess CTP outcomes using the CARRA Registry.
Methods: Patients with new-onset sJIA were enrolled if they received initial treatment according to the biologic
CTPs (IL-1 or IL-6 inhibitor) or non-biologic CTPs (glucocorticoid (GC) monotherapy or methotrexate). CTPs could be
used with or without systemic GC. Primary outcome was achievement of clinical inactive disease (CID) at 9 months
without current use of GC. Due to the small numbers of patients in the non-biologic CTPs, no statistical comparisons
were made between the CTPs.
Results: Seventy-three patients were enrolled: 63 (86%) in the biologic CTPs and 10 (14%) in the non-biologic CTPs.
CTP choice appeared to be strongly influenced by physician preference. During the first month of follow-up, oral GC
use was observed in 54% of biologic CTP patients and 90% of non-biologic CTPs patients. Five (50%) non-biologic
CTP patients subsequently received biologics within 4 months of follow-up. Overall, 30/53 (57%) of patients achieved
CID at 9 months without current GC use.
Conclusion: Nearly all patients received treatment with biologics during the study period, and 46% of biologic CTP
patients did not receive oral GC within the first month of treatment. The majority of patients had favorable short-term
clinical outcomes. Increased use of biologics and decreased use of GC may lead to improved outcomes in sJIA.
Keywords: Systemic juvenile idiopathic arthritis, Juvenile idiopathic arthritis, Still’s disease, Treatment, Biologics
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Background
Systemic Juvenile Idiopathic Arthritis (sJIA) is character-
ized by systemic inflammation that distinguishes it from
other types of JIA. sJIA can have life-threatening com-
plications, including macrophage activation syndrome
(MAS) which can occur at any time during the disease.
In North America/Europe, sJIA is a rare disease, and
accounts for 5 to 15% of children with JIA. Age at onset is
Open Access
*Correspondence: tbeukelman@peds.uab.edu
1 University of Alabama at Birmingham, 1601 4th Ave South, CPPN G10,
Birmingham, AL 35233, USA
Full list of author information is available at the end of the article
Page 2 of 10
Beukelmanetal. Pediatric Rheumatology (2022) 20:113
often in early childhood, with a peak from 1 to 5 years of
age, but sJIA can develop at any age, and after the age of
16 is called Adult Onset Still Disease (AOSD) [1].
Prior to the availability of biologic medications, treat-
ment of sJIA was difficult, often requiring prolonged
courses of systemic glucocorticoids (GC), which cause
many adverse effects including growth failure, osteopo-
rosis, and infections. Major advances in the treatment of
sJIA began with reports of the effectiveness of the IL-1
inhibitor (IL-1i) anakinra in the mid 2000s [2–4]. Results
of controlled trials of canakinumab and rilonacept con-
firmed the efficacy of IL-1i after 2010 [5, 6]. e IL-6
inhibitor (IL-6i) tocilizumab proved to be equally effica-
cious [7]. Since those studies, IL-1i and IL-6i have been
increasingly used for treating sJIA, along with GC and
methotrexate (MTX). A hypothesis has emerged that the
use of biologics (especially IL-1i and potentially IL-6i)
early in the disease course may allow patients a win-
dow of opportunity to prevent the evolution of chronic,
destructive synovitis [8]. is was suggested by an early
retrospective case series as well as a recent prospective
study in which patients with sJIA were initially treated
with anakinra alone [9]. Interestingly, the aforementioned
published randomized clinical trials enrolled patients
with long-standing (often refractory) sJIA, and so did not
provide information about which treatments are most
effective for patients with new-onset sJIA [5, 7]. As a
result, there continues to be uncertainty about treatment
choice at the time of sJIA diagnosis. is uncertainty
is compounded by continued reports of rare cases of
chronic lung disease which appear temporally associated
with increased use of biologic agents in sJIA [10–13].
To help answer these important questions, the Child-
hood Arthritis and Rheumatology Research Alliance
(CARRA) developed four consensus treatment plans
(CTPs) for new-onset sJIA in 2012 based on the initial
treatments most commonly used at the time. e CTPs
were: (1) GC alone, (2) MTX, (3) IL-1i (anakinra or
canakinumab), and (4) IL-6i (tocilizumab), each of which
could be used with or without GC [14]. e CTPs were
developed as standardized consensus-based treatments
which were intended to be used for observational com-
parative effectiveness research using the CARRA Regis-
try as the data collection vehicle [15]. A pilot study of the
sJIA CTPs was completed in 2016 and showed good dis-
tribution of CTPs used among the 13 sites that enrolled
patients, making a larger comparative effectiveness study
feasible [16]. is approach was also successfully used in
the recently published Start Time Optimization of bio-
logics in Polyarticular JIA (STOP-JIA) study [17, 18].
e FiRst-line Options for SJIA Treatment (FROST)
study was intended to be an observational compara-
tive effectiveness study of the sJIA CARRA CTPs
enrolling new-onset sJIA patients with data collected
in the CARRA Registry. Herein we report the primary
results of the study.
Methods
e CARRA JIA Research Committee prioritized sJIA
as one of 4 initial diseases to develop CTPs for compara-
tive effectiveness research using the Registry funded by
an NIH ARRA Challenge Grant. A group of sJIA experts
worked together to identify current treatments most
commonly used for sJIA. rough a process of surveys,
face-to-face consensus meetings and small workgroup
conference calls, leaders developed the four CTPs which
were finalized and approved by 95% of the CARRA JIA
Research Committee and published in 2012 [14]. To
better conform with the diagnostic approach to sJIA in
clinical practice, the CARRA JIA Research Committee
also voted to modify the sJIA ILAR criteria [19] for this
study. Eligible patients met the following 4 criteria: (1)
age 6 months to 18 years at disease onset; (2) fever for at
least 2 weeks that at some point rises to ≥39 °C at least
once a day and returns to normal between fever peaks;
(3) arthritis in ≥1 joint for at least 10 days; (4) at least one
of (a) evanescent erythematous rash, (b) generalized lym-
phadenopathy, (c) hepatomegaly or splenomegaly, or (d)
serositis.
FROST enrolled at all active CARRA Registry sites
from September 2016 through December 2019. Patients
enrolled in the CARRA Registry with recently diagnosed
sJIA according to the above criteria were included in the
FROST study. Patients were excluded for active infection
(including untreated latent tuberculosis), malignancy, or
immunization with live virus vaccines within the past
4 weeks. Patients were intended to be untreated for sJIA
at the time of FROST enrollment, but prior treatment
with non-steroidal anti-inflammatory drugs of unlim-
ited duration or short-term GC use (up to 14 days of oral
GC and/or 3 high-dose pulses of intravenous GC) were
allowed. To increase the inclusion of patients who were
otherwise eligible for the study, patients were included up
to 72 hours after initiating a CTP. Patients were excluded
if they had MAS (or other severe disease manifesta-
tions) at onset that precluded treatment with one of the
CTP arms according to the judgement of the treating
physician.
In all cases, CTP selection was made by the treat-
ing physician in consultation with the patient’s family.
Details about the reasons for CTP selection were col-
lected. e 4 CARRA sJIA CTPs have been previously
published [14, 20]. In brief, they consist of 2 biologic
CTPs (IL-1i and IL-6i, both with or without GC), and
2 non-biologic CTPs (MTX with or without GC and
GC alone) (see Figs.1 and 2). MTX was not included
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Beukelmanetal. Pediatric Rheumatology (2022) 20:113
Fig. 1 Schematic of the non-biologic consensus treatment plans for the treatment of new-onset sJIA
Fig. 2 Schematic of the biologic consensus treatment plans for the treatment of new-onset sJIA
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Beukelmanetal. Pediatric Rheumatology (2022) 20:113
in the biologic CTPs but could be added if patients
failed to improve or worsened. For all CTPs, if GC were
used, then the stated goal was to reduce the initial GC
dose by at least 50% by 3 months and to discontinue
GC by 6 months, if possible. For all CTPs, an assess-
ment of the clinical status was to occur 3 months fol-
lowing enrollment; in instances where disease activity
was unchanged or worsened or GC could not be safely
decreased to < 50% of the initial dose, then the CTPs
suggest initiating or switching to a different biologic.
Initiation or switching of biologics could also occur at
any point during the study at the discretion of the treat-
ing physician.
Clinical data were collected at baseline and 2 weeks
as well as 1, 3, 6, 9, and 12 months following enroll-
ment. Informed consent and data collection activities for
FROST followed the CARRA Registry protocol (Duke
University IRB [Pro00054616]). Written informed con-
sent and/or assent was obtained from all subjects and/or
their legal guardians.
e primary study outcome was the achievement of
clinical inactive disease (CID) according to the Wallace/
American College of Rheumatology provisional criteria
[21] without current GC use as assessed at 9 months fol-
lowing enrollment. CID criteria include satisfaction of
all of the following: (1) no active arthritis; (2) physician
global assessment equal to zero; (3) ESR and/or CRP in
normal range; (4) no extra-articular features of sJIA;
(5) no active uveitis; (6) duration of morning stiffness
≤15 minutes. Not all patients had ESR or CRP values
available at the 9 month visit; if the remaining 5 criteria
were satisfied, then it was assumed that the patient had
achieved CID.
Secondary outcomes included the clinical juvenile
arthritis disease activity score based on 10 joints (cJA-
DAS-10) and absence of current GC use. e cJADAS-10
is composed of the physician global assessment (0-10),
the patient/parent global assessment (0-10), and the
number of joints with active arthritis (to a maximum of
10) [22]. e values of the three components are added
together for a total score ranging from 0 to 30. cJA-
DAS-10 scores of ≤1 and ≤ 2.5 have been previously pro-
posed as cut-offs for inactive and low/minimal disease
activity for polyarticular JIA, respectively [23], and we
additionally required the absence of fever. CID and cJA-
DAS-10 outcomes also were assessed at 12 months after
enrollment. Current systemic GC use was assessed at
each study visit and is reported as both an independent
outcome and in combination with CID and cJADAS-10.
We also assessed the proportion of patients receiving oral
GC in the first month after enrolment who were able to
successfully decrease their dose by > 50% by 3 months
after enrollment.
e proportions of patients achieving inactive disease
by CID and cJADAS-10, both without current use of GC
and irrespective of (i.e., with or without) current GC use
were calculated. e results were presented according
to the CTP declared at enrollment, irrespective of sub-
sequent treatment (i.e., intention-to-treat). Due to the
small numbers of patients in the non-biologic CTPs, no
statistical comparisons were made between the CTPs.
Pre-specified safety events of special interest [24],
including MAS, were collected for all patients following
enrollment. Other safety events were collected if they
met the definition of serious adverse events.
Results
Overall, 73 patients enrolled in the FROST study from
32 clinical sites. eir baseline characteristics are shown
in Table1. Most patients (63/73, 86%) were enrolled in
the one of the biologic CTPs. Most patients enrolled
early in the disease course. e mean number of days
since symptom onset was 46. e median number of
days since diagnosis was 2.0, and 75% of patients enrolled
within 8 days of sJIA diagnosis. No association was
found between patient age, sex, or race/ethnicity with
the elapsed time from symptom onset or diagnosis to
study enrollment. e mean physician and patient global
assessments were 6.0 and 5.6, respectively. e mean
number of active joints was numerically lower among
patients in the non-biologic CTPs (4.1) than patients
in the biologic CTPs (7.0). e median ferritin was also
numerically lower among patients in the non-biologic
CTPs (363 versus 884). Consistent with study inclusion
criteria, all patients had fever and arthritis prior to enroll-
ment. Rash was present prior to enrollment in nearly all
patients (95.9%) with other disease manifestations occur-
ring less frequently but relatively equally among patients
in the biologic and non-biologic CTPs. Laboratory values
at the time of enrollment were consistent with ongoing
systemic inflammation.
Of the patients enrolled in the biologic CTPs, 59 (94%)
were treated with IL-1i and 4 (6%) were treated with
IL-6i. Among the 59 initial IL-1i users, the first IL-1i
used was anakinra in 48 patients (81%) and canakinumab
in 11 patients (19%). During follow-up, 8 (14%) patients
initially treated with IL-1i switched to IL-6i treatment;
the reason for switching was lack of effectiveness in 2
patients (both receiving anakinra) and their active joint
counts near the time of switching were 2 and 8. No
patients switched from IL-6i to IL-1i. Nine patients in
the biologic CTPs (14%) also started MTX prior to the
9-month outcome assessment.
Among patients in the biologic CTPs, 75% started bio-
logic therapy within 1 day of enrollment and 95% started
within 15 days. In addition, 5 (50%) of the patients in the
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Beukelmanetal. Pediatric Rheumatology (2022) 20:113
non-biologic CTPs started biologic therapy (3 canaki-
numab, 1 anakinra, 1 tocilizumab). e elapsed time
from enrollment to biologic initiation in the non-biologic
CTP patients was 10, 24, 30, 90, and 101 days.
CTP choice appeared to be strongly influenced by
physician factors. Ten clinical sites enrolled 3 or more
patients in the study. Of these 10 sites, 8 sites enrolled
all their patients in the biologic CTPs. Eight of the 10
(80%) patients in the non-biologic CTPs were treated
by physicians who self-reported that they initiate treat-
ment with a biologic agent at the time of diagnosis for a
typical patient with sJIA of moderate severity less than
50% of the time. On the other hand, only 4% of patients
(2 of 56) treated by physicians who self-reported that
they initiate treatment of sJIA with a biologic agent at
least 75% of the time were enrolled in the non-biologic
CTPs.
e three most commonly reported reasons for
selecting the biologic CTPs were likelihood of effec-
tiveness for systemic features, minimization of sys-
temic glucocorticoids, and likelihood of effectiveness
for arthritis. Two of the three most commonly reported
reasons for selecting the non-biologic CTPs were simi-
lar citing likelihood of effectiveness for systemic fea-
tures and likelihood of effectiveness specifically for
arthritis; however, safety profile was also included.
Table 1 Baseline patient characteristics, overall and stratified by consensus treatment plan choice
a More than 1 race or ethnicity per patient could be reported
Characteristic All Patients Biologic CTP
IL-1i/IL-6i Non-Biologic CTP
GC/Methotrexate
Number of Patients 73 63 10
Age in years (median (IQR)) 6.8 (4.1, 11.0) 7.0 (4.0, 11.3) 6.2 (5.6, 7.8)
Male sex (%) 44 (60.3) 40 (63.5) 4 (40.0)
Patient-Reported Race/Ethnicitya
White (%) 48 (65.8) 43 (68.3) 5 (50.0)
Black (%) 7 (9.6) 5 (7.9) 2 (20.0)
Hispanic (%) 14 (19.2) 11 (17.5) 3 (30.0)
Asian (%) 6 (8.2) 6 (9.5) 0 (0.0)
Days since symptom onset
(mean (SD)) 46.4 (63.5) 49.3 (67.6) 28.1 (18.3)
Days since diagnosis
(median (IQR)) 2.0 (0.0, 8.0) 1.0 (0.0, 8.0) 5.5 (0.5, 7.0)
Physician global assessment
(mean (SD)) 6.0 (2.2) 6.3 (2.1) 4.7 (2.8)
Patient global assessment
(mean (SD)) 5.6 (3.3) 5.7 (3.3) 5.4 (3.6)
Number of active joints
(mean (SD)) 6.6 (7.6) 7.0 (8.0) 4.1 (4.4)
sJIA manifestations prior to enrollment
Fever (%) 73 (100.0) 63 (100.0) 10 (100.0)
Arthritis (%) 73 (100.0) 63 (100.0) 10 (100.0)
Rash (%) 70 (95.9) 60 (95.2) 10 (100.0)
Lymphadenopathy (%) 24 (32.9) 22 (34.9) 2 (20.0)
Hepatomegaly or Splenomegaly (%) 15 (20.5) 13 (20.6) 2 (20.0)
Serositis (%) 7 (9.6) 6 (9.5) 1 (10.0)
Laboratory values at time of enrolment (median (IQR))
ESR (mm/hr) 73 (57, 97) 71 (54, 97) 88 (76, 90)
CRP (mg/L) 15.4 (7.5, 58.1) 16.4 (7.5, 58.1) 13.5 (7.3, 51.4)
Ferritin (ng/mL) 829 (249, 2603) 884 (290, 2652) 363 (81, 779)
Hemoglobin (g/dL) 10.2 (9.1, 11.4) 10.7 (9.1, 11.5) 9.4 (9.0, 10.2)
White blood cell count (109/L) 12.2 (8.5, 19.1) 12.0 (8.4, 19.0) 14.5 (10.6, 22.7)
Platelets (109/L) 458 (353, 571) 452 (353, 565) 509 (375, 735)
CHAQ (mean (SD)) 1.3 (1.0) 1.4 (1.0) 1.2 (0.9)
cJADAS-10 (median (IQR)) 17.0 (10.5, 21.5) 17.5 (12.0, 21.0) 14.0 (8.0, 23.0)
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Beukelmanetal. Pediatric Rheumatology (2022) 20:113
More than one-half (43/73, 59%) of patients overall
received oral GC at any time during the first month after
enrollment, including 34/63 (54%) of patients in the bio-
logic CTPs and 9/10 (90%) in the non-biologic CTPs. At
the 3 month assessment, 25/34 (74%) of patients in the
biologic CTPs and 5/9 (56%) in the non-biologic CTPs
treated with GC, had reduced the GC dose by 50% or
more.
Table 2 summarizes the clinical outcomes 9 and
12 months after study enrollment. Data were available
for 57 patients at 9 months (16 patients did not have a
9 month visit recorded). Overall, 57% of patients met
the primary outcome of CID without current GC use,
and 75% had cJADAS-10 scores ≤2.5 with no fever and
no current GC use. Patients in the biologic and non-
biologic CTPs had similar outcomes, although 4 of the 6
(67%) patients evaluable for CID in the non-biologic CTP
had initiated biologics during the study. Outcomes at
12 months were highly similar to the 9 month outcomes
(Table 2). Of the patients in the biologic CTPs who
subsequently started MTX, 1 of 6 (17%) had CID with-
out concurrent GC use at 9 months. Of the patients in the
biologic CTPs who switched from IL-1i to IL-6i, 1 of 6
(17%) had CID without concurrent GC use at 9 months.
Figure 3 shows the proportions of patients receiving
current GC at each study visit, stratified by biologic and
non-biologic CTP. At 1 month following study enroll-
ment, 22 of 52 (42%) patients treated with biologic
CTPs were receiving GC, and 7 of 9 (78%) patients ini-
tially treated with non-biologic CTPs were receiving GC.
At 6 months following study enrollment, 8 of 53 (15%)
patients treated with biologic CTPs were receiving GC,
and 2 of 8 (25%) patients initially treated with non-bio-
logic CTPs were receiving GC. At 9 and 12 months fol-
lowing study enrollment, the proportion of patients
receiving GC was less than 15% in both biologic and non-
biologic CTPs.
Overall, there were 16 CTCAE grade 3 or higher safety
events observed in 13 patients during follow-up, and all
of these events occurred in patients in the biologic CTPs.
Table 2 Clinical outcomes at 9 and 12 months following study enrollment
Outcome All Patients Biologic
CTPs Non-biologic CTPs
9 months following study enrollment:
CID
without current GC use (N (%)) 30/53 (57%) 27/47 (57%) 3/6 (50%)
CID
irrespective of current GC use (N (%)) 32/53 (60%) 29/47 (62%) 3/6 (50%)
cJADAS-10 ≤ 1 + no fever
without current GC use (N (%)) 32/48 (67%) 29/43 (67%) 3/5 (60%)
cJADAS-10 ≤ 1 + no fever
irrespective of current GC use (N (%)) 34/48 (71%) 31/43 (72%) 3/5 (60%)
cJADAS-10 ≤ 2.5 + no fever
without current GC use (N (%)) 36/48 (75%) 33/43 (77%) 3/5 (60%)
cJADAS-10 ≤ 2.5 + no fever
irrespective of current GC use (N (%)) 38/48 (79%) 35/43 (81%) 3/5 (60%)
cJADAS-10 (mean (SD)) 1.5 (3.3) 1.3 (3.0) 3.4 (5.6)
cJADAS-10 (median (IQR)) 0 (0, 1.0) 0 (0, 1.0) 0 (0, 4.0)
12 months following study enrollment:
CID
without current GC use (N (%)) 31/55 (56%) 28/49 (57%) 3/6 (50%)
CID
irrespective of current GC use (N (%)) 34/55 (62%) 30/49 (61%) 4/6 (67%)
cJADAS-10 ≤ 1 + no fever
without current GC use (N (%)) 33/47 (70%) 31/42 (74%) 2/5 (40%)
cJADAS-10 ≤ 1 + no fever
irrespective of current GC use (N (%)) 35/45 (78%) 32/40 (80%) 3/5 (60%)
cJADAS-10 ≤ 2.5 + no fever
without current GC use (N (%)) 36/47 (77%) 33/42 (79%) 3/5 (60%)
cJADAS-10 ≤ 2.5 + no fever
irrespective of current GC use (N (%)) 38/45 (84%) 34/40 (85%) 4/5 (80%)
cJADAS-10 (mean (SD)) 2.0 (5.7) 1.7 (5.4) 4.0 (7.9)
cJADAS-10 (median (IQR)) 0 (0, 0.5) 0 (0, 0.5) 0 (0, 2.0)
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Beukelmanetal. Pediatric Rheumatology (2022) 20:113
Table3 lists the events and the current biologic and non-
biologic medications at the time of the safety event. One
patient treated with a biologic CTP died 2.6 years after
study enrollment of acute liver failure in the absence clin-
ical signs of MAS or drug reaction with eosinophilia and
systemic symptoms (DRESS).
Discussion
e FROST study prospectively enrolled a large cohort
of patients with new-onset sJIA treated with one of four
CTPs from 2016 through 2019 in the CARRA Registry.
Most patients were treated with biologics (mostly IL-1i)
and achieved the primary endpoint of CID off GC at 9
and 12 months. Seventy-five percent of patients achieved
a cJADAS-10 of <=2.5 (cJADAS-10 “inactive disease” for
polyarticular JIA) without fever and GC use. e origi-
nal goal of the study was to compare the effectiveness of
starting a biologic CTP (IL-1i or IL-6i) vs a non-biologic
CTP (MTX or GC alone) using propensity scores to cre-
ate balance between CTP groups at baseline and Bayes-
ian methods that incorporated prior expert opinions [25].
is was not possible because too few patients started
on a non-biologic CTP. In addition, 50% of the patients
starting a non-biologic CTP initiated a biologic by the
3 month visit, making the comparison of outcomes at
9 months less meaningful. However, despite these short-
comings, the outcomes at 9 and 12 months demonstrate
that most patients in the current era with sJIA, a previ-
ously difficult to treat disease, are faring well.
Our results, which showed that more than 50% of
patients achieved CID off GC and 75% of patients
achieved cJADAS10 inactive disease status at 9 months,
Fig. 3 Proportion of patients with current glucocorticoid use at each study visit
Table 3 Biologic and non-biologic medication use at the time of
safety events with CTCAE grade 3 or higher
Event CTCAE grade CTP Arm Current Biologic and
Non-Biologic Use
Acute liver failure 5 Biologic anakinra
Liver enzyme eleva-
tion 4 Biologic anakinra
MAS 4 Biologic anakinra
Injection site reaction 3 Biologic anakinra
Infection (osteomy-
elitis) 3 Biologic canakinumab
Liver enzyme eleva-
tion 3 Biologic anakinra
MAS 3 Biologic canakinumab
MAS 3 Biologic canakinumab
MAS 3 Biologic canakinumab
MAS 3 Biologic none
MAS 3 Biologic none
Neutropenia 3 Biologic tocilizumab
Neutropenia 3 Biologic anakinra
Protein losing enter-
opathy 3 Biologic anakinra
SJIA flare 3 Biologic canakinumab
SJIA flare 3 Biologic anakinra, cyclosporine
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Beukelmanetal. Pediatric Rheumatology (2022) 20:113
generally align with previous studies of early biologic
use in sJIA. e initial study assessing the impact of
anakinra treatment on sJIA was a 2011 retrospective
case series of 46 patients from multiple centers treated
with anakinra as part of initial therapy [4], found that
at 6 or more months after starting anakinra, 89% did
not have active arthritis, and 60% had a “complete
response.” e prior study results appear better at first
glance, but it was a retrospective study that was unable
to assess CID status or JADAS scores. A more recent
prospective Treat to Target study of 42 patients treated
with anakinra in the Netherlands and published in
2019, showed that 76% had inactive disease at 1 year
with 52% in inactive disease off all medications (includ-
ing anakinra) [9]. Impressively, after up to 5 years of
follow up, less than 5% reported joint damage and only
33% were ever treated with GC. A third study published
in 2021 of 56 patients treated with anakinra showed
that 73% had achieved CID off GC at 6 months, and
that patients treated prior to 3 months disease duration
had a better outcome [26].
Together, current and prior studies suggest a poten-
tial window of opportunity for new onset sJIA patients:
early treatment with biologics (IL-1i but potentially other
biologics as well), can lead to rapid disease control asso-
ciated with better long-term outcomes. e pathophysi-
ological basis for such a window remains incompletely
defined, but has been postulated to reflect the efficacy of
early cytokine antagonist therapy to abrogate the devel-
opment of a population of arthritis-causing T cells, a
possibility for which experimental evidence has begun
to accumulate [8, 27, 28]. Previously it was commonly
reported that sJIA patients developed chronic relapsing
systemic disease with recurrent MAS and/or chronic,
often severe and debilitating arthritis that necessitated
early joint replacement, although these reports may
have been subject to selection bias. With early effective
treatment the disease phenotype indeed appears to be
altered in many patients, some of whom appear to go into
remission without further need for medications, and/or
never develop the chronic arthritis phenotype. It is worth
mentioning that a minority of sJIA patients remit spon-
taneously in the first year of disease, complicating the
interpretation of single-arm observational studies [29].
A potential downside to early use of biologics may be
the development of chronic and often fatal lung disease
in sJIA patients which has only recently been described.
While a rare phenomenon, chronic lung disease appears
to be occurring with increased frequency since 2005,
raising the possibility that early treatment with biologics
could be at least partially responsible [10–13]. It is note-
worthy that no patient in the present study developed
this complication.
e early pilot study results of the sJIA CTPs indi-
cated there was a reasonable distribution of CTP
usage that appeared to be related to specific sites,
with some sites preferring non-biologic CTPs while
others preferred biologic CTPs, raising the possibil-
ity of “pseudo-randomization” (i.e., approximating
cluster randomization by clinical site) might be pos-
sible in a larger observational study [16, 25]. Pseudo-
randomization in FROST by physician preference was
observed (i.e., some sites nearly always initially treated
patients with biologics, irrespective of the clinical cir-
cumstances). Nevertheless, most clinicians preferred
starting with a biologic CTP (especially with IL-1i) by
the time this study began, reflecting a shift in clinical
practice, and making the original aim of a compara-
tive effectiveness study infeasible. ere would likely
have been a more balanced distribution of CTP use
with more patients receiving non-biologic CTPs if this
study had been performed soon after the development
of the original CTPs. However, since the original intent
of CARRA CTP development was to standardize com-
munity treatments, eliminating unsuccessful or unused
treatments, the next iteration of the sJIA CTPs will con-
sider the treatment preferences and results observed in
FROST when determining the treatment arms. More-
over, randomization of patients, even if open-label,
would have not been feasible or ethical in this popula-
tion of patients with a rare illness in which practice has
dramatically changed due to the availability of effective
treatments.
It remains a limitation of this study, however, that there
was no randomization which may have resulted in con-
founding by treatment choice. e relative availability of
different biologics can vary by country (due to cost, regu-
latory approval, etc.), and the treatment choices in this
study may not be generalizable to all regions outside of
the United States and Canada. ere were missing data
on some components of the various study outcomes and
some missed study visits that limited the assessment of
outcomes. Notably, there was difficulty enrolling patients
even with the modified sJIA criteria; many providers
were reportedly unwilling to delay potentially efficacious
treatment in patients suspected of having sJIA even if
they did not fulfill all FROST criteria, especially arthri-
tis. Despite the inclusion of sJIA in the disease classifica-
tion of JIA, not all sJIA patients develop arthritis, and is
not a requirement in the Yamaguchi criteria for AOSD
[30] or the proposed PRINTO classification criteria [31].
Lastly, we were unable to use the new systemic JADAS
[32] as a measure of disease activity because the precise
body temperatures (required for scoring) were not col-
lected. Instead, we used the cJADAS10 with the addition
of absence of fever.
Page 9 of 10
Beukelmanetal. Pediatric Rheumatology (2022) 20:113
Conclusions
It is strongly encouraging that the majority of patients
with new onset sJIA had excellent outcomes, with less
GC usage than was necessary prior to the availability of
biologics. e availability of biologics effective for treat-
ing sJIA has undoubtedly changed outcomes for the
vast majority of patients with this disease. We look for-
ward to following the outcomes of these patients in the
longer term, since all FROST patients are enrolled in the
CARRA Registry, enabling follow up for at least 10 years.
Abbreviations
AOSD: Adult-onset Still disease; CARRA : Childhood Arthritis and Rheumatol-
ogy Research Alliance; CHAQ: Childhood health assessment questionnaire;
CID: Clinical inactive disease; cJADAS-10: Clinical juvenile arthritis disease
activity score based on 10 joints; CRP: C-reactive protein; CTP: Consensus
treatment plan; ESR: Erythrocyte sedimentation rate; FROST: First-line options
for sJIA treatment; GC: Glucocorticoids; IL-1i: IL-1 inhibitor; IL-6i: IL-6 inhibitor;
IQR: Interquartile range; JIA: Juvenile idiopathic arthritis; sJIA: Systemic juvenile
idiopathic arthritis; MAS: Macrophage activation syndrome; MTX: Methotrex-
ate; SD: Standard deviation; STOP-JIA: Start time optimization of biologics in
polyarticular JIA; WBC: White blood cell count.
Acknowledgements
This work could not have been accomplished without the aid of the following
organizations: The NIH’s National Institute of Arthritis and Musculoskeletal and
Skin Diseases (NIAMS) & the Arthritis Foundation. We would also like to thank
all participants and hospital sites that recruited patients for the CARRA Regis-
try. The authors thank the following CARRA Registry site principal investigators,
sub-investigators, and research coordinators:
R. Agbayani, S. Akoghlanian, E. Allenspach, E. Anderson, S. Ardoin, S. Arm-
endariz, I. Balboni, L. Ballenger, S. Ballinger, F. Barbar-Smiley, K. Baszis, H. Bell-
Brunson, H. Benham, W. Bernal, T. Bigley, B. Binstadt, M. Blakley, J. Bohnsack,
A. Brown, M. Buckley, D. Bullock, B. Cameron, S. Canna, E. Cassidy, J. Chang, V.
Chauhan, T. Chinn, P. Chira, A. Cooper, J. Cooper, C. Correll, L. Curiel-Duran, M.
Curry, A. Dalrymple, D. De Ranieri, F. Dedeoglu, M. DeGuzman, N. Delnay, V.
Dempsey, J. Dowling, J. Drew, K. Driest, Q. Du, D. Durkee, M. Eckert, C. Edens,
M. Elder, S. Fadrhonc, L. Favier, B. Feldman, I. Ferguson, B. Ferreira, L. Fogel, E.
Fox, R. Fuhlbrigge, J. Fuller, N. George, D. Gerstbacher, M. Gillispie-Taylor, I. Goh,
D. Goldsmith, S. Grevich, T. Griffin, M. Guevara, P. Guittar, M. Hager, T. Hahn, O.
Halyabar, M. Hance, S. Haro, J. Harris, J. Hausmann, K. Hayward, L. Henderson,
A. Hersh, S. Hillyer, L. Hiraki, M. Hiskey, P. Hobday, C. Hoffart, M. Holland, M.
Hollander, M. Horwitz, J. Hsu, A. Huber, M. Ibarra, C. Inman, S. Jackson, K. James,
G. Janow, S. Jones, K. Jones, J. Jones, C. Justice, U. Khalsa, B. Kienzle, S. Kim,
Y. Kimura, M. Kitcharoensakkul, T. Klausmeier, K. Klein, M. Klein-Gitelman, S.
Kramer, J. Lai, B. Lang, S. Lapidus, E. Lawson, R. Laxer, P. Lee, T. Lee, M. Lerman, D.
Levy, S. Li, C. Lin, N. Ling, M. Lo, S. Lvovich, J. Maller, A. Martyniuk, K. McConnell,
I. McHale, E. Meidan, E. Mellins, M. Miller, R. Modica, K. Moore, T. Moussa, V.
Mruk, E. Muscal, K. Nanda, L. Nassi, J. Neely, L. Newhall, P. Nigrovic, B. Nolan, E.
Oberle, O. Okeke, M. Oliver, K. O’Neil, R. Oz, A. Paller, J. Patel, P. Pepmueller, K.
Phillippi, R. Pooni, S. Protopapas, B. Puplava, S. Radhakrishna, S. Ramsey, H. Reid,
S. Ringold, M. Riordan, M. Riskalla, M. Ritter, M. Rodriquez, K. Rojas, M. Rosen-
kranz, T. Rubinstein, C. Sandborg, L. Scalzi, K. Schikler, K. Schmidt, E. Schmitt,
R. Schneider, C. Seper, J. Shalen, R. Sheets, S. Shenoi, J. Shirley, E. Silverman, V.
Sivaraman, C. Smith, J. Soep, M. Son, L. Spiegel, H. Stapp, S. Stern, A. Stevens, B.
Stevens, K. Stewart, E. Stringer, R. Sundel, M. Sutter, R. Syed, R. Syed, T. Tanner,
G. Tarshish, S. Tarvin, M. Tesher, A. Thatayatikom, B. Thomas, D. Toib, K. Torok,
C. Toruner, S. Tse, T. Valcarcel, N. Vasquez, R. Vehe, J. Velez, E. von Scheven, S.
Vora, L. Wagner-Weiner, D. Wahezi, M. Waterfield, P. Weiss, J. Weiss, A. White, L.
Woolnough, T. Wright, M. Yee, R. Yeung, K. Yomogida, Y. Zhao, A. Zhu.
Authors’ contributions
TB, PAN, AD, VD, LES, and YK contributed to the conception and design of the
study. TB, AD, VD, MER, LES, and YK contributed to the acquisition of data. GT
and AD performed the analysis. All authors participated in the interpretation
of results. TB wrote the initial draft of the manuscript. All authors critically
reviewed the draft manuscript. All authors read and approved the final
manuscript.
Funding
Funding for this project was provided to CARRA, Inc. in part by Genentech, a
member of the Roche Group.
TB is supported by CARRA. PAN is funded by NIAMS awards 2R01AR065538
and R01AR073201. LES is supported by the NIAMS award number
U19AR069522, the Patient-Centered Outcomes Research Institute under
award number PaCr-2017C2-8177, and the CARRA. YK is supported by CARRA.
Availability of data and materials
The data that support the findings of this study are available from CARRA but
restrictions apply to the availability of these data, which were used under a
data use agreement for the current study, and so are not publicly available.
Data are however available from CARRA upon reasonable request (carra group.
org).
Declarations
Ethics approval and consent to participate
Ethics approval for this study was granted by the Duke University Institutional
Review Board (Pro00054616). Written informed consent and/or assent was
obtained from all subjects and/or their legal guardians.
Consent for publication
Not applicable.
Competing interests
TB has received consulting fees from Novartis and UCB. PAN receives investiga-
tor-initiated research grants from Bristol-Myers Squibb and Pfizer; consulting
from Bristol-Myers Squibb, Cerecor, Exo Therapeutics, Miach Orthopedics,
Novartis, and Pfizer; royalties from UpToDate Inc.; and salary support from the
Childhood Arthritis and Rheumatology Research Alliance. LES has received
research support from Bristol-Myers Squibb. LES serves on the data and safety
monitoring board for Sanofi (sarilumab) and UCB (certolizumab). SM and EP
are employees and shareholders of Genentech, Inc. YK has received research
support from Genentech.
Author details
1 University of Alabama at Birmingham, 1601 4th Ave South, CPPN G10, Bir-
mingham, AL 35233, USA. 2 Institute of Health Policy, Management and Evalu-
ation, Dalla Lana School of Public Health, University of Toronto, Toronto, ON,
Canada. 3 Division of Immunology, Boston Children’s Hospital, Boston, MA
02115, USA. 4 Division of Rheumatology, Inflammation, and Immunity, Brigham
and Women’s Hospital, Boston, MA 02115, USA. 5 Duke Clinical Research Insti-
tute, Duke University, Durham, NC 27715, USA. 6 Childhood Arthritis and Rheu-
matology Research Alliance, Washington, DC, USA. 7 Joseph M Sanzari
Children’s Hospital, Hackensack Meridian School of Medicine, Nutley, NJ 07110,
USA. 8 Department of Pediatrics, Duke University School of Medicine, Durham,
NC 27710, USA. 9 Genentech Inc., South San Francisco, CA 94080, USA.
Received: 29 July 2022 Accepted: 6 November 2022
References
1. Kimura Y, Vastert S. Systemic juvenile idiopathic arthritis (chapter 17). In:
Petty RE, Laxer RM, Lindsley CB, Wedderburn LR, Mellins ED, Fuhlbrigge
RC, editors. Textbook of pediatric rheumatology. 8th ed. Philadelphia:
Elsevier, Inc.; 2021.
2. 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):1479–86.
3. Quartier P, Allantaz F, Cimaz R, Pillet P, Messiaen C, Bardin C, et al.
A multicentre, randomised, double-blind, placebo-controlled trial
with the interleukin-1 receptor antagonist anakinra in patients with
systemic-onset juvenile idiopathic arthritis (ANAJIS trial). Ann Rheum Dis.
2011;70(5):747–54.
Page 10 of 10
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4. Nigrovic PA, Mannion M, Prince FH, Zeft A, Rabinovich CE, van Rossum
MA, et al. Anakinra as first-line disease-modifying therapy in systemic
juvenile idiopathic arthritis: report of forty-six patients from an interna-
tional multicenter series. Arthritis Rheum. 2011;63(2):545–55.
5. Ruperto N, Brunner HI, Quartier P, Constantin T, Wulffraat N, Horneff G,
et al. Two randomized trials of canakinumab in systemic juvenile idi-
opathic arthritis. N Engl J Med. 2012;367(25):2396–406.
6. Ilowite NT, Prather K, Lokhnygina Y, Schanberg LE, Elder M, Milojevic D,
et al. Randomized, double-blind, placebo-controlled trial of the efficacy
and safety of rilonacept in the treatment of systemic juvenile idiopathic
arthritis. Arthritis Rheumatol. 2014;66(9):2570–9.
7. De Benedetti F, Brunner HI, Ruperto N, Kenwright A, Wright S, Calvo I,
et al. Randomized trial of tocilizumab in systemic juvenile idiopathic
arthritis. N Engl J Med. 2012;367(25):2385–95.
8. Nigrovic PA. Review: is there a window of opportunity for treat-
ment of systemic juvenile idiopathic arthritis? Arthritis Rheumatol.
2014;66(6):1405–13.
9. Ter Haar NM, van Dijkhuizen EHP, Swart JF, van Royen-Kerkhof A, El Idrissi
A, Leek AP, et al. Treatment to target using recombinant interleukin-1
receptor antagonist as first-line monotherapy in new-onset systemic
juvenile idiopathic arthritis: results from a five-year follow-up study.
Arthritis Rheumatol. 2019;71(7):1163–73.
10. Kimura Y, Weiss JE, Haroldson KL, Lee T, Punaro M, Oliveira S, et al. Pulmo-
nary hypertension and other potentially fatal pulmonary complications
in systemic juvenile idiopathic arthritis. Arthritis Care Res (Hoboken).
2013;65(5):745–52.
11. Schulert GS, Yasin S, Carey B, Chalk C, Do T, Schapiro AH, et al. Systemic
juvenile idiopathic arthritis-associated lung disease: characterization and
risk factors. Arthritis Rheumatol. 2019;71(11):1943–54.
12. Saper VE, Chen G, Deutsch GH, Guillerman RP, Birgmeier J, Jagadeesh K,
et al. Emergent high fatality lung disease in systemic juvenile arthritis.
Ann Rheum Dis. 2019;78(12):1722–31.
13. Saper VE, Ombrello MJ, Tremoulet AH, Montero-Martin G, Prahalad S,
Canna S, et al. Severe delayed hypersensitivity reactions to IL-1 and
IL-6 inhibitors link to common HLA-DRB1*15 alleles. Ann Rheum Dis.
2022;81(3):406–15.
14. DeWitt EM, Kimura Y, Beukelman T, Nigrovic PA, Onel K, Prahalad S, et al.
Consensus treatment plans for new-onset systemic juvenile idiopathic
arthritis. Arthritis Care Res (Hoboken). 2012;64(7):1001–10.
15. Ringold S, Nigrovic PA, Feldman BM, Tomlinson GA, von Scheven E, Wal-
lace CA, et al. The childhood arthritis and rheumatology research alliance
consensus treatment plans: toward comparative effectiveness in the
pediatric rheumatic diseases. Arthritis Rheumatol. 2018;70(5):669–78.
16. Kimura Y, Grevich S, Beukelman T, Morgan E, Nigrovic PA, Mieszkalski K,
et al. Pilot study comparing the Childhood Arthritis & Rheumatology
Research Alliance (CARRA) systemic juvenile idiopathic arthritis consen-
sus treatment plans. Pediatr Rheumatol Online J. 2017;15(1):23.
17. Kimura Y, Schanberg LE, Tomlinson GA, Riordan ME, Dennos AC, Del
Gaizo V, Murphy KL, Weiss PF, Natter MD, Feldman BM, Ringold S. CARRA
STOP-JIA Investigators. Optimizing the Start Time of Biologics in Polyar-
ticular Juvenile Idiopathic Arthritis: A Comparative Effectiveness Study
of Childhood Arthritis and Rheumatology Research Alliance Consensus
Treatment Plans. Arthritis Rheumatol. 2021;73(10):1898-1909. https:// doi.
org/ 10. 1002/ art. 41888.
18. Ong MS, Ringold S, Kimura Y, Schanberg LE, Tomlinson GA, Natter MD,
et al. Improved disease course associated with early initiation of biologics
in polyarticular juvenile idiopathic arthritis: trajectory analysis of a child-
hood arthritis and rheumatology research alliance consensus treatment
plans study. Arthritis Rheumatol. 2021;73(10):1910–20.
19. Petty RE, Southwood TR, Manners P, Baum J, Glass DN, Goldenberg J, et al.
International league of associations for rheumatology classification of
juvenile idiopathic arthritis: second revision, Edmonton, 2001. J Rheuma-
tol. 2004;31(2):390–2.
20. Kimura Y, DeWitt EM, Beukelman T, Stoll ML, Nigrovic PA, Onel K, et al.
Adding canakinumab to the Childhood Arthritis and Rheumatology
Research Alliance consensus treatment plans for systemic juvenile idi-
opathic arthritis: comment on the article by DeWitt et al. Arthritis Care
Res (Hoboken). 2014;66(9):1430–1.
21. Wallace CA, Giannini EH, Huang B, Itert L, Ruperto N, Childhood Arthritis
Rheumatology Research A, et al. American College of Rheumatol-
ogy provisional criteria for defining clinical inactive disease in select
categories of juvenile idiopathic arthritis. Arthritis Care Res (Hoboken).
2011;63(7):929–36.
22. McErlane F, Beresford MW, Baildam EM, Chieng SE, Davidson JE, Foster
HE, et al. Validity of a three-variable juvenile arthritis disease activity score
in children with new-onset juvenile idiopathic arthritis. Ann Rheum Dis.
2013;72(12):1983–8.
23. Consolaro A, Negro G, Chiara Gallo M, Bracciolini G, Ferrari C, Schiappa-
pietra B, et al. Defining criteria for disease activity states in nonsystemic
juvenile idiopathic arthritis based on a three-variable juvenile arthritis
disease activity score. Arthritis Care Res (Hoboken). 2014;66(11):1703–9.
24. Beukelman T, Kimura Y, Ilowite NT, Mieszkalski K, Natter MD, Burrell G,
et al. The new Childhood Arthritis and Rheumatology Research Alliance
(CARRA) registry: design, rationale, and characteristics of patients enrolled
in the first 12 months. Pediatr Rheumatol Online J. 2017;15(1):30.
25. Nigrovic PA, Beukelman T, Tomlinson G, Feldman BM, Schanberg
LE, Kimura Y, et al. Bayesian comparative effectiveness study of four
consensus treatment plans for initial management of systemic juvenile
idiopathic arthritis: FiRst-line options for systemic juvenile idiopathic
arthritis treatment (FROST). Clin Trials. 2018;15(3):268–77.
26. Pardeo M, Rossi MN, Pires Marafon D, Sacco E, Bracaglia C, Passarelli C,
et al. Early treatment and IL1RN single-nucleotide polymorphisms affect
response to anakinra in systemic juvenile idiopathic arthritis. Arthritis
Rheumatol. 2021;73(6):1053–61.
27. Kessel C, Lippitz K, Weinhage T, Hinze C, Wittkowski H, Holzinger D, et al.
Proinflammatory cytokine environments can drive interleukin-17 overex-
pression by gamma/delta T cells in systemic juvenile idiopathic arthritis.
Arthritis Rheumatol. 2017;69(7):1480–94.
28. Henderson LA, Hoyt KJ, Lee PY, Rao DA, Jonsson AH, Nguyen JP, et al.
Th17 reprogramming of T cells in systemic juvenile idiopathic arthritis. JCI
Insight. 2020;5(6):e132508.
29. Lomater C, Gerloni V, Gattinara M, Mazzotti J, Cimaz R, Fantini F. Systemic
onset juvenile idiopathic arthritis: a retrospective study of 80 consecutive
patients followed for 10 years. J Rheumatol. 2000;27(2):491–6.
30. Yamaguchi M, Ohta A, Tsunematsu T, Kasukawa R, Mizushima Y, Kashiwagi
H, et al. Preliminary criteria for classification of adult Still’s disease. J Rheu-
matol. 1992;19(3):424–30.
31. Martini A, Ravelli A, Avcin T, Beresford MW, Burgos-Vargas R, Cuttica R,
et al. Toward new classification criteria for juvenile idiopathic arthritis: first
steps, pediatric rheumatology international trials organization interna-
tional consensus. J Rheumatol. 2019;46(2):190–7.
32. Tibaldi J, Pistorio A, Aldera E, Puzone L, El Miedany Y, Pal P, et al.
Development and initial validation of a composite disease activity
score for systemic juvenile idiopathic arthritis. Rheumatology (Oxford).
2020;59(11):3505–14.
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