Access to this full-text is provided by Wiley.
Content available from ACR Open Rheumatology
This content is subject to copyright. Terms and conditions apply.
Determinants of Tumor Necrosis Factor Inhibitor Use
in Juvenile Spondyloarthropathy and Impact on
Clinical Disease Outcomes
Melissa Oliver, Julia F. Simard, Tzielan Lee, Dana Gerstbacher, and Christy Sandborg
Objective. The objectives of this study were to characterize the reasons for tumor necrosis factor inhibitor (TNFi)
initiation in patients with juvenile spondyloarthropathy (JSpA) and identify clinical correlates and to assess the effect
of TNFi therapy on JSpA disease activity.
Methods. We conducted a retrospective cohort study of 86 patients with JSpA with first-time use of a TNFi over a
7-year period at Stanford Children’s Health. We assessed the physician’s reason for TNFi initiation, disease activity at
6 months, and clinical disease status at 12 months following TNFi start. Changes in active joint count, enthesitis count,
and pain were measured. Demographics, physician reasons for TNFi initiation, and clinical characteristics were
summarized.
Results. The mean age at JSpA diagnosis was 12.4 years (SD 4.0 years), and the mean time from diagnosis to TNFi
initiation was 1.6 years (SD 2.3 years). The most common reason for initiating a TNFi was active disease on physical
examination (61%). At 6 months post TNFi initiation, patients on average had three fewer active joints and one fewer
active enthesitis point. Patient-reported pain improved from moderate/severe to mild. After 12 months, 54% of patients
had active disease.
Conclusion. The physician’s decision to initiate a TNFi relied mostly on physical examination findings. Despite
improvement in arthritis, enthesitis, and patient-reported pain at 6 months post TNFi initiation, the majority of the
patients still had active disease after 1 year of therapy.
INTRODUCTION
Juvenile idiopathic arthritis (JIA) is one of the most common
chronic childhood diseases seen by pediatric rheumatologists.
The prevalence of JIA varies between 16 and 150 per 100 000
(1). The juvenile spondyloarthropathy (JSpA) subtype accounts
for up to 20% of all cases of JIA (2,3). When compared with other
JIA subtypes, patients with JSpA have higher disability and pain
scores, as well as worse function, poorer quality of life, and lower
rates of clinical remission (4). The characteristic features of JSpA
differ from other JIA subtypes and include enthesitis, dactylitis,
HLA antigen B27 positivity, inflammatory back pain, acute ante-
rior uveitis, and sacroiliitis. Some clinical parameters that assess
active disease, such as inflammatory back pain or entheseal ten-
derness, can be challenging to measure without imaging. Addi-
tionally, some children may have silent sacroiliitis (5). Sacroiliitis
and enthesitis predict poor prognosis in JSpA, and it is important
that, when assessing disease activity, these are taken into
account (4,6). These disease-specific features are generally not
included in many JIA clinical disease assessments, with the
exception of the Juvenile Spondyloarthritis Disease Activity Index
(JSpADA), which is a composite clinical disease activity score that
has been retrospectively validated (7).
In the biologic era, long-term follow-up studies of more than
15 years have shown that only 20% to 37% of patients with JSpA
achieved clinical remission while off medication (8,9). Biologics,
such as tumor necrosis factor inhibitors (TNFi), produce clinical
improvements in numerous rheumatic diseases, including adult
ankylosing spondylitis, and are increasingly being used for pediat-
ric inflammatory arthritis (10,11). In patients with JSpA, TNFi
induced clinical remission after 6 months in one observational
study and decreased disease activity measures in a double-blind
randomized controlled trial of enthesitis-related arthritis (ERA)
(12,13). Despite their efficacy, some studies showed that
Supported by an NIH T32 training grant (grant 2-T32-AR-050942-11).
Melissa Oliver, MD, MS (current address: Indiana University, Indianapolis,
Indiana), Julia F. Simard, ScD, Tzielan Lee, MD, Dana Gerstbacher, MD, Christy
Sandborg, MD: Stanford University, Stanford, California.
No potential conflicts of interest relevant to this article were reported.
Address correspondence to Melissa Oliver, MD, MS, Indiana University,
CL200, 1120 West Michigan Street, Indianapolis, IN 46202. Email:
msoliver@iu.edu.
Submitted for publication February 23, 2021; accepted in revised form
September 8, 2021.
19
ACR Open Rheumatology
Vol. 4, No. 1, January 2022, pp 19–26
DOI 10.1002/acr2.11353
© 2021 The Authors. ACR Open Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits
use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or
adaptations are made.
pediatric patients did not start a TNFi until 2 to 3 years after dis-
ease onset. In these instances, however, they were typically
started for worsening disease activity, failure to respond to prior
treatments, or new radiographic findings, which is typically a late
disease finding (10,14–16). TNFi are indicated for sacroiliitis with
inadequate nonsteroidal antiinflammatory drug (NSAID) response,
but disease-modifying antirheumatic drugs (DMARDs) remain first
line for peripheral disease following an NSAID trial (17).
Because JSpA is typically more challenging to manage than
other subtypes of JIA and because TNFi therapy is not consid-
ered first line unless there is advanced disease or evidence of
sacroiliitis, we aim to gain insight on TNFi usage in this particular
patient population. By examining the factors that influence a
physician’s decision to escalate therapy to a TNFi in patients
with JSpA, such as physical examination or imaging findings or
pain, we can highlight areas for improvement in disease man-
agement and potentially identify a specificorearlierrolefortheir
use. We evaluated the reasons for escalating to TNFi therapy in
a JSpA population and assessed whether there were specific
disease characteristics or factors that influenced the decision.
Our study characterizes the reasons for TNFi initiation in patients
with JSpA and the effect of TNFi therapy on clinical disease
activity.
MATERIALS AND METHODS
Patient population. Patients with JSpA who initiated their
first TNFi between 2007 and 2014 were identified retrospectively
from the Pediatric Rheumatology Department at Stanford Chil-
dren’s Health using International Classification of Diseases, Ninth
Revision (ICD-9) codes and confirmed by the primary author
(MO). Patients with a diagnosis of JSpA were included if they were
16 years or younger at the time of diagnosis; had any of the fol-
lowing subtypes: ERA, psoriatic arthritis (PsA), undifferentiated
spondyloarthritis (USpA), juvenile ankylosing spondylitis (JAS),
reactive arthritis, and arthritis associated with inflammatory bowel
disease (IBD); and were prescribed TNFi therapy (etanercept,
adalimumab or infliximab) for the first time during the study period.
JSpA subtype diagnoses were defined as meeting criteria for the
International League of Associations for Rheumatology (ILAR) cri-
teria for ERA, USpA, and PsA (18). For JAS, the diagnosis was
adapted from the ILAR criteria for ERA, and patients had to have
imaging confirmation, either by x-ray or magnetic resonance
imaging (MRI), of sacroiliitis. Arthritis associated with IBD is not
included in the ILAR criteria, so for this study, it was defined as
enthesitis or arthritis for greater than 6 weeks associated with
IBD. Exclusion criteria included patients starting a TNFi for indica-
tions other than treatment of arthritis or enthesitis, eg, active or
worsening IBD or chronic uveitis. Patients with any history of prior
TNFi use or use of other biologic DMARDs were also excluded.
This study was approved by the Stanford University Institutional
Review Board (protocol No. 36088).
Data collection and study variables. Data were col-
lected from four study time points: 1) JSpA diagnosis, 2) TNFi ini-
tiation, 3) 6 months post TNFi initiation, and 4) 12 months post
TNFi initiation. The physician’s reason for TNFi initiation was
determined on the basis of the primary rheumatologist’s clinical
documentation of physical examination and imaging findings and
assessment of the patient and was categorized into physical
examination findings of active disease alone, image findings of
active disease alone, both physical examination and imaging find-
ings, and/or pain. The primary author (MO) reviewed all clinical
documentation and the assessment and plans for each patient
at each study time point. Documented imaging findings were con-
firmed with radiology reports. Additional data collected included
age, race and ethnicity, sex, date of diagnosis, disease subtype,
radiographic imaging studies (such as x-rays, ultrasounds, and
MRI reports), HLA antigen B27 status, TNFi type, TNFi start and
stop dates, concomitant medications, inflammatory markers
(erythrocyte sedimentation rate and C-reactive protein level),
physical examination findings, presence of uveitis, patient-
reported morning stiffness, pain score on a visual analog scale
(VAS), and patient verbally reported description of pain at each
time point. Imaging was cross-checked with the radiology
records. For patients who delayed their TNFi medication start
after it was recommended by their physician, their start date was
recorded as the actual date they started the medication and not
when it was prescribed.
Pain on a VAS was not documented for every patient, but the
patient’s verbally reported pain was well documented in the inter-
val history; thus, an imputed categorical pain variable was used as
a surrogate for the pain VAS score. This was derived from an
expert consensus from a group of pediatric rheumatologists
(MO, TL, DG, CS) who reviewed the documentation of patients’
verbally reported pain in the clinic notes from a sample of
10 patients. Pain was categorized by specific descriptors and
correlated with three levels of a verbal rating pain scale: 1) none,
2) mild, or 3) moderate/severe pain. For example, if the patient
reported no pain, that was categorized as none; if the patient
reported some pain or pain a couple days a week, that was cate-
gorized as mild; or if the patient reported significant pain or pain
on most days, that was categorized as moderate/severe. The
clinical disease status (ie, active, inactive, clinical remission while
on or off medications) at 12 months post TNFi initiation was
derived from the clinical documentation and determined by one
pediatric rheumatologist (MO). Four pediatric rheumatologists
performed an internal validation study on the clinical disease
status at 12 months post TNFi initiation in eight patients. Cohen’s
κcoefficient was used to assess the interrater agreement for
12-month clinical disease activity status, and there was an
observed high level of agreement among the multiple raters (κ
=0.86). The primary author (MO) surveyed the physicians in the
Pediatric Rheumatology Department at Stanford Children’s Health
regarding their practices on documenting physical examination
OLIVER ET AL20
findings at clinic visits, specifically their joint and enthesitis exami-
nation techniques. All physicians had been trained at Stanford Chil-
dren’s Health and had a similar physical examination technique for
assessing joint count and enthesitis. Duration of disease at TNFi
initiation was defined as the time from JSpA diagnosis to the date
the physician initiated a prescription of a TNFi. This was catego-
rized as: less than or equal to 1 month, greater than 1 to 6 months,
and greater than 6 months. Study data were collected and man-
aged by using REDCap, hosted at the Stanford Center for Clinical
Informatics (19).
Exposure. Exposure was the initiation of a TNFi therapy
(etanercept, adalimumab, or infliximab) based on the physician’s
documentation of their recommendation to start a TNFi in the
patient medical record and/or whether the medical reconciliation
listed the medication.
Outcomes. Outcomes of interest were the physician’srea-
son for TNFi initiation and the improvement in disease activity after
TNFi initiation. Disease activity was assessed by using the active
joint count, the active enthesitis count, and the imputed pain vari-
able. These were calculated at the four study time points, and the
change between TNFi initiation and 6 months post TNFi initiation
was the primary outcome. The clinical disease activity status at 12
months after TNFi initiation was also assessed as a secondary out-
come and measured as 1) active disease, 2) inactive disease, 3)
clinical remission while on medication, or 4) clinical remission while
off medications, according to the Wallace criteria for clinical inactive
disease (20).
Statistical analysis. Baseline patient demographics, phy-
sician’s reason for TNFi initiation, and clinical characteristics at
TNFi initiation were summarized by using descriptive statistics.
At 6 months post TNFi initiation, median changes in active joint
and enthesitis counts and the median change in the imputed pain
variable were measured. The clinical disease status at 12 months
post TNFi initiation was measured by using descriptive statistics.
We compared median changes in active joint and enthesitis
counts by physician’s reason for TNFi initiation and by disease
duration at TNFi start. Similarly, we compared the 12-month clin-
ical disease status by physician’s reason for TNFi initiation and
by disease duration at TNFi start. Additionally, JSpA clinical char-
acteristics at diagnosis and at TNFi initiation were compared with
the 12-month clinical disease status. Nonparametric measures
were used because of the small sample size. Between-group
comparisons were made by using the Kruskal-Wallis test for con-
tinuous outcomes and Fisher’s exact test for categorical out-
comes. Comparisons made within two groups used the
Wilcoxon signed rank test for changes in joint and enthesitis
counts and analysis of median scores for change in pain score.
Statistical analysis was performed on SAS software v9.4 (SAS
Institute, Inc).
RESULTS
Baseline demographics. There were 101 patients who
met initial inclusion criteria (a JSpA ICD-9 code and TNFi exposure).
Fifteen patients were excluded from the final analysis because they
did not have clinical documentation from all three of the study time
points (ie, TNFi initiation, 6 months after initiation, and 12 months
after initiation). A total of 86 patients had clinical documentation
available at JSpA diagnosis, TNFi initiation, and 6 months postTNFi
initiation. Of those 86 patients, 80 had clinical documentation avail-
able at 12 months after TNFi initiation, and these patients were
used to assess the 12-month clinical disease activity status.
Baseline characteristics and demographics are summarized
in Table 1. The mean age at JSpA diagnosis was 12.4 years
(SD 4.0 years). The mean age at TNFi initiation was 14.0 years
(SD 3.5 years), and the mean time from JSpA diagnosis to start
of a TNFi was 1.6 years (SD 2.3 years). Of patients, 11.6% started
a TNFi within 1 month of being diagnosed with JSpA, 41.9%
started a TNFi greater than 1 to 6 months after being diagnosed
with JSpA, and 46.5% started a TNFi more than 6 months after
being diagnosed with JSpA. Approximately 63% had abnormal
imaging findings suggestive of active disease prior to starting TNFi
therapy. Sacroiliitis or bone erosions, both indicators for starting a
TNFi sooner, were noted on imaging in 49% of all patients. Most
patients were still on TNFi therapy 12 months after starting
(85%). No TNFi discontinuations were due to inactive disease.
Table 1. Baseline characteristics and demographics (N =86)
Value
Mean age at JSpA diagnosis (SD), y 12.4 (4.0)
Mean age at TNFi start (SD), y 14.0 (3.5)
Male sex, n (%) 48 (55.8)
Race, White, n (%) 49 (57.0)
JSpA subtype, n (%)
Enthesitis-related arthritis 33 (38.4)
Juvenile ankylosing spondylitis 26 (30.2)
Psoriatic arthritis 15 (17.4)
Arthritis associated with IBD 8 (9.3)
Undifferentiated spondyloarthritis 4 (4.7)
HLA antigen B27–positive, n (%) 33 (38.4)
a
Sacroiliitis/bone erosions on imaging prior
to TNFi start, n (%)
37 (48.7)
Prior JSpA treatment, n (%)
NSAIDs 81 (94.2)
DMARDs 60 (69.8)
Steroids, oral 39 (45.4)
Steroids, intraarticular 20 (23.5)
Prescription pain medicine 10 (11.6)
First TNFi prescribed, n (%)
Etanercept 74 (86.1)
Adalimumab 8 (9.3)
Infliximab 4 (4.6)
Abbreviations: DMARD, disease-modifying antirheumatic drug; IBD,
inflammatory bowel disease; JSpA, juvenile spondyloarthropathy;
NSAID, nonsteroidal antiinflammatory drug; TNFi, tumor necrosis
factor inhibitor.
a
Sixteen (18.6%) had unknown HLA antigen B27 positivity (included
in the denominator).
TNFi USE IN JSpA 21
Reason for TNFi initiation. The most common physician
reason for TNFi initiation was physical examination findings of
active disease alone (61%), followed by abnormal imaging find-
ings alone (24%) and both physical examination and abnormal
imaging findings (14%). One patient initiated TNFi therapy
because of intolerance to methotrexate. Pain was included as a
reason for TNFi initiation in 23% of patients, but pain was never
the only reason for initiation, nor was it found in combination with
abnormal imaging findings as a reason for initiation.
The physician’s reason for TNFi initiation differed among the
JSpA subtypes. Compared with other subtypes, more patients
with ERA and PsA subtypes started a TNFi for physical
examination findings alone, and more patients with JAS started
a TNFi for imaging findings alone (P< 0.0001).
Clinical outcome at 6 months. The median active joint
count at TNFi initiation was 2 (interquartile range [IQR] 1-7), and
at 6 months, it decreased to 1 (IQR 0-2). The median active enthe-
sitis count at TNFi initiation was 1 (IQR 0-2), and at 6 months, it
was 0 (IQR 0-1). There was also an improvement seen in pain
after the first 6 months of treatment, which went from moderate/
severe pain to mild pain.
The median joint and enthesitiscountsatTNFiinitiationand
6 months post TNFi initiation varied by physician’s reason for
Figure 1. Median joint and enthesitis counts at tumor necrosis factor inhibitor (TNFi) initiation and at 6 months, by physician’s reason for initiation.
*P< 0.01; **P< 0.001.
Figure 2. Median joint and enthesitis counts at tumor necrosis factor inhibitor (TNFi) initiation and at 6 months, by disease duration. **P< 0.001.
OLIVER ET AL22
TNFi initiation (Figure 1) and by disease duration prior to TNFi
initiation (Figure 2). The greatest improvement in active joint
count was observed in the physical examination findings alone
group compared with the other physician’sreasongroups
(P< 0.0001). The active enthesitis count also decreased in each
of the physician’s reason groups, although this observed
decrease was not as large as that for the active joint count.
The patients with a disease duration of greater than 1 month at
the start of a TNFi demonstrated the largest decrease in their
active joint counts compared with the group who started a TNFi
within 1 month of diagnosis. Active enthesitis counts also
decreased, with the exception of those who started a TNFi
within 1 month.
Patients who had active disease on radiographic imaging
prior to initiating a TNFi did not differ from patients who had nor-
mal imaging findings regarding clinical characteristics and labora-
tory measures after 6 months of TNFi therapy.
Clinical outcome at 12 months. Of the 80 patients who
had clinical documentation available at 12 months after TNFi initi-
ation, 53.8% were considered to still have active disease, 28.8%
had inactive disease, and 17.5% were in clinical remission on
medications. Table 2 shows the 12-month clinical disease status
by the physician’s reason for TNFi initiation, and Table 3 shows
the 12-month clinical disease status by the disease duration at
TNFi start. Although there was a slightly higher proportion of
patients with active disease after 1 year of TNFi therapy compared
with those with inactive disease and clinical remission, this was
not statistically significant for either the physician’s reason for TNFi
initiation or the disease duration (P=0.38 and 0.95, respectively).
The initial joint and enthesitis counts at diagnosis and TNFi
initiation are shown in Table 4. Patients who were in clinical remis-
sion at 12 months post TNFi initiation had a lower enthesitis count
at the time of JSpA diagnosis and at the time of TNFi initiation
compared with those who still had active disease or inactive
Table 2. Clinical disease status at 12 mo, grouped by the physician’s reason for TNFi initiation (n =80
a
)
Reason for physician-initiated TNFi
Clinical disease status at 12 mo, n (%)
Active Inactive
Clinical remission
on medication
Physical examination findings 26 (55.3) 11 (23.4) 10 (21.3)
Imaging of active disease 9 (43.0) 8 (38.0) 4 (19.0)
Both physical examination and imaging findings 8 (66.7) 4 (33.3) 0 (0)
Abbreviation: TNFi, tumor necrosis factor inhibitor.
a
n=80 (number of patients with a 6-mo follow-up who also had a 12-mo follow-up).
Table 3. Clinical disease status at 12 mo, grouped by the disease duration prior to TNFi (n =80
a
)
Disease duration prior to TNFi
Clinical disease status at 12 mo, n (%)
Active Inactive
Clinical remission
on medication
≤1 mo 5 (55.6) 2 (22.2) 2 (22.2)
>1-6 mo 16 (50.0) 10 (31.2) 6 (18.8)
>6 mo 22 (56.4) 11 (28.2) 6 (15.4)
Abbreviation: TNFi, tumor necrosis factor inhibitor.
a
n=80 (number of patients with a 6-mo follow-up who also had a 12-mo follow-up).
Table 4. Initial joint and enthesitis counts and corresponding to 12-mo clinical disease status (n =80
a
)
Clinical disease status at 12 mo
PvalueActive Inactive
Clinical
remission on
medication
At JSpA diagnosis
Joint count, median (IQR) 2 (0-5) 2 (1-4) 2 (2-5) 0.27
Enthesitis count, median (IQR) 2 (0-2) 2 (0-2) 0 (0-1) 0.66
At TNFi initiation
Joint count, median (IQR) 2 (0-6) 3.5 (1-10) 3 (2-5) 0.51
Enthesitis count, median (IQR) 1 (0-2) 2 (0-2) 0 (0-0) 0.0044
Abbreviations: IQR, interquartile range; JSpA, juvenile spondyloarthropathy; TNFi, tumor necrosis factor
inhibitor.
a
n=80 (number of patients with a 6-mo follow-up who also had a 12-mo follow-up).
TNFi USE IN JSpA 23
disease (P=0.0044). There were no other differences in the clin-
ical characteristics found at the time of diagnosis of JSpA or TNFi
initiation when compared with the 12-month clinical disease sta-
tus. Furthermore, there were no associations noted between the
JSpA subtypes or HLA antigen B27 status and the 12-month clin-
ical disease status.
DISCUSSION
Our study explored the relationship between TNFi initiation
and clinical disease activity in patients with JSpA at one center.
We found that the majority of physicians escalated therapy in
patients with JSpA to a TNFi solely because of physical examina-
tion findings, and there was an improvement in their active joint
counts, active enthesitis counts, and patient-reported pain at
6 months post TNFi initiation. However, many of the patients still
had active disease 1 year after starting a TNFi.
When compared with other JSpA cohorts, our study popula-
tion was similar regarding age at JSpA diagnosis, age at start of a
TNFi, and sex. These prior cohorts were also predominantly male
(60%-80%) and had a similar average age at diagnosis and start
of TNFi, which ranged from 11 to 13 years and 14 to 15 years,
respectively (12,13,21). In our cohort, ERA was the most com-
mon subtype. Of the patients who had a documented HLA anti-
gen B27 test result, the percentage of patients who were HLA
antigen B27–positive in our cohort was smaller (38%) when com-
pared with the other cohorts. However, another study suggested
the prevalence may be closer to 50% in the pediatric population
(21), and a more recent study reported a similar HLA antigen
B27 positivity finding of 36% (22).
Although the majority of the patients escalated therapy to a
TNFi because of physical examination findings of active disease,
there were no differences regarding clinical disease status at
12 months post TNFi (active vs inactive vs remission). Further-
more, our study found that active enthesitis did not improve as
dramatically as active arthritis did following 6 months of TNFi ther-
apy. One consideration for this that the authors discussed was
that because clinically identifying enthesitis in children is challeng-
ing, this may have impacted the overall enthesitis counts. This
raises an important issue of whether we need more reliable phys-
ical examination techniques or imaging modalities for detecting
enthesitis and sacroiliitis in this patient population. In a recent
study, Weiss et al (23) assessed the accuracy of physical exami-
nation for the detection of sacroiliitis on MRI in patients with newly
diagnosed JSpA and healthy controls. In this cohort, researchers
found that the prevalence of reported inflammatory back pain
symptoms and traditional physical examination measures used
for detecting clinical sacroiliitis (eg, sacroiliac tenderness) were
similar in those with MRI evidence of sacroiliitis and those without
(23). Another study that compared the accuracy of ultrasound
and clinical examination in patients with ERA found that ultra-
sound detected more active enthesitis counts compared with
clinical examination (24). Better physical examination techniques
or imaging modalities in this patient population would ultimately
help guide the physician’s decision on whether to escalate ther-
apy to a TNFi. Patients with JSpA have also been shown to have
higher pain scores compared with patients with other JIA sub-
types (4). This concern led us to assess how much pain alone
contributed to the decision to start a TNFi. However, pain without
any accompanying definitive signs of active disease was not
found to be a reason for escalation in our study.
In our study, TNFi therapy appeared to improve active joint
and enthesitis counts and patient-reported pain at 6 months of
TNFi therapy. This improvement in the active joint count was con-
sistent with earlier studies that demonstrated the efficacy of TNFi
for the treatment of arthritis in JSpA (12,13,25). Among 22
patients with ERA in the Dutch Arthritis and Biologicals in Children
Register, the mean number of active joints decreased from 5.5 to
1 after 3 months of TNFi treatment (16). Hugle et al (12) showed in
a study of 16 patients with JSpA treated with TNFi that 83% had
achieved clinical remission 6 months into the treatment, although
inferior efficacy was noted for control of sacroiliac joint disease.
In our study, the active enthesitis count decreased, although this
improvement was not as large as the decrease in the active joint
count, especially for those starting on a TNFi for physical exami-
nation findings. Although the initial enthesitis count prior to TNFi
initiation was less than the active joint count, it still did not
completely resolve after 6 months of therapy. This may highlight
the need for more effective therapy for enthesitis or, again, the
need for better ways to measure enthesitis in children with JSpA.
Additionally, the enthesitis count may be a prognostic indication
and predictor of response to TNFi. In our study, we also found
that the initial enthesitis count at the time patients started a TNFi
was lowest in those who achieved clinical remission on medica-
tions at 12 months compared with those with active disease and
inactive disease. Higher enthesitis counts may predict poorer
response to TNFi therapy and poorer outcomes. However, there
may be differences in disease phenotypes and disease progres-
sion that could account for some of the variations in response to
TNFi, and this should be studied further.
Those patients with a shorter disease duration prior to start-
ing a TNFi (<1 month after diagnosis) showed improvement in
their arthritis only, but this was not as significant statistically or
clinically as for those with a longer disease duration. Enthesitis
did not improve at all in those who started on a TNFi with a dis-
ease duration of less than 1 month. Prior studies have shown that
pediatric patients did not start a TNFi until 2 to 3 years after dis-
ease onset (10,15,16). In our study, the patients who initiated a
TNFi very early in their disease course might have had more
severe disease and potentially disease damage at the time of TNFi
initiation.
In our study, we were limited to the data available from the
medical record chart review. As previously mentioned, there was
a large amount of missing data for certain JSpADA components,
OLIVER ET AL24
which precluded us from using our initial outcome of interest, the
total JSpADA scores, and assessing TNFi effect on axial disease
(eg, presence of clinical sacroiliitis and abnormal back mobility).
Analysis of the missing data suggested that data were not miss-
ing at random and were likely missing because of systematic
processes with electronic medical record documentation that
led to specific variables being repeatedly missing. We cannot
exclude the possibility that potentially some of the variables that
were not missing randomly might have contributed to the physi-
cian’s decisions to escalate therapy. The missing variables also
created a smaller patient population for some comparisons,
which could introduce selection bias and threaten generalizabil-
ity. We relied on a combination of ICD-9 codes to identify
patients because there is not one specificICD-9codeforthe
diagnosis of JSpA, and this might have also contributed to the
smaller sample size and potential misclassification. Potential
confounding by indication could explain some of the improve-
ment seen in joint and enthesitis counts at 6 months post TNFi
initiation. Patients who started a TNFi earlier might have had
more severe disease, more active disease, other characteristics
that would influence their overall outcome and response to TNFi
therapy. Because TNFi are not traditionally first-line therapy, our
cohort is likely to be considered high risk with active disease and
thus needed to be exposed to a TNFi. Lastly, studies have
shown that patients with JSpA report significant limitation in
function from axial involvement (4); however, TNFi therapy’s
effect on axial disease in our study could not be assessed
because of missing data on Schober’s test for back mobility
and Patrick’s test for clinical sacroiliitis.
The reasons for which a physician escalates therapy in the
JSpA population have not been formally evaluated before. Our
hope is that by addressing the decision-making process and rea-
sons why physicians escalate medication, we can ultimately
improve outcomes. In our study, most physicians relied on their
physical examination skills for detecting active disease to escalate
therapy, and the group of patients who started a TNFi because of
physical examination findings alone also had the largest improve-
ment in their active joint counts. Our study also evaluated the
effects of TNFi on arthritis and enthesitis. After 6 months of TNFi
therapy, our patients had improvement in their peripheral symp-
toms. The effect on the active enthesitis count was not as great
as that on the active joint count, which may highlight the need
for better ways to measure and manage enthesitis. The manage-
ment for JSpA has generally been adapted from that for adult
ankylosing spondylitis or other JIA subtypes. Considering that
more than half of our JSpA population continued to have active
disease after 1 year of TNFi therapy, we need to consider whether
this is the best approach and we need to find better ways to man-
age the pediatric JSpA population. Future studies should con-
tinue to look at the effect of TNFi and their role in the
management of patients with JSpA, specifically those with pre-
dominantly enthesitis features.
AUTHOR CONTRIBUTIONS
All authors were involved in drafting the article or revising it critically
for important intellectual content, and all authors approved the final ver-
sion to be published. Dr. Oliver had full access to all of the data in the
study and takes responsibility for the integrity of the data and the accu-
racy of the data analysis.
Study conception and design. Oliver, Simard, Lee, Sandborg.
Acquisition of data. Oliver, Simard, Lee.
Analysis and interpretation of data. Oliver, Simard, Lee, Gerstbacher,
Sandborg.
REFERENCES
1. Ravelli A, Martini A. Juvenile idiopathic arthritis. Lancet 2007;369:
767–78.
2. Tse SM, Laxer RM. New advances in juvenile spondyloarthritis.
Nat Rev Rheumatol 2012;8:269–79.
3. Weiss PF. Diagnosis and treatment of enthesitis-related arthritis.
Adolesc Health Med Ther 2012;2012:67–74.
4. Weiss P, Beukelman T, Schanberg LE, Kimura Y, Colbert R, CARRA-
net Investigators. Enthesitis is a significant predictor of decreased
quality of life, function, and arthritis-specific pain across juvenile arthri-
tis (JIA) categories: preliminary analyses from the CARRAnet registry
[abstract]. Arthritis Rheum 2011;63 Suppl 10:S105.
5. Stoll ML,Bhore R, Dempsey-Robertson M, Punaro M. Spondyloarthritis
in a pediatric population: risk factors for sacroiliitis. J Rheumatol 2010;
37:2402–8.
6. Flatø B, Hoffmann-Vold AM, Reiff A, Førre Ø, Lien G, Vinje O. Long-
term outcome and prognostic factors in enthesitis-related arthritis: a
case–control study. Arthritis Rheum 2006;54:3573–82.
7. Weiss PF, Colbert RA, Xiao R, Feudtner C, Beukelman T, DeWitt EM, et al.
Development and retrospective validation of the juvenile spondyloarthritis
disease activity index. Arthritis Care Res (Hoboken) 2014;66:1775–82.
8. Bertilsson L, Andersson-Gäre B, Fasth A, Petersson IF, Forsblad-D’elia H.
Disease course, outcome, and predictors of outcome in a
population-based juvenile chronic arthritis cohort followed for
17 years. J Rheumatol 2013;40:715–24.
9. Selvaag AM, Aulie HA, Lilleby V, Flatø B. Disease progression into
adulthood and predictors of long-term active disease in juvenile idio-
pathic arthritis. Ann Rheum Dis 2016;75:190–5.
10. Otten MH, Anink J, Prince FH, Twilt M, Vastert SJ, ten Cate R
et al. Trends in prescription of biological agents and outcomes
of juvenile idiopathic arthritis: results of the Dutch National Arthritis and
Biologics in Children Register. Ann Rheum Dis 2015;74:1379–86.
11. Haroon N, Inman RD, Learch TJ, Weisman MH, Lee M, Rahbar MH,
et al. The impact of tumor necrosis factor αinhibitors on radiographic
progressioninankylosingspondylitis. Arthritis Rheum 2013;65:2645–54.
12. Hugle B, Burgos-Vargas R, Inman RD, O’Shea F, Laxer RM, Stimec J,
et al. Long-term outcome of anti-tumor necrosis factor alpha block-
ade in the treatment of juvenile spondyloarthritis. Clin Exp Rheumatol
2014;32:424–31.
13. Horneff G, Foeldvari I, Minden K, Trauzeddel R, Kümmerle-Deschner JB,
Tenbrock K, et al. Efficacy and safety of etanercept in patients with
the enthesitis-related arthritis category of juvenile idiopathic arthritis:
results from a phase III randomized, double-blind study. Arthritis
Rheumatol 2015;67:2240–9.
14. Ramanathan A, Hemalatha S, Colbert RA. Update on juvenile spondy-
loarthritis. Rheum Dis Clin North Am 2013;39:767–88.
15. Sevcic K, Orban I, Brodszky V, Bazso A, Balogh Z, Poor G, et al.
Experiences with tumour necrosis factor-αinhibitors in patients with
juvenile idiopathic arthritis: Hungarian data from the National Institute
of Rheumatology and Physiotherapy Registry. Rheumatology
(Oxford) 2011;50:1337–40.
TNFi USE IN JSpA 25
16. Otten MH, Prince FH, Twilt M, Ten Cate R, Armbrust W,
Hoppenreijs EP, et al. Tumor necrosis factor-blocking agents for chil-
dren with enthesitis-related arthritis: data from the Dutch Arthritis and
Biologicals in Children Register, 1999–2010. J Rheumatol 2011;38:
2258–63.
17. Ringold S, Angeles-Han ST, Beukelman T, Lovell D, Cuello CA,
Becker ML, et al. 2019 American College of Rheumatology/Arthritis
Foundation guideline for the treatment of juvenile idiopathic arthritis:
therapeutic approaches for non-systemic polyarthritis, sacroiliitis,
and enthesitis. Arthritis Care Res 2019;71:717–34.
18. Petty RE, Southwood TR, Manners P, Baum J, Glass DN,
Goldenberg J, et al. International League of Associations for Rheuma-
tology classification of juvenile idiopathic arthritis: second revision,
Edmonton, 2001. J Rheumatol 2004;31:390–2.
19. Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG.
Research electronic data capture (REDCap): a metadata-driven meth-
odology and workflow process for providing translational research
informatics support. J Biomed Inform 2009;42:377–81.
20. Wallace CA, Giannini EH, Huang B, Itert L, Ruperto N, Childhood
Arthritis Rheumatology Research Alliance, et al. American College of
Rheumatology provisional criteria for defining clinical inactive disease
in select categories of juvenile idiopathic arthritis. Arthritis Care Res
(Hoboken) 2011;63:929–36.
21. Weiss PF, Klink AJ, Behrens EM, Sherry DD, Finkel TH, Feudtner C,
et al. Enthesitis in an inception cohort of enthesitis-related arthritis.
Arthritis Care Res (Hoboken) 2011;63:1307–12.
22. Rumsey DG, Lougee A, Matsouaka R, Collier DH, Schanberg LE,
Schenfeld J, et al. Juvenile spondyloarthritis in the Childhood Arthritis
and Rheumatology Research Alliance Registry: high biologic use,
low prevalence of HLA-B27, and equal sex representation in sacroilii-
tis. Arthritis Care Res (Hoboken) 2021;73:940–6.
23. Weiss PF, Xiao R, Biko DM, Chauvin NA. Assessment of sacroiliitis at
diagnosis of juvenile spondyloarthritis by radiography, magnetic reso-
nance imaging, and clinical examination. Arthritis Care Res (Hoboken)
2016;68:187–94.
24. Shenoy S, Aggarwal A. Sonologic enthesitis in children with
enthesitis-related arthritis. Clin Exp Rheumatol 2016;34:143–7.
25. Tse SM, Burgos-Vargas R, Laxer RM. Anti-tumor necrosis factor α
blockade in the treatment of juvenile spondyloarthropathy. Arthritis
Rheum 2005;52:2103–8.
OLIVER ET AL26
Available via license: CC BY-NC-ND
Content may be subject to copyright.
