O1 Identifying juvenile scleroderma immunophenotype subsets
Kathryn Torok1, Suzanne Li2, Anne Stevens3, Marvin Fritzler4, Laura Schanberg5, Kelly
Mieszkalski5, Anne Dennos5, Sarah Ringold3, Marc Natter6, Min-Lee Chang6, Emily Mirizio1,
Kaila Schollaert-Fitch1, for the CARRA scleroderma subcommittee
1University of Pittsburgh, Pittsburgh, PA, USA; 2Hackensack University Medical Center,
Hackensack, NJ, USA, Hackensack, NJ, USA; 3Seattle Children’s Research Institute,
University of Washington, Seattle, WA, USA; 4University of Calgary, Calgary, AB, Canada;
5Childhood Arthritis and Rheumatology Research Alliance, Inc./Duke Clinical Research
Institute, Durham, NC, USA; 6Boston Children’s Hospital, Boston, MA, USA
Background
The overall aims are to: (1) determine the predominant circulating cellular phenotype,
cytokine profile and autoantibody profile in pediatric systemic sclerosis (SSc) and
localized scleroderma (LS) patients and (2) to test the ability of these immunophenotypes
to predict disease manifestations, response to therapy, and define biological subsets
of LS and SSc patients. Childhood Arthritis and Rheumatology Research Alliance (CARRA)
centers interested in scleroderma will collect standardized outcome measures and biological
specimens longitudinally. Preliminary immunophenotyping from the lead center is described
and may serve as a platform for expansion of analyses of the larger sample set.
Methods
Eighteen CARRA centers were identified that could adequately enroll subjects and dedicate
time and effort to this project. Disease-specific pediatric LS and SSc case report
forms (CRFs) were designed and implemented into a REDCap database. Institutional review
board (IRB) approval was obtained. Preliminary immunophenotyping was performed on
the lead center’s pediatric LS and SSc cohort, investigating circulating cellular
and cytokine/chemokine phenotypes of interest, to address the proposed aims and establish
a statistical methodology template for the inclusion of data from multiple centers.
Plasma longitudinally obtained from 87 pediatric patients (n=70 LS, n=8 SSc, n=9 healthy)
were examined via 60 analyte Luminex panel to compare active and inactive disease
states. PBMC flow cytometry was performed (n =35 LS, n=8 SSc, n=12 healthy) with T-cell
and monocyte markers. The modified Localized Scleroderma Severity Index (mLoSSI) anchored
correlative cytokine/chemokine and cellular phenotype results for LS subjects, followed
by multiple regression analyses of the significantly correlated cytokines using R
language to improve prediction models of disease.
Results
Preliminary data from the lead center demonstrates moderate to strong correlations
between interferon-gamma (IFN-γ) inducible cyto/chemokines and TH1-like associated
cellular subtypes (TH1, Tc1) with the mLoSSI (Table 1). Of these, CXCL9 and IL-10
were statistically significant predictors in multiple linear regression analyses (p
= 0.001 and 0.002, respectively), with an adjusted R-squared of 0.71; meaning the
change of CXCL9 and IL-10 are related to the change in mLoSSI, signifying change in
disease activity status.
Conclusion
The infrastructure of a multi-center translational pediatric scleroderma study established
through CARRA is feasible. Preliminary immunophenotyping demonstrates an IFN-γ signature
(CXCL9, CXCL10/ IP-10, IFN-γ) during active LS disease along with disease activity
regulation via IL-10 production and M2 phenotype. Further analyses are underway using
a best fit modeling approach to find the strongest core set of biomarkers/immunophenotype
that highly predicts the mLoSSI in patients with LS, signifying degree of disease
activity. Additional longitudinal samples across all 18 pediatric scleroderma CARRA
sites will be collected and analyzed using this approach to determine core biomarkers
for LS and SSc disease activity.
Table 1
(abstract O1). Correlation of the mLoSSI to the peripheral blood cyto/chemokine and
cellular subtypes
Cyto/chemokine
Spearman’s correlation
p-value
Cell subtype
Spearman’s correlation
p-value
IP-10 (CXCL10)
0.57
0.0112
Monocyte CD40+CD163+
0.89
0.0029
IL-10
0.46
0.0005
TH1 (TCRαβ+CD4+IFNγ+)
0.87
0.0103
MIG (CXCL9)
0.42
0.0018
TC1 (TCRαβ+CD8+IFNγ+)
0.75
0.0544
GM-CSF
0.38
0.0049
IFN-γ
0.33
0.0161
MIP-3β
0.30
0.0255
TNF-α
0.30
0.0266
Acknowledgements
This study received funding from the Scleroderma Foundation through the SF Collaborative
Research (SCORE) award, Childhood Arthritis and Rheumatology Research Alliance (CARRA)
small grant award, and support from the Nancy Taylor Foundation for Chronic Diseases
Inc.
O2 Increased Exposure to Adverse Childhood Experiences is Associated with Arthritis
in a National Sample of US Youth
Tamar Rubinstein1, Danielle R. Bullock2, Kaveh Ardalan3, Wenzhu Mowrey1, Nicole Brown1,
Ruth E. Stein1
1Albert Einstein College of Medicine/Children’s Hospital at Montefiore, Bronx, NY,
USA; 2University of Minnesota/Masonic Children’s Hospital, Minneapolis, MN, USA; 3Northwestern
University Feinberg School of Medicine/Ann & Robert H. Lurie Children’s Hospital of
Chicago, Chicago, IL, USA
Correspondence: Tamar Rubinstein
Background
Adverse Childhood Experiences (ACEs) such as witnessing violence in the home or neighborhood,
parental incarceration, and racial or ethnic discrimination are associated with increased
risk of chronic disease and poorer health in children and adults. Emerging data suggest
an association between exposure to ACEs and autoimmune diseases in adults, but the
relationship between ACEs and childhood-onset rheumatologic diseases has not been
examined. Our objective was to investigate the relationship between ACEs and arthritis,
the most common manifestation of childhood-onset rheumatologic disease.
Methods
We used data from the 2016 National Survey of Children’s Health (NSCH) to describe
the distribution of ACEs among children with current arthritis compared to 1) children
with other chronic acquired physical conditions (CAPC)* and 2) all other children.
The NSCH is a survey of sampled households with children <18 years conducted by the
National Center for Health Statistics at the Centers for Disease Control. Children
were determined to have current conditions, including arthritis, if their guardian
indicated yes to both “has a doctor or other health care provider ever told you that
this child has…” and “does this child currently have the condition?” We performed
bivariate and multivariable logistic regression to determine associations between
arthritis and cumulative ACE scores, measured as a categorical variable (0 ACEs, 1
ACE, 2-3 ACEs, >=4 ACEs). Logistic regression was also utilized to determine the relationship
between cumulative ACE exposure and comorbid depression/anxiety.
Results
Among 50,212 children included in the survey, 16,892 had CAPC and 138 had current
arthritis. More children with arthritis had any ACE exposure compared to both children
with other CAPC (63.4% vs 46.9%, p<0.001) and all other children (40.1%, p<0.001).
The prevalence of all individual ACE categories except racial/ethnic discrimination
was significantly higher among children with arthritis compared to other CAPC and
all other children. A graded relationship was observed between ACE scores and arthritis
in logistic regression models for 1) children with CAPC and 2) all children. An overall
significant association between ACE score and arthritis persisted after adjusting
for confounders in both models (Table 1). No significant interaction was found between
ACE and minority status or between ACE and poverty. Among youth with current arthritis,
a graded relationship was observed between ACE scores and odds of comorbid depression/anxiety
(Table 2).
Conclusions
A markedly high prevalence of ACEs is reported among youth with arthritis from a large
national survey. Higher ACE scores were associated with increased odds of arthritis.
Future investigations should examine how adversity may play a role in arthritis development,
disease severity, and physical and mental health outcomes. Protective psychosocial
factors, such as resilience, may mitigate the impact of ACEs and should be studied
further to inform development of effective interventions.
*Allergies, asthma, diabetes, and epilepsy.
Ethics Approval
Approval for exemption was obtained from the Einstein-Montefiore Institutional Review
Board.
ᅟ
Table 1
(abstract O2). Odds Ratios (OR) for Arthritis by Adverse Childhood Experience (ACE)
Exposure
Number of ACEs
Arthritis among children with CAPC*
Arthritis among all children**
OR
Confidence Interval
p value
OR
Confidence Interval
p value
0 ACEs
1
---
---
1
---
---
1
1.17
0.66 - 2.08
0.59
1.45
0.82 - 2.57
0.20
2-3
2.38
1.55 - 3.67
<0.001
3.29
2.13 - 5.05
<0.001
>=4
3.39
2.02 - 5.68
<0.001
5.20
3.11 - 8.70
<0.001
Adjusted models^
OR^
Confidence Interval
p value
OR^
Confidence Interval
p value
0 ACEs
1
----
----
1
---
---
1
1.01
0.57 - 1.79
0.98
1.09
0.61 - 1.94
0.77
2-3
1.98
1.27 - 3.09
0.002
2.33
1.50 - 3.63
<0.001
>=4
2.54
1.48 - 4.36
0.001
3.30
1.93 - 5.65
<0.001
* CAPC = Chronic acquired physical conditions: allergies, asthma, arthritis, diabetes,
and epilepsy.
** Children with a history of arthritis, but no current arthritis, were censored from
this analysis.
^ Adjusted for age, sex, minority race/ethnicity, and poverty status.
Table 2
(abstract O2). Increased Odds Ratio (OR) of Comorbid Depression/Anxiety by Level of
ACE Exposure in Youth with Arthritis
Youth with current arthritis (N = 123)
Cumulative ACE exposure
OR
Confidence Interval
p value
1 ACE vs none
4.48
1.22 – 16.47
0.024
2-3 ACEs vs none
5.30
1.87 – 15.05
0.002
≥4 ACEs vs none
12.47
3.70 – 42.00
<0.001
O3 Working Towards Comparative Effectiveness Studies for Moderate to Severe Juvenile
Localized Scleroderma: Results of a 1-Year Pilot Study of Three Methotrexate-Based
Consensus Treatment Plans
Suzanne Li1, Kathryn Torok2, Sandy Hong3, Polly Ferguson3, C. Egla Rabinovich4, Mara
Becker5, Maria Ibarra5, Fatma Dedeoglu6, Robert Fuhlbrigge7, Katie Stewart8, Elena
Pope9, Ronald Laxer9, Tom Mason10, Gloria Higgins11, Marilynn Punaro8, Laura Schanberg4,
Tracy Andrews12, for the CARRA Registry
1Hackensack University Medical Center, Hackensack, NJ, USA; 2University of Pittsburgh,
Pittsburgh, PA, USA; 3University of Iowa, Iowa City, IA, USA; 4Duke University, Durham,
NC, USA; 5Children's Mercy Hospital, Kansas City, MO, USA; 6Boston Children's Hospital,
Boston, MA, USA; 7Children's Hospital of Colorado, Denver, CO, USA; 8Texas Children's
Hospital, Dallas, TX, USA; 9Hospital for Sick Kids, Toronto, CA; 10 Mayo Clinic, Rochester,
MN, USA; 11Nationwide Children's Hospital, Columbus, OH, USA; 12Hackensack University
Medical Center, Hackensack, NJ, USA
Correspondence: Suzanne Li
Background
Juvenile localized scleroderma (jLS) is an inflammatory and fibrosing disease associated
with major morbidity including hemiatrophy and arthopathy. Treatment is focused on
controlling inflammation to limit damage. Optimal treatment is not known and regimens
differ greatly. To work towards comparative effectiveness studies, standardized treatment
regimens (consensus treatment plans, CTPs) were developed by an LS Childhood Arthritis
Rheumatology Research Alliance (CARRA) group. We report on our pilot study of these
CTPs.
Methods
We conducted a prospective observational study at 10 CARRA sites. Eligible subjects
had a diagnosis of jLS, fulfilled activity criteria, and were willing to be treated
with one of three CTPs: methotrexate (mtx) alone (A), mtx + intravenous corticosteroids
[CS] (B), or mtx + oral CS (C). Treating physicians chose the specific CTP for their
patients. Subjects were ineligible if they had received CS in preceding 2 weeks, or
mtx or mycophenolate mofetil in preceding 3 months. Assessments included clinical
scoring of lesion features; physician global assessments (PGA), physician assessment
of activity status compared to baseline (MD Activity); and patient and parent health
related quality of life (HRQOL) measures. Data was captured in the CARRA Legacy Registry.
Analyses included Chi-Square or Fisher’s exact tests for categorical data, Wilcoxon
Rank Sum Tests or Sign Rank Tests, and Spearman’s correlation.
Results
We met our target enrollment (50), with subjects enrolled into all CTPs. Subjects
were typical for jLS, with most new to systemic treatment (Table 1).
Table 1
(abstract O3). Subject characteristics
All, # (%)50 subjects
CTP A, # (%)15 subjects
CTP B, # (%)24 subjects
CTP C, # (%)11 subjects
P value
Female
35 (70.0)
11 (73.3)
16 (66.7)
8 (72.7)
NS
Caucasian
46 (92.0)
13 (86.7)
23 (95.8)
10 (90.9)
NS
Age of onset Median (IQR)
9.62 (6.3, 11.6)
9.30 (6.9, 11.9)
9.27 (4.8, 10.5)
10.3 (5.7, 13.4)
NS
Age at study entry Median (IQR)
13 (9.8, 14.5)
13.2 (9.8, 14.1)
11.9 (6.8, 15.2)
13.3 (11.2, 14.3)
NS
Subtype:
0.011
Circumscribed superficial
4 (8.0)
0
1 (4.2)
3 (27.3)
Circumscribed deep
3 ( 6.0)
0
0
3 (27.3)
Linear head
12 (24.0)
3 (20.0)
6 (25.0)
3 (27.3)
Linear trunk/limb
18 (36.0)
8 (53.3)
9 (37.5)
1 (9.1)
Generalized
5 (10.0)
2 (13.3)
3 (12.5)
0
Pansclerotic
1 (2.0)
0
1 (4.2)
0
Mixed
6 (12.0)
2 (13.3)
4 (16.7)
0
Anatomic Location
Head
20 (40.0)
4 (26.7)
11 (45.8)
5 (45.5)
NS
Trunk
23 (46.0)
7 (46.7)
11 (45.8)
5 (45.5)
NS
Limb
29 (58.0)
11 (73.3)
15 (62.5)
3 (27.3)
0.052
Prior SystemicTreatment
9 (18.0)
2 (13.3)
7 (29.2)
0
0.097
ANA positivity
23 (54.8)
5 (41.7)
15 (79.0)
3 (27.3)
0.013
Extracutaneous morbidity
37 (74.0)
11 (73.3)
18 (75.0)
8 (72.7)
NS
Deviation from CTP
24 (48.0)
8 (53.3)
11 (45.8)
5 (45.5)
NS
MD Activity status at 12 months vs baseline
NS
Major improvement
22 (50.0)
4 (33.3)
13 (56.5)
5 (55.5)
Moderate improvement
15 (34.1)
6 (50.0)
7 (30.4)
2 (22.2)
Mild improvement
6 (13.6)
2 (16.7)
2 (8.7)
2 (22.2)
Mild worsening
1 (2.3)
0
1 (4.4)
0
Inadequate response to CTP
13 (26.0)
4 (33.3)
8 (33.3)
1 (9.1)
NS
Any Adverse Event
33 (66.0)
7 (46.7)
17 (70.8)
9 (81.8)
NS
AE grade 1
26 (52.0)
6 (40.0)
11 (45.8)
9 (81.8)
NS
AE grade 2
22 (44.0)
4 (26.7)
14 (58.3)
4 (36.4)
NS
AE Grade 3
1 (2.3)
0
1 (4.4)
0
NS
At the 12-month visit, most subjects were rated as having a major or moderate improvement
in activity status compared to baseline with no differences across groups (Table 1).
Adverse events were common (Table 1), and typical for mtx and CS. There was one grade
3, hospitalization for viral gastroenteritis and dehydration. Almost half the subjects
had a major deviation from initial CTP, with most common reasons medication intolerance
resulting in dose adjustment or medication change (30%), inadequate response (26%),
and non-compliance (18%). The PGA-Activity and Skin Activity scores changed significantly
between the baseline and last visit, while PGA-Damage, Skin Damage scores, and HRQOL
did not (Table 2).
Table 2
(abstract O3). Comparison of Medians Between Baseline and Last Visit
All Subjects
Covariate
Baseline: median (IQR)
Last Visit:median (IQR)
P-Value
PGA-Activity
4 (3,6)
0.5 (0,2)
<0.001
PGA-Damage
4 (3,6)
3 (2,5)
0.089
Overall HRQOL
2 (1,2)
2 (1,2)
0.311
CHAQ
0 (0,0.3)
0.1 (0,0.5)
<0.001
Pain Score
0 (0,2)
1 (0,4)
<0.001
Skin Activity score: consists of these variables:
6 (4,11)
1 (0,2)
<0.001
New lesion
1 (1,2)
0 (0,0)
<0.001
Erythema
2 (1,4)
0 (0,0)
<0.001
Violaceous color
0 (0,1)
0 (0,0)
0.001
Waxy white or Yellow
1 (0,2)
0 (0,1)
<0.001
Tactile Warmth
0 (0,1)
0 (0,0)
<0.001
Skin thickening of edge
1 (0,2)
0 (0,0)
<0.001
Skin Damage score:consists of these variables:
12 (4,19)
10 (5,16)
0.071
Skin thickening of center
2 (0,3)
1 (0,2)
<0.001
Dermal atrophy
3 (1,5)
3 (2,5)
0.690
Subcutaneous atrophy
2 (1,5)
2 (1,5)
0.474
Hyperpigmentation
2 (0,5)
2 (1,4)
0.493
Hypopigmentation
1 (0,2)
1 (0,1)
0.147
Significant correlations were found between PGA-Activity and MD Activity (r = -0.543),
and between PGA-Activity and activity variables, with the highest correlation with
erythema and white waxy (r=0.627, 0.589, respectively). PGA-Damage was associated
with subcutaneous and dermal atrophy, and hyperpigmentation (r=0.693, 0.616, 0.590,
respectively).
Conclusions
We demonstrate the feasibility of comparative effectiveness studies in jLS. Most subjects
were rated as having major or moderate improvement irrespective of CTP. About a quarter
of the subjects were considered to have an inadequate response. Larger studies are
needed to assess relative treatment efficacy and factors associated with inadequate
response.
Acknowledgements
The authors gratefully acknowledge funding for this study from an Arthritis Foundation
Innovative Research Grant and CARRA, and funding for the CARRA Legacy Registry from
NIAMS, Friends of CARRA, and Arthritis Foundation.
O4 Biologic switching among JIA patients: a cohort study in the Childhood Arthritis
and Rheumatology Research Alliance Registry
Melissa L. Mannion1, Fenglong Xie1, Daniel B. Horton2, Sarah Ringold3, Colleen K.
Correll4, Anne Dennos5, Timothy Beukelman1, for the CARRA Registry Investigators
1University of Alabama at Birmingham, Birmingham, AL, USA; 2Rutgers University, New
Brunswick, NJ, USA; 3Seattle Children’s Hospital, Seattle, WA, USA; 4University of
Minnesota, Minneapolis, MN, USA; 5Duke Clinical Research Institute, Durham, NC, USA
Correspondence: Melissa L. Mannion
Background
Biologic medications have allowed a significant proportion of JIA patients to achieve
inactive disease. However, some patients will have ongoing moderate to high disease
activity or will not tolerate the medication. Current treatment recommendations suggest
changing biologic medications when inactive or low disease activity is not attained,
but the switching patterns and reasons for switching in clinical practice in North
America are not currently known.
Methods
We used the Childhood Arthritis & Rheumatology Research Alliance (CARRA) Registry
of clinical data from >55 pediatric rheumatology clinics in the United States and
Canada. Individuals with JIA were included if they newly started a biologic medication
after January 1, 2008 and had a minimum of 12 months of observable time following
medication start. They were censored at the most recent visit. Individuals with systemic
JIA were excluded. Subjects were labelled switchers if they had subsequent use of
any other biologic medication with <6 months between discontinuation of the 1st and
start of the 2nd biologic and were labelled delayed switchers if the time between
biologics was >6 months. Subjects were labelled non-switchers if they had no subsequent
biologic medication use in the data. We compared characteristics of switchers, delayed
switchers, and non-switchers using descriptive statistics, chi-square for categorical
variables, and Wilcoxon rank sum testing for continuous variables.
Results
There were 708 children with JIA who newly started a biologic medication in the medication
log, of whom 146 (21%) were switchers and 45 (6%) were delayed switchers (Table 1).
The median time before switching was 434 days (interquartile range (IQR) 194 - 924)
and the median time between the first and second biologic medications was 14 days
(IQR 0 – 159). The majority of patients had started on etanercept (476, 67%). There
was no difference in the presence of uveitis or inflammatory bowel disease between
those who did and did not switch. Among the switchers, the most common reason for
switch was inefficacy (77, 52%), followed by disease flare (19, 13%), and intolerance
of medication or delivery method (16, 11%).
Conclusion
In a multicenter cohort of children with JIA who started a biologic, 20% of children
switched biologic medication after a median of 14 months. Etanercept was the most
common first biologic medication. Additional studies are needed to evaluate the clinical
predictors of switching, the outcomes following biologic switching, to identify the
optimal timing of switching and the preferred second-line agent.
Table 1
(abstract O4). Characteristics of biologic initiators in the CARRA Registry
All biologic initiatorsN= 708
Non switchers n=517
Switchers n=146
Delayed switchersn=45
Comparison of non-switchers vs switchersP value
Age (years) median, range, IQR
10 (IQR 6, 13)
10 (6, 13)
10.5 (8, 14)
8 (4, 11)
ns
Sex (F) n, %
547 (77%)
388 (75%)
119 (82%)
40 (89%)
<0.05
Race: n, %
White
582 (82%)
427 (83%)
117 (80%)
38 (84%)
ns
Black
27 (4%)
19 (4%)
5 (3%)
3 (7%)
ns
Asian
29 (4%)
17 (3%)
9 (6%)
3 (7%)
ns
Hispanic, Latino
68 (10%)
55 (10%)
11 (8%)
2 (4%)
ns
Other
13 (2%)
7 (1%)
5 (3%)
1 (2%)
ns
JIA subtype: n, %
ns
RF+ poly
90 (13%)
69 (13%)
16 (11%)
5 (11%)
RF- poly
376 (53%)
278 (54%)
71 (49%)
27 (60%)
Persistent Oligo
66 (10%)
51 (10%)
11 (8%)
4 (9%)
Extended oligo
44 (6%)
32 (6%)
10 (7%)
2 (4%)
ERA
72 (10%)
49 (10%)
21 (14%)
2 (4%)
psoriatic
44 (6%)
27 (5%)
14 (10%)
3 (7%)
undifferentiated
15 (2%)
10 (2%)
3 (2%)
2 (4%)
Uveitis n, %
48 (7%)
35 (7%)
9 (6%)
4 (9%)
ns
IBD n, %
18 (3%)
14 (3%)
3 (2%)
1 (2%)
ns
Time from diagnosis to start biologic (days) median, range, IQR
217 (66-1126)
218 (70, 1113)
209 (54, 1211)
217 (75, 927)
ns
Time from disease onset to diagnosis (days, median, IQR)
119 (48-298)
119 (47, 305)
118 (44, 278)
135 (52, 232)
ns
MTX use (all) n, %
554 (78%)
394 (76%)
119 (82%)
41 (91%)
<0.05
PO MTX n, %
249 (35%)
186 (36%)
45 (31%)
18 (40%)
ns
SQ MTX n, %
389 (55%)
272 (53%)
87 (60%)
30 (67%)
ns
sulfasalazine use n, %
36 (5%)
25 (5%)
8 (5%)
3 (7%)
ns
Leflunomide use n, %
16 (2%)
12 (2%)
3 (2%)
1 (2%)
ns
Calendar year of biologic start: median, IQR
2014 (2012-2015)
2014 (2013, 2015)
2014 (2012, 2015)
2012 (2010, 2014)
<0.05
Medication starting: n, %
ns
TNF (all)
etanercept
476 (67%)
336 (65%)
103 (71%)
37(82%)
adalimumab
152 (21%)
118 (23%)
29 (20%)
5 (11%)
infliximab
36 (5%)
30 (6%)
3 (2%)
3 (7%)
golimumab
3 (0.4%)
2 (0.4%)
1 (0.7%)
0
certolizumab
3 (0.4%)
3 (0.6%)
0
0
Non TNF (all)
tocilizumab
14 (2%)
12 (2%)
2 (1%)
0
abatacept
17 (2%)
11 (2%)
6 (4%)
0
rituximab
3 (0.4%)
3 (0.6%)
0
0
ustekinumab
0
0
0
0
anakinra
3 (0.4%)
1 (0.2%)
2 (1%)
0
canakinumab
1 (0.1%)
1 (0.2%)
0
0
IQR, interquartile range; JIA, juvenile idiopathic arthritis; RF, rheumatoid factor;
ERA, enthesitis related arthritis; IBD, inflammatory bowel disease; MTX, methotrexate;
PO, oral; SQ, subcutaneous; TNF, tumor necrosis factor inhibitor.
Ethics Approval
The study was approved by University of Alabama's Institutional Review Board, protocol
number X170112004.
P1 Feasibility of Conducting Epigenetic Analysis in Pediatric Lupus B Cells
Joyce S. Hui-Yuen1,2, James N. Jarvis3
1Division of Pediatric Rheumatology, Cohen Children’s Medical Center, Lake Success
NY; 2Department of Pediatrics, Hofstra-Northwell Health School of Medicine, Hempstead
NY; 3Genetics, Genomics, and Bioinformatics Program, University at Buffalo, Buffalo
NY
Background
Bennett et al identified the presence of interferon gene expression signatures in
peripheral blood of children with systemic lupus erythematosus (pSLE). Here, we aim
to identify how B cells contribute to those signatures. We hypothesize that disordered
transcription in pSLE will be prominent in B cells and attributed to disease-specific
epigenetic alterations. Thus we will not only identify important disease mechanisms
in SLE, we will shed light on the genetics of SLE. Our previously published work demonstrates
that most genetic risk for SLE is located within non-coding regions of the genome,
where epigenetic modifications of DNA and histone proteins regulate and coordinate
transcription.
Methods
Our specific aim is to assess regions of open chromatin in untreated pSLE and compare
findings with healthy children. We propose to use assays of transposase-accessible
chromatin with sequencing (ATACseq) to broadly survey open regions of chromatin and
clarify the functional epigenome. In this pilot study, we propose to determine feasibility
of performing this assay and developing methods for data analysis using 5 pediatric
lupus patients and 5 healthy children.
Anticipated Results and Conclusion
Our long-term goal is to gain a mechanistic understanding of the aberrant transcriptional
signatures in untreated SLE. The data generated by this pilot study will provide the
basis for a rigorous power analysis, and firmly establish the working relationship
between the Buffalo and Cohen Children’s Medical Center groups, both of which will
be essential for a competitive application to NIH. Our preliminary findings from this
pilot study will also allow us to begin the exciting process of linking the genetics
and epigenetics of pSLE to the well-established transcriptional aberration.
Ethics Approval
The study was approved by the Northwell Health Institutional Review Board, approval
number HS 07-021.
Funding
This study is supported by a CARRA-AF Small Grant for 2018.
P2 Kappa-Deleting Recombination Excision Circles (KREC) in B Cells: an Aid in Predicting
Juvenile Dermatomyositis Response to Rituximab
Amer Khojah1,2, Victoria Hans3, Michael Miller1,4, Marisa Klein-Gitelman1,4, Megan
Curran1,4, Ramsay Fuleihan2,4, Gabrielle Morgan3, Chiang-Ching-Huang5, Lauren M. Pachman1,3,4
1Division of Rheumatology, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago,
IL, USA; 2Division of Allergy & Immunology, Ann & Robert H. Lurie Children's Hospital
of Chicago, Chicago, IL, USA; 3Cure JM Center of Excellence, Stanley Manne Research
Center, Chicago, IL, USA; 4Northwestern University Feinberg School of Medicine, Chicago,
IL, USA; 5Joseph J. Zilber School of Public Health, University of Wisconsin, Milwaukee,
WI, USA
Correspondence: Amer Khojah
Background
Rituximab is used for the treatment of juvenile dermatomyositis (JDM) with variable
success. Some of this variability is presumed to be related to the effectiveness of
tissue B cells depletion. Forming new B cells requires B cell receptor recombination,
which leads to the formation of KREC, a circular DNA that does not replicate as B
cells divide, so the KREC remains only in one cell and not the progeny. The recombination
site on chromosomal DNA after the excision of KREC is known as the joining code (JC),
found in all B cell progeny. The ratio of JC to KREC determined by qRT-PCR estimates
the number of B cell divisions that have occurred in the patient’s B cell population.
We hypothesized that rituximab treated JDM who have complete or near complete B cell
depletion will have a low JC to KRECs ratio which is associated with a more effective
response to rituximab.
Methods
This is an IRB approved, retrospective study conducted at The Cure JM Center of Excellence, Lurie
Children’s Hospital. We included all 10 JDM patients (mean age of 12.5 years, 6 females,
7 Caucasians, 7 subjects with P155/140+ autoantibody) who had received rituximab therapy
and had serial PBMC stored (-80oC) in our repository. DNA was isolated stored PBMCs;
qRT-PCR measured JC and KREC. We defined oligoclonal B cell expansion as JC:KRECs
ratio of 8 or more before rituximab therapy. A JC:KRECs ratio of 2 or less on the
first detectable sample post-rituximab was considered as an evidence of good B cell
depletion. We defined a good response to therapy as improvement of the Disease Activity
Score (DAS) by at least 2 points in two consecutive visits. This project was funded
by Children’s Arthritis and Rheumatology Research Alliance (CARRA).
Results
JC and KREC were detectable in all samples that had B cell count of 10cell/mm3 or
more. 6 out 10 JDM patients had evidence of oligoclonal B cell expansion. Of the 6
subjects with oligoclonal B cell expansion, three had good B cell depletion (JC:KREC
ratio of 2 or less) and responded well to rituximab therapy (Fig1). On the other hand,
2 out 3 subjects with poor B cells depletion had a lack of response to rituximab (Fig2).
The majority of the subjects (3 out of 4) without oligoclonal B cell expansion had
a poor response to rituximab therapy (Fig 3).
Conclusions
In this study, we showed that qRT- PCR of JC and KREC can replace B cell count by
flow cytometry to monitor B cell reconstitution. Furthermore, this method can differentiate
between the B cells that come from the bone marrow vs peripheral B cell expansion.
Subjects with oligoclonal B cell expansion have a more favorable response to rituximab.
If this finding is confirmed in a larger patient cohort, it may serve as a criterion
for continuing rituximab therapy, thus improving the patient’s outcome.
Fig. 1
(abstract P2). JDM subject responded well to rituximab therapy who had evidence of
oligoclonal B cell expansion and good B cell depletion based on the JC: KRECs ratio
Fig. 2
(abstract P2). JDM subject who had poor B cell depletion and lack of response to rituximab
therapy
P3 Nasopharyngeal Pneumococcus Colonization in patients with Childhood Onset Systemic
Lupus Erythematosus (cSLE)
Fatima Barbar-Smiley1,2, Stacy Ardoin1,2, Vidya Sivaraman1,2, Cagri Yildirim Toruner1,2,Chack
Yung Yu1,3, Octavio Ramilo1,3
1Nationwide Children's Hospital, Columbus, OH, USA; 2The Ohio State University College
of Medicine, Columbus, OH, USA; 3The Research Institute at Nationwide Children's Hospital,
Columbus, OH, USA
Correspondence: Fatima Barbar-Smiley
Background
Pneumococcal infections are significant causes of morbidity and mortality in both
the general and immunocompromised populations. Streptococcus pneumoniae may lead to
severe infections. Lupus patients are five times more likely to have the invasive
pneumococcal disease than healthy controls. The CDC recommends administering pneumococcal
vaccination for children with lupus who are immunosuppressed. Studies have shown an
association between nasopharyngeal (NP) pneumococcal colonization and increased risk
of infection with this pathogenic bacterium. Vaccine effect on pneumococcal NP colonization
(VE-col) is a proper surrogate marker for vaccine effect on invasive pneumococcal
disease. To date, there are no data on the rate nasopharyngeal pneumococcal colonization
in children diagnosed with cSLE and how it correlates with the incidence of invasive
disease. In this study, we assess rate and density of pneumococcal nasopharyngeal
colonization following receipt of recommended pneumococcal vaccination in cSLE patients
compared with age-matched healthy controls.
Methods
We will perform a prospective case-control study involving cSLE versus healthy controls
at a single center, large free-standing children’s hospital. We will collect one NP
swab and analyze for quantitative pneumococcal PCR. Positive samples will be saved
to study specific serotypes in the future. We will collect the following information
from the medical records: demographics, medication list, immunization history, SLE
disease activity index, laboratory results. Rates of positive NP swabs will be compared
between patients with cSLE versus healthy controls using chi-square or Fisher’s exact
tests. We will examine the density of colonization by two-sample t-tests or Wilcoxon
rank sum and chi-square tests for trend. We will compare clinical and patient characteristics
by cSLE status and by NP positivity using chi-square or Fishers’ exact tests for continuous
variables and two-sample t-tests or Wilcoxon rank sum tests for continuous variables.
A multivariable logistic regression model will be assessed to determine whether cSLE
status is associated with higher likelihood of positive NP swabs while accounting
for possible confounders.
Results/Conclusion
We anticipate that patients with cSLE will have higher rate and density of positive
pneumococcal NP swabs following receipt of the recommended pneumococcal vaccinations
as compared with healthy controls. Results will help us better understand indirect
markers for immune response to pneumococcal vaccination and to explore factors that
may impact the response to pneumococcal vaccine in childhood lupus. Following this
study, we plan to carry in-depth mechanistic studies for serum vaccine response and
genetics that will help with providing precision medicine approach to vaccinations
in cSLE and other autoimmune diseases.
Ethics Approval
Study was approved by the local Institutional Review Board (IRB) IRB17-00018.
Funding
This research study is supported by Childhood Arthritis and Rheumatology research
Alliance- Arthritis Foundation (CARRA-AF) small grant award.
P4 Stopping medicines for inactive juvenile idiopathic arthritis: what do patients
and families consider?
Daniel B. Horton1,2, Jomaira Salas3, Aleksandra Wec4, Tim Beukelman5, Alexis D. Boneparth6,
Jaime Guzman7, Ky Haverkamp8, Melanie Kohlheim9, Melissa L. Mannion5, Lakshmi N. Moorthy1,
Elizabeth Stringer10, Lori Tucker7, Sarah Ringold11, Marsha Rosenthal2
1Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA; 2Rutgers Institute
for Health, Health Care Policy and Aging Research, New Brunswick, NJ, USA; 3Department
of Sociology, Rutgers, the State University, New Brunswick, NJ, USA; 4Mathematica
Policy Research, Princeton, NJ, USA; 5University of Alabama at Birmingham, Birmingham,
AL, USA; 6Columbia University Medical Center, New York, NY, USA; 7British Columbia
Children’s Hospital, University of British Columbia, Vancouver, BC, Canada; 8University
of Washington School of Medicine, Seattle, WA, USA; 9Pediatric Rheumatology Care and
Outcomes Improvement Network, Cincinnati, OH, USA; 10IWK Health Centre, Dalhousie
University, Halifax, NS, Canada; 11Seattle Children's Hospital, Seattle, WA, USA
Background
Prior research has examined factors important to clinicians in deciding whether to
withdraw therapy for inactive JIA, but few studies have investigated what is important
to patients with JIA and their families. Recently, we interviewed patients and their
caregivers about stopping JIA medications. One of the major themes to emerge was the
perceived trade-off between risks and fears of medicines and risks and fears of the
disease itself. This trade-off was influenced strongly by negative prior experiences
and complications of JIA or its treatment as well as perceived threats of long-term
damage. We administered an anonymous online survey to learn how widespread these beliefs
and actions are.
Methods
We recruited participants via social media, email, and paper advertisements in pediatric
rheumatology clinics in the US and Canada, in collaboration with PARTNERS (Patient,
Advocates, and Rheumatology Teams NEtwork for Research and Service). The online survey
was administered via REDCap hosted at Rutgers University and was available in English
and Spanish. The format and questions of the survey were based on the findings from
semi-structured interviews exploring decision-making around withdrawing JIA treatment.
Questions were refined with additional input from patients and parents who pilot tested
the survey. Participant enrollment will conclude in February 2018.
Results
To date, 130 participants have completed the online survey, including 108 parents,
17 young adults, and 5 adolescents. Participants reported living in the USA (103,
82%), Canada (16, 12%), or other countries (8, 6%). Participants were asked to rate
and rank a number of disease- and treatment-related factors that may influence decisions
to stop JIA treatment, such as JIA-related damage, duration of inactive disease, concerns
about flare, concerns about drug side effects or long-term effects, and cost or inconvenience
of medicines. Other questions were designed to judge how reluctant or eager individuals
were to stop their (or their children's) medicines, particularly in cases of disagreement
with the treating clinician. Background questions asked for demographic information
and their (or their children’s) history of JIA and medication use.
Conclusion
This online survey will provide important new information about the factors of greatest
importance for patients with JIA and their families in making decisions about treatment
withdrawal. It will help us better understand how people balance the trade-off between
risks and fears of medicines and risks and fears of having JIA. Greater awareness
of this trade-off and related influential factors may help improve shared decision-making
around withdrawing treatment for inactive JIA.
Ethics Approval
The study was approved by the Rutgers University Institutional Review Board, protocol
number Pro20160000193.
Acknowledgements
Funding for this work came from a CARRA-AF Small Grant.
P5 Clinical Disease Manifestations associated with TNF inhibitor failure in Juvenile
Spondyloarthritis
Melissa Oliver1, Pamela F. Weiss2, Robert A. Colbert3 Hemalatha Srinivasalu4, for
the CARRA spondyloarthropathy subcommittee
1Indiana University, Indianapolis, IN, USA; 2Children’s Hospital of Philadelphia,
Philadelphia, PA, USA; 3National Institute of Arthritis and Musculoskeletal and Skin
Diseases, NIH, Bethesda, MD, USA; 4George Washington University School of Medicine,
Washington, DC
Correspondence: Melissa Oliver
Background
Until recently, tumor necrosis factor inhibitors (TNFi) were the only class of biologics
with demonstrable effectiveness in pediatric and adult spondyloarthritis, and thus
they represent the first-line for biologic therapy in children with juvenile spondyloarthritis
(JSpA). Although most patients respond well to TNFi, not all do, failing either secondary
to lack of effectiveness or adverse events. Children who do not respond to initial
TNFi are either switched to a different TNFi or treated with second-line biologics.
We aim to quantify and describe the population of children who fail TNFi.
Methods
This is a multi-center retrospective cohort study of JSpA patients who have failed
TNFi therapy, specifically, etanercept, adalimumab, infliximab, golimumab or certolizumab
pegol. A survey will be sent to sites to collect data on JSpA patients who have failed
TNFi therapy. Standardized definitions for primary and secondary treatment failure
for the JSpA population based on prior literature and survey results will be outlined.
Descriptive statistics will be used to summarize the survey results and clinical characteristics
of JSpA patients who failed TNFi. Correlation analysis and uni- and multi-variable
models will be used to assess the association of TNFi failure with clinical and laboratory
attributes.
Results
A systematic literature review of treatment failure in the adult and pediatric inflammatory
arthritis populations was performed. Based on this review, working definitions for
treatment failure in JSpA population have been generated, which will be reviewed and
discussed with the JSpA workgroup to develop a final standardized definition. In order
to understand the various reasons for switching TNFi, an initial data generating questionnaire
was developed to collect clinical and laboratory attributes of children who meet our
definition of TNFi failure.
Conclusions
This study will educate physicians on specific disease characteristics that may be
associated with TNFi failure, thereby aiding management decisions for patients with
JSpA. The ability to identify patients who are more likely to fail TNFi therapy will
be an important step toward tailoring patient-specific treatments. Knowledge about
indicators of TNFi failure may help in targeting newer alternatives to TNFi in this
particular subset of patients.
Ethics Approval
IRB has been accepted at Indiana University SOM.
P6 Identifying trajectories of disease activity states in Juvenile Idiopathic Arthritis
(JIA) early after treatment: shortening time to decision to change treatment
Lily Lim1, Sarah Ringold2, Eleanor Pullenayegum3, Earl Silverman4, Fabrizio de Benedetti5,
Laura Schanberg6, Yukiko Kimura7
1Children’s Hospital Research Institute of Manitoba, University of Manitoba; 2Seattle
Children’s Hospital, Seattle, WA; 3Child Health Evaluative Sciences, SickKids Research
Institute, SickKids, Toronto, Canada; 4SickKids, Toronto, Canada; 5IRCCS Ospedale
Pediatrico Bambino GesÙ; 6Duke Clinical Research Institute, Duke University Medical
Center, Durham, NC; 7Hackensack University Medical Center, Hackensack, NJ
Background
The treatment of juvenile idiopathic arthritis (JIA) has been revolutionized by introduction
of biological therapies resulting in improved disease control and decreased joint
damage. However, there is heterogeneity in patients’ response times to biologics.
As there are currently no data to identify patients with clinically meaningful differences
in response times early, providers must wait for response and expose these children
to ongoing active disease and potential joint damage. Current trial designs commonly
lead in with 16 weeks of trial medication. We hypothesize that we will be able to
identify individuals who will not respond, earlier than 16 weeks by studying their
treatment response trajectories. This study aims to measure the probabilities of attaining
clinically significant therapeutic responses as measured by the ACR Pedi response
states and clinically inactive disease (CID) or juvenile arthritis disease activity
state (JADAS) in trial participants before week 16. We will identify the non-responders
using baseline clinical phenotype, biomarkers and demographic predictors.
Methods
This study uses data from prior completed trials including the Trial of Early Aggressive
Therapy (TREAT), CHERISH (tocilizumab), etanercept and abatacept trials. All patients
have polyarticular course JIA. The outcomes studied are the ACR Pedi 50,70,90, CID
states or the JADAS low, moderate, high and inactive disease activity states. We will
build two Markov multistate models (MSM) with interval censoring to determine the
probabilities of attaining each state at each visit of trial assessment and transitioning
between states. We will test baseline (study entry) clinical and laboratory factors
for prediction of state attainment and transition. Concomitant prednisone use will
be tested as a time-varying prognostic factor in the model throughout the 16 weeks.
Results
We have finished the negotiations of data sharing agreements (DSA) in 3 of the 4 studies.
The final DSA negotiations should be concluding soon. The data transfer from one of
the drug company to the analysis site is complete. The data transfer from another
2 of the trials is being arranged. Preliminary analysis will be starting in the spring
of 2018.
Conclusions
We expect that by identifying non-responders of biological therapy earlier, the results
from our study will inform future trial designs, allowing for shorter trials. This
will translate into cost savings for pharmaceutical companies. The information may
also be used in clinical practice to allow pediatric rheumatologists to identify non-responders
early and to change their therapy accordingly, so as to avoid irreversible joint damage.
Funding
This study is funded via a CARRA small grant 2017.
P7 Optimizing the electronic health record to capture Childhood Arthritis and Rheumatology
Research Alliance (CARRA) Data
Alysha J. Taxter1, Julisa M. Patel1, Ajay Dharod2
1Brenner Children’s Hospital, Section of Pediatric Rheumatology, Winston-Salem, NC,
USA; 2Wake Forest Baptist Hospital, Department of Internal Medicine, Winston-Salem,
NC, USA
Correspondence: Alysha J. Taxter
Background
Technology has revolutionized how people gather information and communicate with medical
providers. Patients desire to play an active role in their care and to participate
in research. However, limited integration of technology into clinical care and research
can impede their participation. Such information can easily be obtained by collecting
patient-reported outcomes (PROs) on tablet devices which seamlessly integrate into
the electronic health record (EHR). The goal of this project is to implement and evaluate
efforts to electronically capture PROs and clinical data, and evaluate patient interest
in participating in clinical research projects.
Methods
This is a proof of concept study in an outpatient tertiary rheumatology clinic. We
delivered PRO questionnaires in English or Spanish through an electronic patient portal.
The PRO questionnaire included questions about current symptoms, pain, fatigue, disease
activity, function, and interest in research. We built clinic note templates in our
EHR to capture pertinent CARRA registry data, including physician global disease activity
assessment and active joint count. Providers can trend longitudinal data during a
clinic visit using flowsheet functions which can also be shared with patients. This
discrete data can also be easily abstracted using EHR reporting functions. Data capture
was evaluated for validity and missingness. Clinic processes needed to accurately
and timely obtain this data were evaluated with staff surveys.
Results:
There were 617 clinic visits from March to December 2017, with 615 (99%) PRO questionnaires
completed prior to or at the clinic visit. PRO questionnaires were completed by the
patient, parent, and clinic staff 39%, 48%, and 14% of the time, respectively. Of
the 472 patients answering the question on interest in information on future research
opportunities, 327 (70%) were interested in being contacted. We were able to utilize
EHR reporting functions to abstract all patient and physician-reported variables.
Providers reported this patient questionnaire and longitudinal flowsheet data saved
an approximate 5 minutes per visit and allowed them to focus on pertinent positive
responses. Staff surveys reported that barriers to administering questionnaires are
activation of parent-proxy access and password recovery workflow.
Conclusion:
We successfully developed infrastructure to capture and report on both patient- and
provider-entered data. Providers reported increased efficiency during visits. The
majority of patients within our clinic are interested in participating in research.
Clinic processes will need to be modified and staff education provided to improve
access and password recovery workflow. We plan to build on this infrastructure to
ultimately streamline data collection and reporting to the CARRA registry.
Ethics Approval
The study was approved by Wake Forest Institutional Review Board, approval number
IRB00043463.
Acknowledgements
This work was supported by the CARRA Small Grant Application. The authors wish to
acknowledge CARRA, and the ongoing Arthritis Foundation financial support of CARRA.
P8 Utility of the pain symptom assessment questionnaire (PSAQ) to assess fibromyalgia
in JIA patients
Melissa Tesher1, Thomas Brent Graham2, Tracy V. Ting3, Jennifer Weiss4
1University of Chicago Medical Center, Chicago, IL USA; 2Vanderbilt University Medical
Center, Nashville TN USA; 3Cincinnati Children’s Hospital Medical Center, Cincinnati
OH USA; 4Hackensack University Medical Center, Hackensack NJ USA
Correspondence: Melissa Tesher
Background
Pain in children with JIA has a significant impact on patient quality of life. Persistence
of significant patient-reported pain despite normal objective measures of disease
activity poses a quandary for the pediatric rheumatologist. The Pain Symptom Assessment
Questionnaire (PSAQ) is a modified version of the 2010 ACR fibromyalgia criteria,
and has demonstrated good specificity and sensitivity for diagnosis of juvenile primary
fibromyalgia syndrome in adolescents. With this investigation, we aim to: 1. Evaluate
the utility of the PSAQ in identifying JIA patients with Juvenile Fibromyalgia (JFM),
in comparison to the Yunus and Masi criteria for JFM; and 2. Identify differences
amongst JIA patients with and without JFM including potential variables such as demographic
data, disease characteristics, functional disability, and physician and patient/parent
global assessments.
Methods
Children and adolescents ages 11-17, with a known diagnosis of any subtype of JIA,
are eligible for the study. We are collecting the following data from each subject:
1. Demographics: age, ethnicity, age of diagnosis/disease duration; disease subtype
2. Physician global and patient/parent global assessment
3. Active joint count, determined by physician
4. Pain VAS score (pain in the past week)
5. PSAQ (Pain Symptom Assessment Questionnaire)
6. FDI (functional disability index)
7. Tender points manual exam (performed in a subset of subjects)
Results
Three sites are actively enrolling subjects, with a fourth in progress (target N=160).
We will use descriptive statistics to report the number of patients with JIA overall
who meet criteria for JFM using the PSAQ. In addition we plan to investigate whether
there is a significant relationship between: 1. JIA subtype and incidence of JFM by
PSAQ; 2. Demographic and other variables (sex, active joint count, physician global
assessment) and the incidence of JFM; 3. Higher score on PSAQ (more pain/symptoms)
and disparity between physician and patient/parent global assessments; 4. Higher scores
on the PSAQ and greater functional disability with higher pain VAS. For the subset
of patients for whom the tender points exam is performed, we will assess sensitivity
and specificity of the PSAQ for diagnosis of JFM, using the criteria of Yunus and
Masi as the gold standard.
Conclusions
The study design has thus far demonstrated feasibility. We anticipate completion of
data collection by summer 2018. Findings from this study may provide pediatric rheumatologists
with a simple tool to evaluate JIA patients with secondary chronic widespread pain
conditions whom would benefit from specific pain focused treatments.
Ethics Approval
This study was approved by the Institutional Review Board at the University of Chicago
Medical Center, Vanderbilt University Medical Center, and Cincinnati Children’s Hospital
Medical Center. IRB approval is pending at Hackensack University Medical Center.
Funding
This work is supported by a CARRA-AF Small Grant.
P9 A pilot study: can musculoskeletal ultrasound (MSUS) be utilized as an objective
measure of disease activity in a consensus treatment plan for patients newly diagnosed
with Polyarticular Juvenile Idiopathic Arthritis (JIA)?
Heather Benham1, Leandra Woolnough1,2, Yassine Kanaan1, David Wilkes1, Tracey Wright1,2
for the CARRA Investigators
1Texas Scottish Rite Hospital for Children, Dallas, TX, USA; 2Department of Pediatrics,
UT Southwestern Medical Center, Dallas, TX, USA
Background
In adult rheumatoid arthritis (RA), longitudinal studies have demonstrated correlations
between clinical measures of disease activity, including the DAS-28, ESR and CRP,
and objective measures of joint inflammation by musculoskeletal ultrasound (MSUS).1,2
Hyperemia, or increased blood flow detected by Power Doppler signal, is a key indicator
of disease activity in adults with RA. The Childhood Arthritis and Rheumatology Research
Alliance (CARRA) is conducting a Consensus Treatment Plan (CTP) utilizing a “treat
to target” approach in newly diagnosed Polyarticular JIA patients, STOP-JIA.
The primary objective of this study is to examine the correlations between two MSUS
measures of disease activity and clinical measures of disease activity including clinical
active joint count, CHAQ, cJADAS-10 and ESR in patients with Polyarticular JIA followed
longitudinally through treatment.
Methods
STOP-JIA patients were followed longitudinally with MSUS and clinical measures of
disease activity including clinical active joint count, CHAQ, ESR, and cJADAS-10.
MSUS assessments included scans of bilateral elbows, wrists, 2nd MCPs, knees, and
ankles by grey-scale and Power Doppler. Semi-quantitative grading scales were used
and pathologic lesions were measured across the greatest dimension (mm). Ultrasound
Active Joint Count (USAJC) was calculated in two ways (Table 1).
Results
Six newly diagnosed polyarticular JIA subjects were included in this longitudinal
pilot study (Table 2). Mean disease duration at baseline visit was 27 weeks (range
11-52.8). Five patients had potential erosive changes on baseline ultrasound scans,
most commonly identified in the ankles, wrists and 2nd MCPs. Improvements in USAJC#1
and USAJC#2 were positively associated with improvements in cJADAS (r = 0.55, p =
0.02; r = 0.45, p = 0.045). Reductions in pathologic lesion size in the wrists (both
mid-carpal and radio-carpal recesses) correlated strongly with improvements in cJADAS.
(Table 3). Improvement in USAJC#1, but not USAJC#2, was strongly correlated with reduction
in ESR (r = 0.71, p = 0.001) and moderately correlated with reduction in CHAQ scores
(r = .51, p = 0.03).
Conclusions
Objective measures of joint activity by MSUS can feasibly be incorporated into a longitudinal
“treat-to-target” study in polyarticular JIA. In this small pilot sample, active joint
count by MSUS correlated with measures of clinical disease activity. While hyperemia
on MSUS is a primary indicator of inflammation in RA, the significance in JIA is less
clear. Future studies will examine these correlations more extensively with a larger
cohort and further delineate the role for MSUS in a treat-to-target management strategy
in JIA. This study was supported with CARRA-AF Funding.
Table 1
(abstract P9). Two Definitions for Ultrasound Active Joint Count
USAJC #1
Number of joints with evidence for any component of MSUS pathology (Synovial thickening,
Joint Effusion or Hyperemia) > 1+ in any recess.
USAJC #2
Number of joints with evidence for Synovial Thickening (> 1+) with Hyperemia (> 1+)
with or without Joint Effusion.
Table 2
(abstract P9). Baseline Characteristics of Polyarticular JIA Cohort
Mean Age, yrs (range)
9.75 (3.5-17)
Gender (% female)
5 (83%)
Race (% white)
5 (83%)
Ethnicity (% Hispanic)
3 (50%)
Mean Disease Duration, wks (range)
27 (11-52.8)
ANA (% positive)
6 (100%)
RF (% positive)
2 (33%)
CCP (% positive)
3 (50%)
Mean cJADAS (range)
16 (11-22)
Mean ESR (range)
41.5 (14-80)
Mean MD Global (range)
3 (2-4)
Mean Pt/Parent Global (range)
4.5 (0-8)
Mean CHAQ (range)
1.48 (0.5-2.5)
Mean CAJC (range)
11.17 (5-18)
Mean USAJC#1 (range)
6.00 (5-8)
Mean USAJC#2 (range)
1.33 (0-4)
Table 3
(abstract P9). Correlations between changes in the Wrist Pathologic Lesion size and
cJADAS
TAP-RW-MC
0.660
0.003
TAP-LW-MC
0.745
0.000
TAP-RW-RC
0.789
0.000
TAP-LW-RC
0.672
0.002
(TAP-RW-MC = Total area of Pathology-Right Wrist- Mid-Carpal Recess; TAP-LW-MC = Total
area of Pathology-Left Wrist- Mid-Carpal Recess; TAP-RW-RC = Total area of Pathology-Right
Wrist- Radio-Carpal Recess; TAP-LW-RC = Total area of Pathology-Left Wrist- Radio-Carpal
Recess).
References
1. Backhus TM et al. The US7 score is sensitive to change in a large cohort of patients
with rheumatoid arthritis over 12 months of therapy. Annals of Rheumatic Diseases
2013;72:1163-1169.
2. Harman H et al. Improvement of large-joint ultrasonographic synovitis is delayed
in patients with newly diagnosed rheumatoid arthritis: results of a 12-month clinical
and ultrasonographic follow-up of a local cohort. Clinical Rheumatology 2015;34(8):1367-74.
P10 Musculoskeletal ultrasound study in childhood arthritis a limited examination
Patricia Vega-Fernandez1, Tracy V. Ting2, Edward J. Oberle3, Johannes Roth4, for the
CARRA Investigators
1Emory University, Atlanta, GA, USA; 2Cincinnati Children's Hospital Medical Center,
Cincinnati, OH, USA; 3Nationwide Children’s Hospital, Columbus, OH, USA; 4University
of Ottawa, Ontario, Canada
Background
Juvenile Idiopathic Arthritis (JIA) is the most common rheumatologic disease of childhood.
Most of the core set of assessment measurements are subjective by nature. A validated,
accessible tool that can evaluate disease response is lacking. Musculoskeletal Ultrasound
(MSUS) is a non-invasive, efficient, well accepted imaging tool capable of being used
at the bedside by a trained ultrasonographer for the assessment of inflammatory arthritis.
MSUS is known to have better sensitivity and reliability to detect synovitis than
clinical examination. The aims of this study are 1. Determine the minimum number of
joints needed to assess MSUS-evidenced disease activity in JIA; 2. Evaluate feasibility
and acceptability from both patient/parent and clinician experience of a limited MSUS.
Methods
Newly diagnosed JIA patients presenting with active joint count >4 without recent
intraarticular corticosteroid injection in the past month, able to perform first visit
within 4 week of starting a Disease-modifying Antirheumatic Drug (DMARD) are eligible
for this study. A total of 30 pts will be enrolled for this pilot study. In addition
to general demographic and clinical data, a comprehensive clinical physical examination
and a 44 joint MSUS examination by an American College of Rheumatology Musculoskeletal
Ultrasound (ACR RhMSUS) certified pediatric rheumatologist will be performed at baseline
and at 3 months. Both gray-scale B mode and power Doppler images will be obtained
for each view. Determination of a limited joint examination will be made by a data
reduction process to detect at least 90% synovitis within the comprehensive exam.
Results
For a 44 joints MSUS examination a total of 247 views per patient were identified.
To assure standardization during the process of imaging collection and scoring the
authors have developed an Image Acquisition Manual and an Image Scoring Manual. A
calibration exercise addressing imaging acquisition, scoring, and feasibility is underway.
Preliminary results revealed time to scan is close to 120-150 min/per patient per
session, therefore, based on available literature, authors are discussing possible
modifications to the included views. Concurrently, a practical exercise for assessment
of interrater reliability is ongoing. Authors have identified the need of a database
that support storage and visualization of collected DICOM images that meets IRB standards
and allows multisite scoring process; this database is being developed.
Conclusions
A limited MSUS examination will help determine the role of MSUS as a diagnostic and
prognostic instrument in pediatrics. It will improve clinical assessment of disease
activity in JIA and strengthen medical decision making.
Ethics Approval
This study was approved by the Institutional Review Board at Emory University, Cincinnati
Children’s Hospital Medical Center, and Nationwide Children’s Hospital. IRB approval
is pending at the University of Ottawa.
Funding
This work is supported by a CARRA-AF Small Grant.
P11 Subclinical synovitis in oligoarticular JIA: a risk factor for Polyarticular Disease?
Deirdre De Ranieri1, Johannes Roth2, Edward Oberle3
1University of Chicago Medicine, Comer Children’s Hospital; 2University of Ottawa,
Ottawa, Canada; 3Nationwide Children's Hospital, Columbus OH
Background
Oligoarticular JIA is associated with a better prognosis than the other subtypes,
with a higher percentage of patients achieving remission off medication (1). Polyarticular
JIA, on the other hand, is associated with poorer functional outcome (2). Musculoskeletal
US is being used increasingly more in the field of rheumatology to evaluate joints
and tendons. In RA, it has been shown that that patients in clinical remission can
have evidence of subclinical disease on ultrasound, and this finding predicted disease
progression in these patients (3). We know that patients with JIA are often re-classified
later in their disease course, i.e. from an oligoarticular subtype to a more extended
or polyarticular subtype (4), and these subtypes are associated with greater disability
and decreased quality of life for children (5). Furthermore, involvement of certain
“high risk” joints in JIA (i.e. ankles and wrists) early in the disease course increases
the likelihood that a patient will progress to polyarticular disease (6). Determining
if these patients are at risk for disease progression would be valuable in terms of
initiating more aggressive therapy earlier, as the likelihood of achieving inactive
disease is higher the earlier treatment is initiated (7). Indications for biologic
medications, such as TNF-inhibitors, are currently restricted to patients with “Polyarticular”
JIA. This is a pilot study to evaluate the presence and significance of subclinical
synovitis in a cohort of patients with newly diagnosed Oligarticular JIA.
Methods
We plan to enroll 40 patients, M and F, ages 2-16 yrs with recently (<12mos) diagnosed
Oligoarticular JIA. Bilateral elbow, ankle, wrist and knee joints will be assessed
clinically and sonographically at time point 0,3,6,9,12 mos for signs of synovitis.
US evaluation will be according to OMERACT guidelines, using a GE Logiq e portable
US machine. Physical exam will occur prior to the US. Baseline information such as
age, sex, ANA status, +/-uveitis, medications will be obtained. Outcome measures screened
at each visit include JADAS, Patient and Physician Global Assessments, ESR and CRP,
Joint count (both by clinical and sonographic assessment), PQRL, and patient’s perceived
joint count.
Statistics
With 40 patients, we will be able to estimate proportions (e.g., the proportion of
children who develop clinical disease within a year, the proportion of children with
at least one joint having a 1+ on ultrasound at baseline) with sufficient precision
so that the half-width of the 95% CI would be no larger than +/-0.16. We will have
80% power to detect a correlation of 0.42-0.43 between change in CRP and US changes
over time, for example. To evaluate the relationship between baseline US findings
and clinical disease development, assuming that 50% of children will have at least
one joint having an effusion on ultrasound at baseline and overall about 30% of children
will develop clinical disease within the following year, we’d have 80% power to detect
a difference between those with an effusion vs. those without of 10% vs. 49% in the
percentage of those developing clinical disease.
Results and Conclusions
To be determined.
Funding
The authors wish to acknowledge CARRA, and the ongoing Arthritis Foundation financial
support of CARRA.
References
1. Nordal E, Zak M, Aalto K, Berntson L, Fasth A, Herlin T, et al. Ongoing disease
activity and changing categories in a long-term nordic cohort study of juvenile idiopathic
arthritis. Arthritis and rheumatism. 2011 Sep;63(9):2809-18. PubMed PMID: 21560116.
2. Packham JC, Hall MA, Pimm TJ. Long-term follow-up of 246 adults with juvenile idiopathic
arthritis: predictive factors for mood and pain. Rheumatology. 2002 Dec;41(12):1444-9.
PubMed PMID: 12468828.
3. Saleem B, Brown AK, Quinn M, Karim Z, Hensor EM, Conaghan P, et al. Can flare be
predicted in DMARD treated RA patients in remission, and is it important? A cohort
study. Annals of the rheumatic diseases. 2012 Aug;71(8):1316-21. PubMed PMID: 22294638.
4. Al-Matar MJ, Petty RE, Tucker LB, Malleson PN, Schroeder ML, Cabral DA. The early
pattern of joint involvement predicts disease progression in children with oligoarticular
(pauciarticular) juvenile rheumatoid arthritis. Arthritis and rheumatism. 2002 Oct;46(10):2708-15.
PubMed PMID: 12384930.
5. Ringold S, Wallace CA, Rivara FP. Health-related quality of life, physical function,
fatigue, and disease activity in children with established polyarticular juvenile
idiopathic arthritis. The Journal of rheumatology. 2009 Jun;36(6):1330-6. PubMed PMID:
19411394.
6. Hemke R, Nusman CM, van der Heijde DM, Doria AS, Kuijpers TW, Maas M, et al. Frequency
of joint involvement in juvenile idiopathic arthritis during a 5-year follow-up of
newly diagnosed patients: implications for MR imaging as outcome measure. Rheumatology
international. 2015 Feb;35(2):351-7. PubMed PMID: 25119829.
7. Wallace CA, Ringold S, Bohnsack J, Spalding SJ, Brunner HI, Milojevic D, et al.
Extension study of participants from the trial of early aggressive therapy in juvenile
idiopathic arthritis. The Journal of rheumatology. 2014 Dec;41(12):2459-65. PubMed
PMID: 25179849.
8. Roth J, Ravagnani V, Backhaus M, Balint P, Bruns A, Bruyn G, Collado P, de la Cruz
L, Guillame-Czitron S, Herlin T, Hernandez C, Iagnocco A, Jousse-Joulin S, Lanni S,
Lilleby V, Malattia C, Magni-Manzoni S, Modesto C, Narrodi A, Nieto JC, Ohrndorf S,
Rossi L, Selvaag AM, Swen N, Ting T, Tzaribachev N, Vega-Fernandez P, Vojinovic J,
Windshall D, D’Agostino MA, Naredo E for the Omeract Ultrasound Group. Preliminary
Definitions for the Sonographic Features of Synovitis in Children. Arthritis Care
& Research. 2016 Oct; PMID: 27748074 [epub ahead of print].
P12 Longitudinal Musculoskeletal Ultrasound in Juvenile Idiopathic Arthritis
Leandra U. Woolnough1,2, Heather Benham2, Yassine Kanaan2, David Wilkes2, Tracey Wright1,2,
Marilynn Punaro1,2
1UT Southwestern Medical Center, Dallas TX, USA; 2Texas Scottish Rite Hospital for
Children, Dallas, TX, USA
Background
Musculoskeletal (MSK) ultrasound (US) is a non-invasive technique that detects joint
inflammation. Inflammation detected by ultrasound has been shown to predict disease
course in adults with rheumatoid arthritis [1]. Preliminary definitions for MSK US
in healthy joints and synovitis have been established for children [2,
3]. Currently, there is no unified approach for identifying early or subclinical joint
inflammation in Juvenile Idiopathic Arthritis (JIA). The objective of this study is
to determine the diagnostic value of MSK US in JIA.
Methods
Aim 1 will distinguish features of MSK US in JIA patients from normal findings in
healthy children. We will perform clinical examinations as well as MSK US assessments
in JIA and age-gender matched controls (Table 1). We will compare MSK US findings
JIA patients and controls using a semi-quantitative scale[4], depth of pathology (mm),
and volume (mm3). Aim 2 will discern the features of active disease from inactive
disease by following newly diagnosed JIA patients prospectively over a 1-year period
with serial MSK US and clinical assessments. Utilizing a linear mixed models approach,
we will determine if a MSK US joint severity score of inflammation distinguishes JIA
patients with persistent clinical disease activity from those with clinically inactive
disease [5].
Results
Over the past year we have successfully enrolled 18 newly diagnosed JIA patients in
a prospective observational study using MSK US to assess selected joints at four month
intervals. Our preliminary data indicates that 35% of joints in newly diagnosed JIA
reveal inflammation by MSK US not detected by clinical exam. The clinical significance
of this discrepancy is unknown.
Conclusions
This will be the first study of its kind in patients with JIA. This project has the
potential to improve the diagnosis and management of JIA patients by identifying objective
measures of disease activity supporting early aggressive treatment to decrease long-term
disability.
Ethics Approval
This study received funding support from the Childhood Arthritis and Rheumatology
Research Alliance (CARRA) and the Arthritis Foundation.
References
1. Filer A, de Pablo P, Allen G, Nightingale P, Jordan A, Jobanputra P, Bowman S,
Buckley CD, Raza K: Utility of ultrasound joint counts in the prediction of rheumatoid
arthritis in patients with very early synovitis. Annals of the rheumatic diseases
2011, 70(3):500-507.
2. Roth J, Jousse-Joulin S, Magni-Manzoni S, Rodriguez A, Tzaribachev N, Iagnocco
A, Naredo E, D'Agostino MA, Collado P: Definitions for the sonographic features of
joints in healthy children. Arthritis care & research 2015, 67(1):136-142.
3. Roth J, Ravagnani V, Backhaus M, Balint P, Bruns A, Bruyn GA, Collado P, De la
Cruz L, Guillaume- Czitrom S, Herlin T et al: Preliminary definitions for the sonographic
features of synovitis in children. Arthritis care & research 2016.
4. Szkudlarek M, Court-Payen M, Jacobsen S, Klarlund M, Thomsen HS, Ostergaard M:
Interobserver agreement in ultrasonography of the finger and toe joints in rheumatoid
arthritis. Arthritis and rheumatism 2003, 48(4):955-962.
5. Wallace CA, Huang B, Bandeira M, Ravelli A, Giannini EH: Patterns of clinical remission
in select categories of juvenile idiopathic arthritis. Arthritis and rheumatism 2005,
52(11):3554-3562.
Table 1
(abstract P12). Anatomical Recesses Evaluated by MSK US
Dorsal Wrist
Midcarpal recess Radiocarpal recess
Knee
Suprapatellar recess Medial recess Lateral recess
P13 Improving care for children with autoinflammatory diseases: CARRA-sponsored network
building
Marinka Twilt1, Eyal Muscal2, Ana Sepulveda1, Rae Yeung3, Susanne Benseler1
1Alberta Children's Hospital, University of Calgary, Calgary, Alberta, Canada; 2Baylor
College of Medicine, Houston, Texas, USA; 3Sickkids, University of Toronto, Toronto,
Ontario, Canada
Background
Over the last 25 years, our expanding knowledge about childhood diseases presenting
with non-infectious, ‘sterile’ inflammatory fever attacks has dramatically increased
and significantly changed our approach to treatment. In 1999, the concept of "autoinflammation"
was proposed by Dan Kastner and colleagues as the molecular mechanisms other than
autoimmunity as cause for known periodic fever syndromes such as FMF and TRAPS. Nowadays,
autoinflammatory conditions are described as a genetically heterogeneous group of
rheumatologic diseases that are caused by single gene mutations and driven by abnormal
activation of the innate immune system. Innate immunity research and discoveries have
led to identification of several disease causing genes associated with an excessive
cytokine release. These diseases were associated with high mortality and morbidity,
however recognition has increased and early targeted treatment can prevent organ damage
and increase outcome and quality of life. In most cases, life-long control of ongoing
inflammation is necessary in order to improve, stabilize and minimize clinical symptoms
and prevent development of damage. To date, however, all of the studies have been
focused on well-described disease entities with a genetic underlying mechanism. In
addition, many of the studies are based on case-reports or case-studies, which may
have led to limitations in identifying the precise molecular pathway.
Methods
CARRA small grant support (2017) has funded infra-structure for the improvement of
care for children with autoinflammatory diseases (AID) through development of a CARRA
autoinflammatory registry and develop CTPs for the treatment of CAPS in the autoinflammatory
registry. Funds were provided for the development of the autoinflammatory network
and the CTPs for CAPS. CARRA funds have supported a portion of a research assistant
at the Alberta Children’s Hospital since September 2017. Research assistant responsibility
included: assistance in development of autoinflammatory registry data fields, set-up
meetings, and literature search and systematic review for CAPS CTP.
Results
The CARRA autoinflammatory subcommittee has reached out to the CARRA PFAPA and CARRA
CRMO group to develop one autoinflammatory registry including all diseases. A first
iteration of data-elements has taken place and another is planned for the 2018 CARRA
meeting. The aim is to reach consensus on the mandatory data elements during the 2018
CARRA meeting. The CTP project is currently in progress. A search has been performed
and 432 papers were identified. Title and abstract selection have been performed and
we are currently in the process of full-text analysis. The results are expected to
be available during the 2018 CARRA meeting to be discussed in the autoinflammatory
network.
Conclusion
Due to the CARRA small grant the CARRA autoinflammatory subcommittee was able to establish
an autoinflammatory network including the CARRA working groups that deal with AID.
The network has been able to pursue the establishment of an autoinflammatory registry
and the systematic review to establish a CTP for CAPS. Continued collaboration with
all partners is necessary to improve the care of children with AID.
Funding
CARRA small grants/Arthritis Foundation.
P14 Continuous temperature monitoring to improve diagnosis and treatment of PFAPA
Jonathan S. Hausmann1,2, Kalpana Manthiram3, Edwin Anderson1, Sivia Lapidus4, Fatma
Dedeoglu1, for the CARRA PFAPA Subcommittee
1Boston Children's Hospital, Boston, MA, USA; 2Beth Israel Deaconess Medical Center,
Boston, MA, USA; 3National Institutes of Health, Bethesda, MD, USA; 4Goryeb Children's
Hospital, Morristown, NJ, USA
Correspondence: Jonathan S. Hausmann
Background
PFAPA (periodic fevers, aphthous stomatitis, pharyngitis, and adenitis) is the most
common autoinflammatory disease in children. It is characterized by fevers lasting
3-5 days and recurring “like clockwork” every 3-6 weeks, with the presence of the
features of the disease name. Between episodes, children are well and demonstrate
normal growth and development.
One of the challenges of diagnosing PFAPA is distinguishing fever episodes from those
of recurrent viral illnesses. As a result, most children with PFAPA have delays in
diagnosis on the order of months to years (Hofer et al. 2014).
Our study seeks to leverage continuous temperature monitoring to determine fever patterns
in patients with PFAPA, with the hopes of improving diagnosis and facilitating treatment.
Methods
Children with PFAPA, as determined by their CARRA-affiliated rheumatologist, will
be eligible to enroll. The PFAPA Consensus Treatment Plans (CTP) diagnostic criteria
will be used. Families will be provided with an informational brochure about our study,
including links to our study website: PFAPAstudy.com. Families interested in participating
will contact the study team at Boston Children’s Hospital and will be consented over
the phone.
Families will be provided with an iThermonitor, an FDA-approved device that records
continuous body temperature and syncs to a smartphone. Children will be asked to wear
the iThermonitor for a few days before, during, and after a PFAPA flare. Temperature
data will be sent automatically and securely to an online dashboard accessible to
study investigators.
Families will complete an online health survey and a fever diary based on the Autoinflammatory
Disease Activity Index (Piram et al., 2014), in which they will record symptoms and
timing of medication administration.
Results
Recruitment of participants is pending IRB approval.
Conclusions
We believe that these fever patterns are unique to the pathophysiology of PFAPA and
may help to provide rapid and accurate diagnoses of children with this syndrome. Also,
use of continuous temperature monitoring could improve earlier recognition of febrile
episodes, facilitate prompt administration of steroids, and result in increased efficacy
of treatment. Finally, continuous temperature monitoring may provide objective data
about the relative efficacy of different treatment options for PFAPA, which could
be useful when conducting comparative effectiveness research studies such as in the
PFAPA CTP.
References
Hofer M, et al. (2014). International periodic fever, aphthous stomatitis, pharyngitis,
cervical adenitis syndrome cohort: description of distinct phenotypes in 301 patients.
Rheumatology (Oxford) 53:1125–1129.
Piram, M., et al. (2014). Validation of the Auto-Inflammatory Diseases Activity Index
(AIDAI) for hereditary recurrent fever syndromes. Annals of the Rheumatic Diseases,
73(12), 2168–2173.
Ethics Approval
The study was approved by the Institutional Review Board at Boston Children’s Hospital.
Funding
This study is funded through a CARRA-Arthritis Foundation Grant.
P15 The impact of psychiatric comorbidity on health care utilization for youth with
SLE
Andrea Knight1,2,3, Alaina Davis4, Marisa Klein-Gitelman5, Jennifer Faerber6, Hannah
Katcoff6, Zuleyha Cidav1,7, David S. Mandell1,7
1Perelman School of Medicine, University of Pennsylvania, PA, USA; 2Center for Pediatric
Clinical Effectiveness, The Children's Hospital of Philadelphia, PA, USA; 3PolicyLab,
The Children's Hospital of Philadelphia, PA, USA; 4Division of Pediatric Rheumatology,
Monroe Carell Junior Children's Hospital at Vanderbilt, TN, USA; 5Division of Pediatric
Rheumatology, Ann & Robert H Lurie Children’s Hospital of Chicago, IL, USA; 6Health
Analytics Unit, The Children's Hospital of Philadelphia, PA, USA; 7Center for Mental
Health Policy and Services Research, University of Pennsylvania, PA USA
Background
Youth with systemic lupus erythematosus (SLE) have high health care utilization, which
may be exacerbated by psychiatric comorbidity. We examined the impact of psychiatric
diagnoses on utilization of medical services in youth with SLE.
Methods
We conducted a retrospective cohort study using administrative claims for 2000 to
2013 from ClinformaticsTM DataMart (OptumInsight, Eden Prairie, MN), a large US database
of privately insured enrollees. We included youth ages 10-24 years with an incident
diagnosis of SLE (≥3 International Classification of Diseases, Ninth Revision codes
for SLE 710.0, each >30 days apart, with > 1 year of preceding continuous enrollment
without a code for SLE). We categorized mutually exclusive groups of youth with SLE
as those with: 1) no psychiatric diagnosis, 2) a psychiatric diagnosis in the 12 months
preceding SLE diagnosis, and 3) an incident psychiatric diagnosis in the 12 months
after SLE diagnosis. We calculated mean ambulatory, emergency and inpatient visits
for medical (non-psychiatric) services in the year after SLE diagnosis, and used Poisson
regression to compare the number of visits among the 3 groups, adjusting for demographic
and disease variables.
Results
We identified 650 youth with an incident diagnosis of SLE. The mean age was 18.4 years
(SD 3.7), 88% were females and 25% had nephritis. Depression was diagnosed in 117
(18%), anxiety in 78 (12%), and other psychiatric disorders in 176 (27%). Psychiatric
diagnoses preceding SLE diagnosis were present in 122 (19%), incident after SLE diagnosis
in 105 (16%), and absent for 423 (65%). In adjusted models, youth with incident psychiatric
diagnoses had higher mean ambulatory visits in the year after SLE diagnosis compared
to those with preceding (p<0.01) and without psychiatric diagnoses (p<0.001) (Figure
1). Youth with incident psychiatric diagnoses had more primary care and rheumatology
visits than the other groups (Figure 2).
Emergency visits were higher for those with preceding (p<0.01) and incident psychiatric
diagnoses (p<0.001), compared to those without (Figure 1). Differences in inpatient
visits did not reach statistical significance.
Conclusion
Psychiatric comorbidity is prevalent in newly-diagnosed youth with SLE, and associated
with higher utilization of medical services in primary care, rheumatology and acute
care settings. Interventions to address existing and newly identified psychiatric
comorbidity may decrease health care burden for youth with SLE.
Fig. 1
(abstract P15). Comparison of Annual Medical Visits by Psychiatric Status for Youth
with new-onset SLE
Fig. 2
(abstract P15). Primary Care and Rheumatology Visits by psychiatric status for youth
with new-onset SLE
P16 Patient and parent acceptability of mental health screening in the rheumatology
clinic for youth with Systemic Lupus Erythematosus
Tamar Rubinstein1, Marija Dionizovik-Dimanovski1, Raphael Kraus1, Jordan T. Jones2,
Julia Harris2, Martha Rodriguez3, Melissa Tesher4, Lauren Faust5, Beth Rutstein5,
Chelsey Smith2, Rebecca Puplava4; Enrique Rojas4, Alaina Davis6, Sangeeta Sule7, Karen
Onel8, Emily von Scheven9, Andrea Knight5, for the CARRA SLE Subcommittee
1Children’s Hospital at Montefiore/Albert Einstein College of Medicine, Bronx, NY,
USA; 2Children's Mercy Hospitals and Clinics, Kansas City, MO, USA; 3Riley Hospital
for Children at Indiana University Health, Indianapolis, IN, USA; 4University of Chicago
Medicine Comer Children's Hospital, Chicago, IL, USA; 5Children's Hospital of Philadelphia,
Philadelphia, PA, USA; 6Vanderbilt University Medical Center, Nashville, TN, USA;
7Johns Hopkins Children's Center, Baltimore, MD, USA; 8Hospital for Special Surgery,
New York, NY, USA; 9UCSF Benioff Children's Hospital, San Francisco, CA, USA
Background/Purpose
Despite high depression and anxiety prevalence in youth with systemic lupus erythematosus
(SLE), standardized mental health screening is not routinely practiced by pediatric
rheumatologists. Gaps in knowledge exist around family acceptance of mental health
screening in subspecialty clinics. Our objectives were to screen youth with SLE for
depression and anxiety in pediatric rheumatology clinics and assess patient and parent
acceptability of screening in this clinical setting.
Methods
In a multi-center study of collaborating clinics from the Childhood Arthritis and
Rheumatology Research Alliance, 12-21 year olds with SLE were consecutively screened
with the Patient Health Questionaire-9 (PHQ-9) for depression and the Generalized
Anxiety Disorder 7-item scale (GAD-7) for anxiety. Patient reported outcomes (PROs)
were collected and follow up surveys were given to patients and/or parents.
Results
From the first 4 sites, 53 patients were screened and follow up surveys were completed
for 74%. The median age was 16.2 years, 87% were female, and 75% were of minority
race/ethnicity. Of those screened, 26% screened positive for depression, 19% for anxiety,
and 15% endorsed suicidal ideation. Most patients reported being previously screened,
17% by their general pediatricians; 15% were newly identified as having symptoms of
depression or anxiety. PHQ-9 scores highly correlated to PROs for fatigue; GAD-7 scores
were highly correlated to fatigue and pain interference. In follow up surveys, 95%
of patients/parents thought that emotional health was an important part of general
health, 91% felt comfortable being screened by their rheumatologist, and 74% felt
they should continue to be routinely screened by their rheumatologist (Figure 1).
Conclusions
While the importance of routine standardized screening for mental health is well recognized
in general pediatric practices, the role of mental health screening in pediatric rheumatology
clinics has not been established. The preliminary results of this study show that
screens picked up new depression/ anxiety cases and a high prevalence of suicidal
ideation. Depression and anxiety screens correlated with PROs, particularly for fatigue
and pain. Most patients and parents surveyed felt mental health was an important aspect
of general health and supported screening by their pediatric rheumatologist. This
data support mental health screening in pediatric rheumatology clinics as an important
and acceptable practice to patients and families across diverse demographics.
Ethics Approval
This study was approved by the Albert Einstein College of Medicine IRB, the University
of Chicago Biological Sciences Division IRB, the Children’s Hospital of Philadelphia
Research Institute IRB, and Children’s Mercy Hospital Pediatric IRB.
Funding
This study was funded by the CARRA-Arthritis Foundation Small Grant Award.
Fig. 1
(abstract P16). Survey responses from patients with SLE and parents after mental health
screenings in the rheumatology clinic
P17 Maintenance therapy discontinuation of mycophenolate mofetil in pediatric proliferative
lupus nephritis: a multi-centered retrospective cohort study
Sherene Mason1, Marietta DeGuzman2, Melinda Carpenter1, Jerome C. Lane3, Samriti Dogra1,
for the CARRA SLE subcommittee
1Connecticut Children’s Medical Center, Hartford, CT, USA; 2Texas Children’s Hospital,
Houston, TX, USA; 3Lurie Children’s Hospital, Chicago, IL, USA
Correspondence: Sherene Mason
Background
In childhood-onset systemic lupus erythematosus (cSLE) with proliferative lupus nephritis,
mycophenolate mofetil (MMF) has been the most commonly used maintenance steroid sparing
and immunomodulatory therapy. There is a great need for information on when lupus
patients can safely discontinue major immunomodulatory therapy after a period of disease
quiescence. Currently the “stopping point” for such treatment is unknown. On the background
of the chronic and episodic course of SLE, which at times could be unpredictable,
it is likely that significant numbers of cSLE patients may tolerate discontinuation
of MMF without clinical and serologic flare. With hydroxychloroquine use, sustained
disease remission after MMF discontinuation has been observed. To date, there have
been no defined algorithms or guidelines as to the optimal duration of maintenance
MMF therapy, both in the adult and childhood SLE population.
A team of pediatric rheumatologists and nephrologists was established to determine
the feasibility of conducting a retrospective chart review across two large research
consortiums, Childhood Arthritis and Rheumatology Research Alliance (CARRA) and the
Midwest Pediatric Nephrology Consortium (MWPNC).
Methods
All members of 2 research organizations, CARRA and the 70 participating MWPNC medical
centers, were sent a short survey through Survey Monkey. Respondents were queried
on their specialty, institution and contact information, numbers of pediatric patients
with proliferative lupus nephritis at their institution who have been discontinued
off MMF due to prolonged remission (defined as 6 months of clinical remission), and
interest in participating in a retrospective chart review on MMF discontinuation in
pediatric lupus nephritis. Findings were used to design the study protocol which has
now been approved by both CARRA and the MWPNC, with Connecticut Children’s Medical
Center serving as the lead coordinating center.
Results:
There were 146 respondents to the survey, 24% of whom were identified as pediatric
nephrologists and 76% as pediatric rheumatologists. Ninety-five respondents (65%)
from 59 centers expressed an interest in participating in the retrospective chart
review (Table 1). Over one-third of respondents (36%) reported treating 5-10 pediatric
proliferative lupus nephritis patients with MMF (Figure 1). The median number of patients
reported per center with proliferative lupus nephritis that have been discontinued
off MMF due to prolonged remission was 2 (IQR = 0-4.5).
Conclusions
As of January 2018, startup packages were sent to 44 centers, some of which have already
joined the study. Eleven centers have declined to participate, citing no research
support, lack of patients meeting inclusion criteria, or for undisclosed reasons.
Ethics Approval
This study has been approved by the Connecticut Children’s Medical Center’s IRB.
Table 1
(abstract P17). Survey Results
Unique centers interested in participating
USA
50
Canada
4
Outside USA/Canada
5
Fig. 1
(abstract P17). Number of patients per center with proliferative lupus nephritis on
MMF maintenance therapy
P18 The relationship between changes in adipokine levels and disease activity in pubertal
children with SLE
Martha Rodriguez, Kathleen M. O’Neil
Riley Hospital for Children at Indiana University Health
Background
Systemic lupus erythematosus (SLE) is 3-4 fold more common in girls than boys. Female
predominance increases after puberty (9:1). This study focuses on contributions individual
hormones and adipokines provide to sexual dichotomy in SLE, the pubertal rise in disease
activity, and by proxy, the increased incidence of lupus during puberty. We are using
an existing database and serum bank to find associations between disease activity
and both physical markers of pubertal progress and hormone/adipokine changes of sexual
maturation.
Methods
We have a comprehensive database including serial history and examination data, Tanner
stages, laboratory assessments and SLEDAI-2K disease activity scores, paired with
sera (for hormone/adipokine measurement) to identify associations between disease
activity and flares/improvements, and hormonal changes. We are extending our preliminary
observations from the first 38 girls completing the study, examining the remaining
31 subjects (10 boys and 21 girls). The database/serum bank represents 59 girls and
10 boys with SLE enrolled in early puberty (PreP, girls 8-13 years old, boys 9-15)
from 10 CARRA sites followed through puberty. 3-monthly assessments continued until
1 year post-menarche (girls) or post Tanner IV (boys) or study end. Subjects and parents
completed CHAQ (Childhood Health Assessment Questionnaire) questionnaires and the
treating MD completed SLICC Damage Measure questionnaires biannually. Serum hormone
and adipokine concentrations are measured using commercial assays (EMD Millipore).
Analysis includes first univariate, then multivariate associations using generalized
equalizing equations (GEE) to correlate SLEDAI scores and hormonal/adipokine concentrations.
A database from girls with SLE beginning after age 15 is the post-pubertal SLE controls
(PostP).
Results
The average participation was 21 months. Of 55 girls with PreP lupus, 100% had ds-DNA
antibody vs 70% in PostP cohort (p=0.001). PreP were twice as likely to have anemia
(37 vs 18%, p=0.01) as PostP. PreP had more nephritis at onset (60 vs 40%, p<0.02).
Serum FSH, LH and estradiol did not correlate temporally with flare. In 270 visits
48 represented mild-moderate flares (MMF, 17.8%) and 19 were severe flares (SvF, 7.04%);
24.8% were any flare. SLEDAI decreased >3 points in 23.3% of visits. 49% of visits
had sufficient change in SLEDAI to consider changing treatment. Flares increased in
Tanner stages 2 and 3 vs stage 1 (p=0.008). No SvF occurred in Tanner 4 or later.
Flares correlated with rapid falls in visfatin (OR 0.072, p=0.002) and high adiponectin
(OR 1.20, p=0.0046). Neither estradiol nor testosterone correlated with flare. Improvement
correlated with testosterone (p=0.023) and followed falls in adiponectin (0.008) and
rises in prolactin (p=0.003) and resistin (p=0.026).
Conclusion
Preliminary results suggest a high rate of SLE flare in PreP SLE during puberty. Adiponectin
correlates positively with SLE flare and testosterone with improvement. This study
should elucidate mechanisms of pubertal SLE activation and may identify pathways for
intervention.
Funding
NIAMS R03AR52453, NIAID R56AI085258, LFA Pediatric Grant, CARRA 2018 grants.
P19 Evaluation of the reliability and validity of the Cutaneous Lupus Erythematosus
Disease Area and Severity Index (CLASI) in pediatrics
C.J. Kushner1,2*, M. Tarazi1,2*, R. Gaffney1,2, R. Feng1, K. Ardalan3, H. Brandling-Bennett4,
L. Castello-Soccio 5, J.C. Chang6, Y.E. Chiu7, S. Gmuca6, R.D. Hunt8, P. Kahn9, A.M.
Knight6, J. Mehta6, D. Pearson1,2, J.R. Treat5, J. Wan5, A. Yeguez1, J.S.S. Concha1,2,
B. Patel1,2, J. Okawa1,2, L.M. Arkin10, V.P. Werth1,2
1Department of Dermatology, University of Pennsylvania, Philadelphia, PA; 2Corporal
Michael J. Crescenz VAMC, Philadelphia, PA; 3Departments of Pediatrics and Medical
Social Sciences, Northwestern University Feinberg School of Medicine; 4Department
of Pediatrics, University of Washington School of Medicine, Seattle, WA; 5Pediatric
Dermatology, Children’s Hospital of Philadelphia, Philadelphia, PA; 6Pediatric Rheumatology,
Children’s Hospital of Philadelphia, Philadelphia, PA; 7Departments of Pediatrics
and Dermatology, Medical College of Wisconsin, Milwaukee, WI; 8Department of Dermatology
and Pediatrics, Texas Children’s Hospital, Baylor College of Medicine, Houston, TX;
9Division of Pediatric Rheumatology, New York University School of Medicine, New York,
NY; 10Departments of Dermatology and Pediatrics, University of Wisconsin School of
Medicine, Madison, WI
*Authors contributed equally
Cutaneous lupus erythematosus (CLE) refers to skin manifestations of the autoimmune
disease lupus erythematosus (LE). Skin involvement is one of the most common presenting
signs of systemic lupus erythematosus (SLE) and its evaluation can be critical in
making a diagnosis and monitoring disease progression. Patients may also present with
isolated CLE without systemic disease. The visible lesions of CLE can be disfiguring
and distressing to patients. While CLE has been extensively researched in the adult
population, few studies exist in the pediatric population. The development of a validated
disease severity tool is crucial for monitoring the natural history of skin involvement
in lupus registry studies. There is also a great need for new therapeutic agents,
and demonstrating the efficacy of these agents will require clinical trials with reliable
outcome measures. The CLASI is a reliable outcome measure for CLE in the adult population,
where it is commonly used in clinical trials for SLE. However, no study has validated
this assessment tool in children, potentially limiting the conduct of clinical trials
in pediatric SLE.
The study will include at least five pediatric dermatologists and five rheumatologists
to independently evaluate patients with pediatric cutaneous lupus. The study will
take place at the autoimmune disease clinic of the University of Pennsylvania, on
March 3rd, 2018. The physicians will be given a training session on the assessment
of cutaneous lupus using 2 measurement tools: the CLASI and the Physician Global Assessment
(PGA), which allow grading of skin activity and skin damage, as well as a score for
the overall findings. One cohort of physicians will apply the PGA before the CLASI
and the other cohort will apply the CLASI before the PGA. Inter-rater reliability
within each physician group will be determined by intraclass correlation coefficient
(ICC), type ICC and its confidence interval.
While many pediatric dermatologists and rheumatologists have shown strong interest
in participation, there have been difficulties recruiting pediatric CLE patients with
currently active disease who are willing to travel to Philadelphia. However we have
reached out to over ten institutions and all physicians are actively searching for
interested patients and we have identified several patients who will participate.
The primary benefit of this study is the validation of a standardized instrument that
can be applied to pediatric cutaneous lupus to facilitate epidemiologic studies and
provide a critical tool for clinical trials. Secondary benefits include more standardized
documentation of skin disease activity and damage between specialties to help facilitate
clinical practice and interdisciplinary collaboration.
Ethics Approval
This study has been approved by the University of Pennsylvania IRB.
Funding
This project was supported by a CARRA-AF grant.
P20 Enhancing care for children with Autoimmune Encephalitis (AE): CARRA-sponsored
multi-disciplinary network building
Eyal Muscal1, Heather Van Mater2, Elizabeth Wells3, Marinka Twilt4, Dominic Co5, Susanne
Benseler2,5, for the CARRA inflammatory brain disease subcommittee
1Baylor College of Medicine, Houston, TX, USA; 2Duke University School of Medicine,
Durham, NC, USA; 3Children's National Medical Center, Washington, D.C., USA; 4University
Of Calgary Cumming School of Medicine, Calgary, Alberta, Canada; 5University of Wisconsin
School of Medicine and Public Health, Madison, WI, USA
Background
Autoimmune encephalitis (AE) encompasses a spectrum of immune-mediated brain disorders
that cause severe neuropsychiatric manifestations due to autoantibody-driven disruption
of normal synaptic communication. AE leads to protracted hospital stays and complex
neurocognitive rehabilitation needs and may pose significant psychosocial strains
on families and care givers. Optimal care of children with AE requires a multidisciplinary
team concept that often includes neurology, rheumatology, psychiatry, rehabilitation,
critical care and nursing support. AE treatment protocols have yet to be validated
and there is still immense variability in the timing of diagnosis and utilization
of immunosuppressive regimens. Under the auspices of the CARRA SVARD sub-committee,
the inflammatory brain disease work group is pursuing AE care projects. The work group
strives to optimize networking between different pediatric specialties. We describe
the work group’s progress and its goals for the upcoming year.
Methods
CARRA small grant support (2016 and 2017) has funded infra-structure support for the
inflammatory brain disease work group. Travel funds were provided to assist pediatric
neurologists in attending recent rheumatology meetings. Pediatric neurologists attended
the 2016 CARRA meeting (Toronto) and 2016 ACR meeting (shadow AE meeting hosted by
Children’s National Hospital, Pediatric Neurology, Washington, D.C.). CARRA funds
have supported a portion of a research coordinator at Texas Children’s Hospital, Houston,
TX since June 2017. Research coordinator responsibilities have included: scheduling
and recording monthly/bi-monthly group conference calls, and designing/maintaining
an AE confluence page (shared site) in the CARRA members’ only site.
Results
The inflammatory brain disease group has completed scheduled conference calls and
has co-leaders for diagnostic work up, CTP design and outcome measures’ projects.
The group has brought in pediatric neurology “champions” to assist with all 3 projects.
Additionally, a larger group of pediatric neurologists with exposure to neuro-immunology
and AE care are being recruited to complete future CTP and outcome measure surveys.
Work group deliverables for 2018 include: a draft of an NMDAR CTP, a multi-specialty
vetted diagnostic algorithm, a proposed battery of validated outcome measures to be
used in conjunction with CTPs, and an initial proposal for a family-engagement project.
Conclusions
Due to CARRA financial support since 2016 the inflammatory brain disease work group
has been able to pursue AE care projects. Continued collaboration between pediatric
neurologists and rheumatologists will hopefully improve the care of children with
AE in North America.
P21 Engaging patients and parents to improve mental health for youth with rheumatologic
disease
Oluwatunmise Fawole1, Michelle Vickery1, Lauren Faust1, Tamar Rubinstein2, Julia Harris3,
Aimee Hersh4, Karen Onel5, Erica Lawson6, Emily von Scheven6, Kaveh Ardalan7, Esi
Morgan8, Anne Paul8, Judith Barlin9, Paola Daly9, Mitali Dave10, Shannon Malloy10,
Shari Hume10, Suzanne Schrandt11, Laura Marrow11, Angela Chapson1, Donna Napoli1,
Michael Napoli1, Miranda Moyer1, Rachel Adamski1, Vincent Delgaizo12, Martha Rodriguez13,
Andrea Knight1, for the CARRA Investigators14
1The Children's Hospital of Philadelphia, Philadelphia, PA, United States; 2Children's
Hospital at Montefiore, New York, NY, United States; 3University of Missouri-Kansas
City, Children’s Mercy-Kansas City, Kansas City, MO, United States; 4University of
Utah, Salt Lake City, UT, United States; 5Hospital for Special Surgery, Weill Cornell
Medicine, New York, NY, United States; 6University of California San Francisco, San
Francisco, CA, United States; 7Lurie Children’s Hospital of Chicago, Chicago, IL,
United States; 8Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United
States; 9Lupus Foundation of America, Washington, DC, United States; 10Cure JM Foundation,
Encinitas, CA, United States; 11Arthritis Foundation, Saint Paul, MN, United States;
12Patient-Centered Outcomes Research Institute, Washington, DC, United States; 13Riley
Children’s Hospital at Indiana, Indianapolis, IN, United States; 14Childhood Arthritis
and Rheumatology Research Alliance, Milwaukee, WI, United States.
Background
Mental health conditions are common in youth with rheumatologic disease, yet intervention
strategies for pediatric subspecialty patients is understudied. Patient-engaged research,
involving patients and families on the research team, is a valuable technique for
examining sensitive topics such as mental health. We used a patient-engaged approach
to investigate mental health needs of youth with rheumatologic disease.
Methods
An online survey examined beliefs and experiences with mental health for patients
with juvenile arthritis, juvenile dermatomyositis, or systemic lupus erythematous.
Youth ages 14-24 years and parents of youth 8-24 years were eligible to participate.
The survey was developed in collaboration with patient and parent advisors, the Childhood
Arthritis & Rheumatology Research Alliance (CARRA), and the Patients, Advocates, and
Rheumatology Teams Network for Research and Service (PARTNERS). Participants were
recruited through the Arthritis Foundation, Lupus Foundation of America, and Cure
JM Foundation. We compared youth and parent responses using regression models (adjusted
for demographic and disease covariates) to examine the prevalence of mental health
problems, and Likert ratings for the impact of disease aspects on mental health, and
comfort level with potential mental health providers.
Results
352 respondents included 93 youth (26%) and 259 (74%) parents. Mental health problems
were highly prevalent, with clinician-diagnosed anxiety reported by 45%, depression
32%, and adjustment disorders 26% (Figure 1); another 13%, 21% and 11% reported self-
diagnosed symptoms of these disorders, respectively. Mean Likert scores indicated
that disease aspects most impacting mental health (0=low, 4=high) were physical limitation
at 2.7 (SD 1.1), taking medications at 2.6 (1.2), and dealing with disease flares
at 2.5 (1.2). Adjusted models showed no difference between youth and parents for reported
mental health problems or impacting factors. Youth were significantly less comfortable
interacting with all potential mental health providers than parents, particularly
social workers and school counselors (Figure 2); both groups felt most comfortable
with rheumatologists and primary care providers.
Conclusion
Youth with rheumatologic disease have high rates of diagnosed and undiagnosed mental
health problems, which are impacted by their disease. Mental health intervention strategies
are needed, focusing on both primary care and subspecialty care settings to provide
mental health education, screening and treatment for these youth.
Ethics Approval
The study was approved by the Children’s Hospital of Philadelphia IRB, Duke University
Health System IRB, and Lupus Foundation of America IRB.
Fig. 1
(abstract P21). Prevalence of Mental Health Problems for Youth with Rheumatologic
Disease: Clinician-diagnosed vs Self-diagnosed
Fig. 2
(abstract P21). Comparison of Level of Comfort with Potential Mental Health Providers
Among Youth Patients and Parents
P22 Preliminary analyses examining correlates of health self-management
Anna Richmond1, Eyal Muscal2, Richard Karl Vehe3, Kathleen M. O’Neil4
1Division of Pediatric Rheumatology, Monroe Carell Junior Children’s Hospital at Vanderbilt,
Nashville, TN, USA; 2Dept. of Pediatrics, Texas Children’s Hospital, Baylor College
of Medicine, Houston, TX, USA; 3Division of Rheumatology, Department of Pediatrics,
University of Minnesota, Minneapolis, MN, USA; 4Rheumatology Division, Indiana University
School of Medicine, Indianapolis, IN, USA
Background
Although outcomes among youth with lupus have improved significantly over the last
20 years, these advances have outpaced our system’s capacity to effectively support
these youth as they transition to adulthood and adult healthcare. Whether measured
as access to quality healthcare, educational, vocational or quality of life outcomes,
too many young adults with SLE are faring poorly. But it need not be so.
The ultimate goal of this study was to examine factors explaining self-management
skills and transition readiness for youth with jSLE in the context of the dynamic
interaction of personal youth, family and healthcare system factors. For the purposes
of this abstract, we report only preliminary results of surveys and linked EMR data
of 27 patients with jSLE. We anticipate being able to present additional results from
our sample which includes youth from four different institutions (~130 youth).
Objective
To examine relations between psychosocial variables and health self-management among
youth with lupus.
Methods
Participants include 27 youth with jSLE from one pediatric rheumatology clinic. Participants
completed several surveys and using RedCap. De-identified data from the electronic
medical record (EMR) was linked with participants’ responses on the survey. Survey
measures include the TRAQ with revised response categories in accord with social loafing
theory. Bivariate correlation analysis (Pearsons r) were conducted. Once our sample
has reached an adequate size (n=30) we will conduct regression analyses to examine
determinants of health self- management among youth with lupus. This study was approved
by the Institutional Review Board of Vanderbilt University and East Tennessee State
University (IRB# 161674). All psychometric information for instruments utilized are
provided in table 1. At the time of abstract submission, demographic information had
not been linked to the de-identified database in RedCap.
Results
Our analyses demonstrated all scales to have good to excellent reliability. Significant
correlations with moderate to strong effect sizes were observed for the associations
between self- rated health and competence, and social loafing. Additionally, significant
correlations with moderately strong effect sizes were demonstrated for the associations
between social loafing and disease knowledge (StarX) and Task value. Further analyses
will be conducted using multiple regression to predict independent health self-management.
Conclusion
These preliminary analyses show that for youth with jSLE competence was moderately
related with poorer health; youth who reported poor health also reported a lack of
competence in managing their health. Youth who reported poorer health also reported
a lack of independent health self-management as indicated by the social loafing TRAQ
scores. Lastly, youth with jSLE who reported more independent health self- management,
as indicated by the social loafing TRAQ, also reported more disease knowledge and
task value for managing their health.
Table 1
(abstract P22). Properties of Study Measures
Measures
Health
range
1-4
mean(sd)
2.33(.80)
SLEDAI
range
0-12
mean(sd)
3.4(3.3)
Social Loafing TRAQ
mean(sd)
3.3 (.47)
reliability
0.87
Task Value
mean(sd)
4.4(.49)
reliability
0.81
Table 2
(abstract P22). Bivariate Correlations of study variables
Bivariate correlations
Health
SLEDAI
Competence
SLTRAQ
StarX
Task Value
Health (higher scores indicate poorer health)
—
0.12
-.56**
-.46*
-.32
-.43
SLEDAI
—
—
.15
.57
.09
.04
Competence
.26
.21
.40
SLTRAQ
—
—
—
—
.58*
.50*
StarX
—
—
—
—
—
.34
Task Value
—
—
—
—
—
—
* =p<.05; **=p<.01
Funding
The authors gratefully acknowledge funding for this project from CARRA and the Arthritis
Foundation.
P23 Epidermal nerve fiber density in juvenile fibromyalgia
Alexis Boneparth1, Shan Chen2, Daniel B. Horton2, L. Nandini Moorthy2, Heather M.
Downs3, Anne Louise Oaklander3
1Columbia University Medical Center, New York, NY, USA; 2Rutgers Robert Wood Johnson
Medical School, New Brunswick, NJ, USA; 3Massachusetts General Hospital, Boston, MA,
USA
Background
Fibromyalgia (FM) is defined by the presence of idiopathic, chronic, widespread pain.
The pathogenesis of FM is poorly understood. Adults with FM are known to have decreased
epidermal nerve fiber density (ENFD), compared to healthy controls. Although the correlation
between decreased ENFD and FM diagnosis is well described in adults, the meaning of
this phenomenon is unknown, and the clinical significance of decreased ENFD in FM
remains to be elucidated. The prevalence of decreased ENFD in juvenile fibromyalgia
(JFM) is unknown. The aims of this study are to: 1) determine whether patients with
JFM and their parents will consent to a skin biopsy for ENFD testing; 2) establish
a preliminary estimate for the prevalence of decreased ENFD in patients with JFM.
Methods
Patients diagnosed with JFM, age 12-22 years old are eligible to participate. Goal
enrollment is 15 subjects for skin biopsy to assess ENFD. Subjects diagnosed with
JFM by their pediatric rheumatologist complete cross-sectional surveys, assessing
2010 ACR criteria for FM (modified for use in JFM), pain severity, functional disability,
and autonomic symptoms severity. Patients meeting 2010 ACR criteria are eligible for
collection of a 3mm punch skin biopsy for analysis of ENFD, with comparison of ENFD
to existing age-, gender-, and race-based normative data.
Results
The first subject was enrolled December 2016. 16 patients with clinically diagnosed
JFM have completed the surveys, and 13 met 2010 ACR criteria for JFM. Nine patients
have consented for skin biopsy, with median age of 17 years. Five of nine (55%) patients
with skin biopsy have ENFD <5th percentile for age/gender/race. Interim analysis does
not suggest a correlation between ENFD and measures of pain severity, functional disability,
or autonomic symptom severity.
Conclusion
Interim results suggest that decreased ENFD is common in JFM. This study continues
to enroll patients with goal enrollment of 15 subjects for skin biopsy. Further studies
will be needed to assess the clinical significance of decreased ENFD in JFM.
Ethics Approval
This study has been approved by the Columbia University Medical Center IRB, protocol
number AAAR3311.
Funding
This study is supported by the CARRA-Arthritis Foundation Grant Program. The authors
wish to acknowledge the ongoing Arthritis Foundation financial support of CARRA.
P24 Development of a systematic approach to identify factors influencing enrollment
in pediatric rheumatology research
Y. Ingrid Goh1,2, Vincent Del Gaizo3, Alexandra Sirois4, Jennifer E. Weiss5, Mary
Ellen Riordan5, Eyal Muscal6, Chivon McMullen-Jackson6, Christi J. Inman7, Suzy Jones7,
Jennifer Huntington7, Brian M. Feldman1,2, for the CARRA Investigators
1Division of Rheumatology, The Hospital for Sick Children, Toronto, Ontario, Canada;
2Child Health Evaluative Sciences, SickKids Research Institute, Toronto, Ontario,
Canada; 3Patients, Advocates, And Rheumatology Teams Network For Research And Service
(PARTNERS), Atlanta, Georgia, USA; 4Rheumatology Family Advisory Council, The Hospital
for Sick Children, Toronto, Ontario, Canada; 5Department of Pediatric Rheumatology,
Hackensack Meridian Health, Joseph M. Sanzari Children’s Hospital, Hackensack, New
Jersey, USA; 6Section of Immunology, Allergy, and Rheumatology, Baylor College of
Medicine, Houston, Texas, USA; 7Division of Pediatric Rheumatology, University of
Utah Hospitals and Clinics, Salt Lake City, Utah, USA
Correspondence: Y. Ingrid Goh
Background
Many variables affect patients’ and caregivers’ decisions to participate in pediatric
clinical research studies. This decision is further complicated when families are
asked to participate in research only moments after they have received a diagnosis.
While some studies have examined factors influencing study participation, to our knowledge
there have not been any studies examining the factors which influence patients’ and
caregivers’ enrollment into pediatric rheumatic studies.
The objective was to develop a research project that would help research teams understand
how to better engage patients with a newly diagnosed rheumatic condition and their
caregivers to join pediatric rheumatology research.
Methods
We reviewed papers on the best practices of engaging patients in research. We also
reviewed studies which examined factors influencing research participation in other
pediatric medical conditions. The knowledge gained through the review was used to
select the research team and design the research project.
Results
The literature clearly indicated that it was important to have patients and caregivers
representation on the research team and have them actively involved in the development
of the research project. We reached out to two individuals who immediately joined
the study team. After reviewing the characteristics of the Childhood Arthritis and
Rheumatology Research Alliance (CARRA) sites, we selected four study sites (The Hospital
for Sick Children, Ontario, Canada; Hackensack Meridian Health, New Jersey, USA; University
of Utah Hospitals and Clinics, Utah, USA; and Baylor College of Medicine Pediatric
Immunology Allergy Rheumatology, Texas, USA.) which represents geographically and
demographically diverse populations.
Studies investigating enrollment facilitators and barriers in pediatrics have been
conducted in patients receiving oncology and diabetic medications. The methodology
used in those studies were adapted to design the following research project.
Patients and caregivers will be recruited to participate in a one-time online focus
group prior to their appointment. We will enroll a) new, undiagnosed patients, b)
previously diagnosed patients, and c) patients who previously declined to participate
in the CARRA registry or other research studies on the day of diagnosis. Individuals
consenting to participate will take part in an online, semi-structured focus group
session.
Survey questions will be developed from the themes identified during the focus groups
to quantify the impact of these themes. This optional one-time anonymous survey will
be distributed to all patients and their caregivers attending the rheumatology clinics
over a one-month period.
Conclusion
Understanding factors which influence enrollment of newly diagnosed patients into
studies has been identified as a priority by many CARRA work groups. We hope the results
of this research project will help researchers and healthcare team members understand
patients' and caregivers' perspectives so they are more mindful in their approach
and more sensitive to patients’ and caregivers’ needs.
Acknowledgements
This project was recently awarded a CARRA Small Grant.
P25 Planning grant: crowdsourcing and improving assessment of skin disease in pediatric
rheumatology
Susan Kim1, Dexter Hadley1, Yvonne Chiu2, Mitali Dave3, Philip Kahn4, Adam Huber5,
for the CARRA JDM subcommittee
1UCSF, San Francisco, CA, USA; 2Medical College of Wisconsin, Milwaukee, WI, USA;
3Cure JM, Encinitas, CA, USA; 4NYU, NY, NY, USA; 5Dalhousie University, Halifax, Canada
Abstract
Skin and muscle disease is the 'sine qua non' of Juvenile Dermatomyositis (JDM), and
is often difficult to diagnose, monitor and treat. Persistent skin disease despite
resolution of muscle disease is common, and skin inflammation is associated with worse
long term outcomes in JDM.
Many factors limit our ability to monitor skin disease in JDM: we do not have universally
accepted approaches to measure and monitor skin disease in JDM. In addition, there
is a wide spectrum of skin disease in JDM, whose appearance may vary depending on
many factors including ethnicity, complexion and duration of disease. Thus, there
is a gap in the measuring and monitoring of skin disease in JDM.
This planning grant was awarded to allow us to develop an approach to “crowd source”
patients and clinicians to capture the wide spectrum of skin disease in JDM, with
a broad visual representation of skin disease through an online platform. We hope
that this will allow the future development of an online platform to capture skin
disease broadly, to help to better assess and monitor rashes in JDM to advance the
quality of care in the future.
Background
The Problem: Skin Disease is important in Juvenile Dermatomyositis (JDM) and is often
difficult to diagnose, monitor and treat. Persistent skin disease despite resolution
of weakness is common in JDM and skin activity predicts worse outcomes. Early skin
disease activity in JDM may predict cardiac dysfunction better than muscle disease,
and persistently active skin disease months after diagnosis may predict continued
active disease [1–4]. Ongoing skin disease reflects ongoing inflammation, which leads
to long-term morbidity including lipodystrophy, calcinosis, contractures [3,4]. Furthermore,
the rash of dermatomyositis is associated with pain, poor self-image and interferes
with normal psychosocial functioning [5]. Thus treatment of JDM-related skin disease
is important, since it predicts worse overall outcomes.
Unfortunately, we typically do not measure JDM skin disease objectively in clinical
practice, and there are insufficient resources are available to help clinicians and
researchers identify and monitor the variety of skin disease in JDM. Without objective
regular measurement of disease activity, the degree of active disease, flares and
remission are difficult to quantify. Also, currently available reference images of
JDM rashes, found in textbooks, online and in manuscripts capture “classic” and severe
rashes, typically in fair skinned children, but the range of skin diseases and severity,
in a range of skin tones are not available [6].
Proposed solution: With the digitally connected world of today and “crowdsourcing”,
we have an opportunity to bridge this gap. “Crowdsourcing” will allow for rapid collection
of images: Collecting photos with conventional approaches, by clinicians alone in
the office setting is time consuming and impractical, since rashes may fluctuate with
time of day, sun exposure, etc. This “crowdsourcing” approach will allow for timely
collection of photos, which is now possible with the broad use of smart phones/cameras
in the community. This work will also empower families to participate in the growth
of knowledge in JDM.
Once we have a sufficient bank of images, we plan to develop an atlas for JDM will
allow improved knowledge and more reliable identification of skin disease in JDM,
in teaching, clinical and research settings. In addition, this work will allow us
to link the atlas’ photos to currently available skin scoring measures, allowing for
broad, effective use outcome measures for skin disease to improve care in JDM.
In summary, we plan to develop an approach to “crowd source” patients and clinicians
to capture the wide spectrum of skin disease in JDM, with a broad visual representation
of skin disease of skin disease through an on line platform. We hope that this will
allow the future development of an online platform to capture skin disease broadly,
to help to better assess and monitor rashes in JDM to advance the quality of care
in the future.
Methods
Aim 1: To develop an approach to “crowdsource” patients and clinicians to capture
a broad visual representation of skin disease in Juvenile Dermatomyositis (JDM): This
will be achieved with consultation with UCSF CTSI Community Engaged Research and Health
Policy Program, Information security office, IT Customer Solutions Management, Legal
Office and UCSF IRB regarding this planned project.
Aim 2: To collaborate with stakeholders in the development of this project, which
include clinicians (pediatric rheumatologists and dermatologists) and patients/families. To
form a patient-centered multidisciplinary task force for this project (which will
include JDM families, rheumatologists, dermatologists) to develop procedures for obtaining
and cataloguing the photos and disseminating the atlas, we plan collaboration with
Rheumatologists and Dermatologists from CARRA and PeDRA, in addition to Cure JM parents
and families.
Results
Aim 1: Meetings to date have helped to identify ethical issues related to broadly
collecting photos of patients from families, to ensure that patients/families understand
the potential risk of providing photos to identify ethical and logistic barriers related
to broad collection of photos of patients from clinicians, while ensuring privacy
and consent from patients/families.
We have identified a secure, HIPAA compliant location where this data can be collected
and managed: images will be stored on a UCSF approved, HIPAA/HITECH compliant and
HITRUST Amazon Web Services (AWS) server. IRB submission for this project was completed
in January 2018.
We have a collaborative agreement with Dexter Hadley, MD PhD at UCSF, whose research
is with big data, digital health and crowdsourcing to develop an APP to allow us to
crowd source images for JDM.
Ongoing/future work: Once IRB is formally approved and APP is updated for our pediatric
patients, a pilot phase of image collection is planned. Determining costs for launching
this project beyond the pilot-planning phase is to be determined after finalization
of the APP.
Aim 2: I have had input from clinician perspective from core group of clinicians within
CARRA and PeDRA via phone conferences. Discussions have included: feasibility of this
project among patients and clinicians, local/individual IRB concerns, developing easy
steps/guidelines for taking photos for clinicians and families. I have engaged Cure
JM members regarding this project, and they have agreed to future collaboration with
this project, which may include dissemination of this project and research opportunity
to Cure JM members.
Ongoing/future work: Face to face meetings at CARRA (April 2018) and PeDRA (October
2018), for introduction/review of this planned project with discussion of project
for feedback from general CARRA and PeDRA members, which will include discussion of
local/individual IRB concerns, discussion of ideal dissemination of information (E-book,
printed book, on-line book, journal publication, etc.), refining steps/guidelines
for taking photos for clinicians and families, discussion of procedures cataloguing
the photos, future dissemination of data and other research projects that could dovetail
with the development of this resource. In addition, we plan for to expand our collaboration
with general Cure JM members at national Cure JM meeting (June 2018), for discussion
and feedback from the patients/families about this project, including privacy concerns,
discussing dissemination of information, research ideas, review of guidelines for
taking photos.
Conclusions
Skin disease is an important component of disease activity in JDM that needs to be
measured and treated. Our planning grant has allowed us to begin to lay the ground
work to “crowd source” digital images of the broad and diverse range of rashes in
JDM, which will allow for the future improved identification and monitoring of skin
disease activity, in hopes of future improvement of overall outcomes in JDM in the
future.
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symptoms of dermatomyositis significantly impact patients’ quality of life. J. Am.
Acad. Dermatol. 2006;54:217–20.
6. Dugan EM, Huber AM, Miller FW, Rider LG. Photoessay of the cutaneous manifestations
of the idiopathic inflammatory myopathies. Dermatol. Online J. 2009;15:1.
P26 Research priorities among parents and families of children with rheumatic disease
Colleen K. Correll1, Mitali Dave2, Anne Paul3, Vincent Del Gaizo4, Esi M. Morgan5,
on behalf of CARRA and PARTNERS
1University of Minnesota Masonic Children’s Hospital, Minneapolis, MN, USA; 2Cure
JM Foundation, Encinitas, CA, USA; 3Anderson Center for Health Systems Excellence,
Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA; 4Parent Partner,
Whitehouse Station, NJ, USA; 5Cincinnati Children's Hospital, Cincinnati, OH, USA
Background
The Patient-Centered Outcomes Research Institute (PCORI) aims to improve the quality
and relevance of research by conducting research that is most important to patients
and to engage patients at all levels of research. Through the PCORI-supported Patient
Powered Research Network, PARTNERS (Patients, Advocates and Rheumatology Teams Network
for Research and Service), we surveyed patients and families of children with juvenile
myositis (JM), juvenile idiopathic arthritis (JIA), and childhood-onset systemic lupus
erythematosus (cSLE) to identify what research topics are most important to them.
Methods
This research prioritization exercise was conducted through web-based surveys and
focus groups. In Step 1, a link to a survey, which included open-ended questions to
assess what concerns patients/families found most important, was emailed to members
of Cure JM Foundation, Arthritis Foundation (AF), and Lupus Foundation of America
(LFA) listservs and posted on their social media sites. Parents, patients ≥13 years
old and family/friends were included. In Step 2, common themes were identified from
the open-ended surveys. These themes were characterized further through focus groups
for Cure JM and AF. In Step 3, final surveys were created based upon these themes
and emailed to the respective listservs and posted to social media sites. Survey respondents
were asked to rank the themes most important to them. Responses were weighted and
the 7 most important themes were identified. This study was approved by Duke University
institutional review board.
Results
In Step 1, there were 138 (77% parents), 57 (93% parents), and 47 (55% parents) respondents
to the open-ended survey for Cure JM, AF, and LFA, respectively. Response rate could
not be calculated because the number of potential respondents from social media sites
is unknown. Open-ended responses were qualitatively reviewed and 23, 28, and 16 research
themes were identified for Cure JM, AF, and LFA, respectively. In Step 2, these themes
were further characterized during two small focus groups affiliated with Cure JM and
AF and consisting of parents of children with JM and JIA. In Step 3, the final ranking
survey asked respondents to rank the 7 most important priorities from these themes.
There were 365, 44, and 32 respondents to this survey for Cure JM, AF, and LFA, respectively.
The three research themes common across all disease groups was 1) medication side
effects, 2) disease flare and 3) genetic/non-genetic etiology (Table 1). Results from
the Cure JM data were presented at two international conferences to help frame the
JM research agenda.
Conclusions
Patient centered research prioritization is increasingly recognized as a valuable
tool in conducting high-quality research, yet there is a lack of publication describing
patient/family preferences, especially in pediatrics. Here, we demonstrate a successful
program from which we assessed patients/family research priorities in order to frame
the agenda for the pediatric rheumatology research community.
Table 1
(abstract P26). Results from final ranking survey. Top 7 priorities from each group,
ranked from highest to lowest priorities
AF
Cure JM*
LFA*
Genetic/Environmental Etiology
New Treatments
Genetic/Environmental Etiology
Personalized medicine
Flares (triggers, prevention, treatment)
Quality of life
Medication side effects
Medication side effects
Medication side effects
Growth and development
Standards to measure disease activity and/or remission
Pain management
Flares (triggers, prevention, treatment)
Genetic/Environmental Etiology
Long-term health/prognosis
New Treatments
JM complications ( i.e. rash, calcinosis, lipodystrophy)
Fatigue
Pain management
Risk of other autoimmune diseases
Flares (triggers, prevention, treatment)
*For Cure JM and LFA, cure was the highest ranking priority. Our aim for this study
was to identify research priorities other than cure and thus we eliminated these from
the final results
P27 Higher Serum Complement C4 Levels and C4B Gene Copy Numbers Are Associated with
Increased Risk for Hypertension and Significant Response to Prophylactic Atorvastatin
for Atherosclerosis Prevention in Pediatric Systemic Lupus Erythematosus (pSLE)
Evan M. Mulvihill1, Stacy P. Ardoin1, Susan D. Thompson2, Bi Zhou1, Gakit R. Yu1,
Nora G. Singer3, Deborah M. Levy4, Hermine I. Brunner2, Yee Ling Wu1, Haikady N. Nagaraja5,
Laura E. Schanberg6, Chack-Yung Yu1, for the APPLE Investigators
1Nationwide Children’s Hospital, Columbus, OH, USA; 2Cincinnati Children’s Hospital
Medical Center, Cincinnati, OH, USA; 3Case Western Reserve University, Cleveland,
OH, USA; 4The Hospital for Sick Children, Toronto, Canada; 5The Ohio State University,
Columbus, OH, USA; 6Duke University, Durham, NC, USA
Correspondence: Evan M. Mulvihill
Objectives
Patients with pSLE are at risk for poor cardiovascular outcomes. In 2009, the Atherosclerosis
Prevention in Pediatric Lupus Erythematosus (APPLE) Trial demonstrated that prophylactic
atorvastatin treatment did not significantly reduce progression of carotid intima
media thickness (CIMT) in patients with pSLE. A secondary analysis, however, identified
a subgroup of post-pubertal individuals with active inflammation at baseline who did
significantly respond to atorvastatin. SLE patients are characterized by fluctuating
levels of serum complement C4. Serum C4 levels in SLE patients are responsive to inflammation,
consumption and variations of gene copy number (GCN) for total C4, C4A or C4B. We
hypothesize that genetic diversity of complement C4 modulates the outcome of prophylactic
atorvastatin therapy in atherosclerosis of pSLE.
Patients and Methods
Clinical data for the 3-year study of 221 pSLE patients, plus genomic DNA and plasma
samples for 199 patients were provided by the APPLE repository. Among them, 48.2%
were White, 25.5% were Black and 26.4% were from other racial backgrounds. GCNs for
total C4, C4A and C4B were measured by TaqMan-based quantitative realtime PCR and
Southern blot analyses using genomic DNA. Matched EDTA-plasma samples were used to
elucidate C4A and C4B protein polymorphisms by immunofixation. Baseline complement
protein levels, and total C4, C4A and C4B GCNs were analyzed with clinical presentations
through Student’s t-test for continuous data, and χ2 analyses for categorical data.
The effects of total C4, C4A and C4B GCN groups on the response to placebo or atorvastatin
treatment and progression of CIMT were examined by logistic regression analyses.
Results
The GCNs for total C4, C4A and C4B varied between 2 and 6, 0 and 5, and 0 and 5 respectively.
At baseline, C4 protein levels were strongly correlated with GCNs of total C4 (p=1.8x10-6)
and C4B (p=0.0002) and less so with C4A (p=0.022). One-third of the patients (N=71)
had a past history of hypertension. Compared with normotensive patients (N=142), hypertensive
subjects had significantly higher levels of serum C4 (18.5±8.6 mg/dL vs 13.5±6.8 mg/dL;
p=4.7x10-6), lower mean GCN of C4A (1.82±.68 vs 2.07±.76, p=0.032) but higher mean
GCN of C4B (2.00±.57 vs 1.78±.67, p=0.023). Individuals with at least two copies of
C4B genes had 2.53 times the odds of having a history of hypertension (p=0.016), and
higher diastolic blood pressure (p=0.015) compared to those with a C4B deficiency.
Baseline CIMT measurements were similar between those two groups (C4B≥2 and C4B≤1).
At the endpoint of the APPLE study, patients with at least two C4B copies who were
in the atorvastatin treatment group demonstrated significantly less progression of
mean-mean CIMT compared to those with the placebo group (p= 0.018).
Conclusion
pSLE patients with hypertension had significantly higher C4 protein levels and higher
GCN of C4B. pSLE patients with ≥2 copies of C4B genes receiving atorvastatin treatment
demonstrated significantly less progression of mean-mean CIMT than those treated with
placebo. Prophylactic atorvastatin for atherosclerosis prevention was more effective
for pSLE patients without C4B deficiency.
Ethics Approval
This study was performed under approved IRB Protocol (IRB14-00544).
P28 Baseline characteristics and medication use in children with JIA: results from
the Childhood Arthritis & Rheumatology Research Alliance Registry
Sarah Ringold1, Anne C. Dennos2, Yukiko Kimura3, Laura E. Schanberg4, Timothy Beukelman5,
and the CARRA Registry Investigators
1Seattle Children's Hospital, Seattle, WA, USA; 2Duke Clinical Research Institute,
Durham, NC, USA; 3Joseph M Sanzari Children's Hospital at Hackensack University Medical
Center, Hackensack, NJ, USA; 4Duke University Medical Center, Durham, NC, USA; 5University
of Alabama, Birmingham, AL, USA
Background
The Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry is a multicenter,
prospective observational study collecting data from children with rheumatic diseases
in order to characterize disease patterns, treatments, and outcomes. The current version
of the Registry began enrolling children with JIA in July, 2015. This abstract describes
baseline characteristics of children with JIA enrolled as of January, 2018.
Methods
Children were enrolled into the CARRA Registry by participating centers in the US
and Canada. Children with all categories of JIA are eligible for enrollment at any
time in their disease course. Both retrospective and prospective medication data are
collected for each patient.
Results
3725 children were enrolled from 59 different centers. The median age at enrollment
was 12 years (IQR 8-16 years). 71% were female, 73% had private health insurance,
and 81% reported white race. Patients were enrolled at a median of 32 months after
their diagnosis (IQR 6 – 74 months), with the majority (78%) enrolled > 12 months
after symptom onset. Patients from each ILAR category have been enrolled. The most
common categories were RF negative polyarthritis (35%) and persistent oligoarticular
arthritis (27%). 73% of patients had used methotrexate at the time of enrollment or
prior to enrollment. 65% had used a tumor necrosis factor α inhibitor at the time
of enrollment or prior to enrollment. Biologics with other mechanisms of action were
used less commonly: 9% interleukin-1 inhibitors, 7% tocilizumab, and 4% abatacept.
Conclusion
Biologic use was common among this large cohort of children with JIA. Longitudinal
data generated from the long-term follow-up of Registry participants will provide
additional important data on patterns of medication use, medication safety, and disease
outcomes.
Acknowledgements
The authors wish to acknowledge CARRA, and the ongoing Arthritis Foundation financial
support of CARRA.
P29 The Childhood Arthritis and Rheumatology Research Alliance start time optimization
of biologic therapy in polyarticular JIA study: interim report of baseline patient
characteristics and treatment choices
Sarah Ringold1, George Tomlinson2, Pamela F. Weiss3, Laura E. Schanberg4, Brian M.
Feldman5, Mary Ellen Riordan6, Anne C. Dennos7, Vincent Del Gaizo8, Katherine L. Murphy8,
Yukiko Kimura*6, and the CARRA Registry Investigators
1Seattle Children's Hospital, Seattle, WA, USA; 2University of Toronto, Toronto, Canada;
3Children's Hospital of Philadelphia, Philadelphia, PA, USA; 4Duke University Medical
Center, Durham, NC, USA; 5The Hospital for Sick Children, Toronto, Canada; 6Joseph
M Sanzari Children's Hospital at Hackensack University Medical Center, Hackensack,
NJ, USA; 7Duke Clinical Research Institute, Durham, NC, USA; 8CARRA Parent/Patient
Partner, Whitehorse Station, NJ, USA
Correspondence: Sarah Ringold
Background
Despite the many available new and effective treatments for polyarticular JIA (P-JIA),
there is significant variation in the timing of when biologic medications are started.
Three consensus treatment plans (CTPs) reflecting the currently most commonly-used
strategies for starting biologic treatment were developed by the Childhood Arthritis
and Rheumatology Research Alliance (CARRA) using consensus methodology. The CARRA
Start Time Optimization of Biologic Therapy in Polyarticular JIA (STOP-JIA) study
aims to compare the effectiveness of the three CARRA P-JIA CTPs using a prospective,
observational study design. This abstract describes interim baseline characteristics
and CTP choices for the patients enrolled in STOP-JIA.
Methods
Untreated P-JIA patients were enrolled into the CARRA Registry. Providers and patients
together chose one of the CTPs to follow: 1) Step-Up treatment (initial therapy with
DMARD and biologic added after 3 months if needed); 2) Early Combination (initial
therapy with both DMARD and biologic); and 3) Biologic First (initial treatment with
biologic monotherapy). Providers had the option of prescribing glucocorticoids at
baseline per their usual practice and were provided with tapering options. There is
no randomization or blinding in this observational study.
Results
Three hundred and six patients were enrolled at 42 sites in the US and Canada between
1 Nov 15 and 11 Jan 18. Patient characteristics of participants with data entered
(n=273) are summarized in Table 1. The most commonly chosen CTP was Step-Up (n=178;
64%). Early Combination CTP was the next most common choice (n=66; 24%). To date,
590 follow up visits have been entered and 89 patients have completed their 12-month
visit. Of the patients who have completed their 3-month visit, 10 patients were reported
to have changed CTP. There were 22 Serious Adverse Events (SAE) or Events of Special
Interest (ESI) including 4 cases of new onset uveitis, 7 infections, and 4 episodes
of hepatitis.
Conclusion
To date, patients have been enrolled into all 3 CTP choices, with the Step-Up CTP
being the most common. Ongoing, prospective data collection from these patients will
allow for a comparison of the effectiveness of the strategies.
Table 1
(abstract P29). Baseline Patient Characteristics
Total Cohort (n= 273)
Step up (n= 178)
Early Combination (n=66)
Biologic First (n=29)
Female N (%)
196 (72)
132 (74)
44 (67)
20 (69)
White N (%)
192 (70)
130 (73)
44 (67)
18 (62)
Age in yrs – mean (range)
10 (1-18)
10 (1-18)
11 (1-17)
11 (1-18)
JIA Category N (%)
Extended Oligoarticular
6 (2)
6 (3)
--
--
Polyarticular (RF-)
174 (64)
127 (71)
35 (53)
12 (41)
Polyarticular (RF+)
48 (18)
27 (15)
17 (26)
4 (14)
Psoriatic
14 (5)
6 (3)
4 (6)
4 (14)
Enthesitis-related
24 (9)
10 (6)
8 (12)
6 (21)
Undifferentiated
6 (2)
2 (1)
2 (3)
2 (7)
Number of Active joints - mean (range)
13 (5-50)
12 (5-49)
17 (5-50)
11 (5-41)
Physician Global Assessment of Disease Activity - mean (range)
6 (0-10)
5 (0-10)
6 (1-10)
6 (1-10)
Juvenile Arthritis Disease Activity Score - mean (range)
18 (5-29)
17 (5-29)
20 (6-29)
20 (14-28)
CHAQ Score - mean (range)
1 (0-3)
1 (0-3)
1 (0-3)
1 (0-3)
Oral steroids prescribed at baseline - N (%)
75 (27)
50 (28)
22 (33)
3 (10)
Trial registration identifying number
NCT02593006
Ethics Approval
Pro00054616 (Duke University)
Acknowledgements
The authors wish to acknowledge CARRA, and the ongoing Arthritis Foundation financial
support of CARRA.
P30 Factors related to sustained discontinuation of medications for well-controlled
JIA in the Childhood Arthritis & Rheumatology Research Alliance Registry
Daniel B. Horton1,2, Fenglong Xie3, Melissa L. Mannion3, Sarah Ringold4, Colleen K.
Correll5, Anne Dennos6, Timothy Beukelman3, for the CARRA Registry Investigators
1Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA; 2Rutgers Institute
for Health, Health Care Policy and Aging Research, New Brunswick, NJ, USA; 3University
of Alabama at Birmingham, Birmingham, AL, USA; 4Seattle Children's Hospital, Seattle,
WA, USA; 5University of Minnesota, Minneapolis, MN, USA; 6Duke Clinical Research Institute,
Durham, NC, USA
Background
Stopping medications is a priority for many patients with well-controlled JIA, but
few factors predict favorable outcomes after discontinuation. We examined factors
associated with sustained discontinuation off disease-modifying drugs in a large pediatric
registry.
Methods
We conducted a case-control study using the Childhood Arthritis & Rheumatology Research
Alliance Registry of clinical data from >55 pediatric rheumatology clinics in the
United States and Canada. The study included children with JIA who started at least
1 conventional or biologic DMARD and had at least 2 years of available subsequent
data. Reasons for drug discontinuation were obtained from the medication log. Cases
with sustained discontinuation had at least 1 year of drug-free follow-up after discontinuation
for well-controlled disease. Comparators included children who stopped DMARDs for
at least 30 days and restarted within 1 year (control group 1) and those who did not
discontinue all DMARDs for well-controlled disease for ≥30 days (control group 2).
Children in each group may have stopped DMARDs for reasons besides well-controlled
JIA. We excluded children with <1 year of follow-up off medicines without restarting
DMARDs. Characteristics of cases and controls were compared using descriptive statistics.
P-values were calculated by Wilcoxon rank sum testing for continuous variables and
by chi-square or Fisher's exact test for categorical variables.
Results
There were 1338 children with JIA in the study who started DMARDs, of whom 545 (41%)
stopped all drugs due to well-controlled disease after median 1.9 years of DMARD use
(interquartile range [IQR] 1.1, 3.2). Of these, 222 (41%) had sustained discontinuation
for ≥1 year (cases) and 323 (59%) restarted DMARDs within 1 year (control group 1)
(Table 1). In control group 1 with unsustained discontinuation, only 24 children (10%
of control group 1, or 2% of the total cohort) subsequently stopped all DMARDs for
≥1 year. Among all children in the study who started a DMARD, cases with sustained
discontinuation were younger at diagnosis (P < 0.01), more likely to have systemic
JIA and less likely to have RF+ polyarticular JIA (P = 0.03), less likely to have
complications from uveitis (P < 0.01), and less likely to have used a biologic DMARD
(<0.01). Compared with controls with unsustained discontinuation, cases were less
likely to have complications from uveitis (P = 0.05) or have used biologics (<0.01).
Time to diagnosis, history of uveitis, radiographic joint damage, and conventional
DMARD use were not associated with sustained discontinuation in either comparison.
Conclusion
In a large multicenter cohort of children with JIA on DMARDs, only 1 in 5 children
stopped DMARDs for well-controlled disease for at least 1 year. Lack of uveitis complications
and exclusive use of conventional DMARDs were associated with sustained discontinuation.
Table 1
(abstract P30). Characteristics of study subjects with JIA who started at least 1
DMARD
Characteristic (N, % unless otherwise noted)
Cases: off DMARDs ≥12 months1 (N=222)
Control group 1: off DMARDs <12 months1 (N=323)
Control group 2: not off DMARDs >30 days (N=793)
P-value2 (cases vs. control groups 1 and 2)
P-value2 (cases vs. control group 1)
Demographic
Age at diagnosis (years), median (IQR)
4.0 (2.0, 8.0)
4.0 (2.0, 8.0)
6.0 (2.0, 11.0)
<0.01
0.70
Time from symptom onset to diagnosis (days), median (IQR)
47 (29, 86)
58 (26, 92)
54 (29, 132)
0.49
0.61
Time from diagnosis to start of first DMARD (days), median (IQR)
37 (1, 201)
28 (1, 230)
34 (1, 350)
0.59
0.93
Time from start of DMARD to first DMARD discontinuation (years), median (IQR)
1.9 (1.2, 3.3)
1.9 (1.1, 3.1)
-
-
0.51
Time from start of first DMARD to end of follow-up (years), median (IQR)
6.0 (4.4, 8.8)
5.9 (3.9, 8.6)
4.2 (2.8, 6.7)
<0.01
0.26
Female sex
160 (72%)
253 (78%)
605 (76%)
0.13
0.09
White race
187 (84%)
272 (84%)
646 (82%)
0.47
0.99
Latino ethnicity
22 (13%)
22 (8%)
83 (12%)
0.83
0.46
Residence in US
217 (98%)
314 (97%)
770 (97%)
0.61
0.70
Clinical
JIA category
0.03
0.14
Systemic
33 (15%)
30 (12%)
107 (14%)
RF+ polyarticular
11 (5%)
19 (6%)
98 (12%)
Other
178 (80%)
272 (85%)
588 (74%)
≥5 total joints affected
193 (87%)
295 (91%)
719 (91%)
0.15
0.23
Radiographic evidence of joint damage
31 (14%)
56 (17%)
117 (15%)
0.55
0.28
ANA positive
96 (43%)
139 (43%)
334 (42%)
0.81
0.96
History of uveitis
19 (9%)
19 (6%)
80 (10%)
0.86
0.23
Uveitis complications
0
7 (2%)
22 (3%)
<0.01
0.05
Any conventional DMARD use
201 (91%)
287 (89%)
719 (91%)
0.86
0.53
Any biologic DMARD use
84 (38%)
174 (54%)
691 (87%)
<0.01
<0.01
ANA antinuclear antibody, DMARD disease-modifying antirheumatic drug, IQR interquartile
range, RF rheumatoid factor
1Refers to discontinuation from all DMARDs for at least 30 days for well-controlled
JIA
2P-values calculated by Wilcoxon rank sum testing for continuous variables and chi-square
or Fisher's exact test for categorical variables
Ethics Approval
The study was approved by University of Alabama's Institutional Review Board, protocol
number X170112004.
Funding
Funding for this work came from a CARRA-AF Publication Support Grant.
P31 Characteristics of patients enrolled in the FiRst line options for systemic jia
treatment (FROST) Consensus Treatment Plan study
Timothy Beukelman1, Peter A Nigrovic2, George Tomlinson3, Vincent Del Gaizo, Marian
Jelinek, Laura E. Schanberg4, Anne Dennos4, Mary Ellen Riordan5, Yukiko Kimura5, for
the CARRA Registry FROST Investigators
1University of Alabama at Birmingham, Birmingham, AL, USA; 2Brigham and Women’s Hospital,
Harvard University, Boston, MA, USA; 3University of Toronto, Toronto, ON, Canada;
4Duke University, Durham, NC, USA; 5Hackensack University Medical Center, Hackensack,
NJ, USA
Background
The optimal initial treatment for systemic juvenile idiopathic arthritis (sJIA) is
unclear. Uncontrolled reports suggest that early treatment with biologic agents likely
produces superior short-term clinical outcomes, but many patients may respond well
to non-biologic therapies. To further study the initial treatment of sJIA, the Childhood
Arthritis and Rheumatology Research Alliance (CARRA) developed Consensus Treatment
Plans (CTPs) to formalize and standardize current treatment practices. Subsequently,
4 CTPs were developed: initial systemic glucocorticoid (GC); initial methotrexate
(MTX) +/- GC; initial IL-1 inhibition (IL-1i) +/- GC; and initial IL-6 inhibition
(IL-6i) +/- GC. The FiRst Line Options for Systemic JIA Treatment (FROST) is an observational
study designed to assess the effectiveness and safety of each of the 4 CTPs and to
the compare the CTPs containing initial biologic therapy (IL-1i and IL-6i) to those
that do not contain initial biologic therapy (GC and MTX).
Methods
Patients with recent onset sJIA who are initiating therapy are considered for enrollment
in FROST. In order to be eligible for FROST, participants must have fever for ≥2 weeks,
arthritis for ≥ 10 days, and at least 1 of the following: evanescent rash, generalized
lymphadenopathy, hepatomegaly, splenomegaly, or serositis. Treatment assignment is
at the discretion of the treating physician and family. All data are collected in
the CARRA Registry. To date, 43 CARRA Registry sites have been activated to enroll
FROST patients. Biosamples are collected at baseline and at 6 months. Patient reported
outcomes (PRO) of presence of fever and rash and pain scores are collected at home
using mobile devices every 2 days during the first 2 weeks of the study. The primary
study outcome is clinical inactive disease (Wallace ACR provisional definition) and
cessation of glucocorticoid therapy at 9 months.
Results
Enrollment in the FROST study began in November 2016. As of January 2018, 21 patients
have been enrolled at 13 sites, and their baseline characteristics are shown in the
Table 1. Overall, 11 participants (52%) have completed every requested home PRO during
the first 2 weeks of the study, and 15 (71%) have completed ≥50% of the requested
home PRO. Study follow-up continues to accrue. Five patients (25%) have completed
the 9-month study visit when the primary study outcome is assessed. Nine patients
(43%) overall have completed the 6-month visit. Of the 20 participants, 10 (50%) had
baseline biosamples collected.
Conclusion
Enrollment in the FROST study has begun. Participants enrolled thus far appear to
be representative of the general population of patients with sJIA. Home PRO collection
is feasible through the CARRA Registry. Additional time is needed to enroll and observe
a sufficient number of patients to assess the comparative effectiveness of initial
treatments for sJIA.
Table 1
(abstract P31). Characteristics of Participants in FROST (N=20)
Characteristic
Overall(N=20)
Age (mean (sd)
7.85 (5.33)
Female (%)
10 (50%)
White Race (%)
10 (52.6%)
Black Race (%)
3 (15.8%)
Other Race (%)
6 (31.6%)
Elapsed Days Since Onset of Symptoms (mean (sd))
47 (58)
Elapsed Days Since Diagnosis (mean (sd))
7 (7)
Physician Global Assessment (mean (sd))
6.00 (2.22)
Parent Global Assessment (mean (sd))
4.53 (3.43)
Number of Active Joints (mean (sd))
5.80 (5.59)
Morning Stiffness >15 minutes (60%)
12 (60%)
ESR (median (IQR))
58 (42-83)
C-RP (median (IQR))
10.6 (6.6-32.1)
Ferritin (median (IQR))
891 (284-1510)
Hemoglobin (median (IQR))
10.2 (9.5-11.3)
WBC (median (IQR))
14.9 (10.5-20.3)
Platelets (median (IQR))
368 (294-510)
AST (median (IQR))
34 (23-45)
ALT (median (IQR))
34 (16-51)
CHAQ (mean (sd))
1.00 (0.86)
Pain VAS (mean (sd))
3.5 (3.332)
P32 Systemic juvenile idiopathic arthritis inactive disease and withdrawal of medications:
a survey of the Childhood Arthritis and Rheumatology Research Alliance
Kabita Nanda1, Susan Shenoi1, Ashley Cooper2, Bridget Edghill3, Miriah Gillispie4,
Baruch Goldberg5, Olha Halyabar6, Daniel B. Horton7, Thomas G. Mason8, Tova Ronis9,
Rayfel Schneider10, Grant Schulert11, Richard Vehe12, Karen Onel13, for the SJIA workgroup
of the CARRA JIA subcommittee
1Seattle Children’s Hospital, University of Washington School of Medicine, Seattle,
WA, USA; 2Children’s Mercy-Kansas City, University of Missouri-Kansas City, Kansas
City, MO, USA; 3Comminuty stakeholder CARRA member; 4Texas Children’s Hospital, Baylor
College of Medicine, Houston, TX, USA; 5McGovern Medical School at UT Health, Houston,
TX, USA; 6Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA; 7Rutgers
Robert Wood Johnson Medical School, New Brunswick, NJ, USA; 8Mayo Clinic, Rochester,
MN, USA; 9Children’s National Health System, The George Washington School of Medicine,
Washington, DC, USA; 10The Hospital for Sick Children, University of Toronto, Toronto,
ON, Canada; 11Cincinnati Children’s Hospital, University of Cincinnati College of
Medicine, Cincinnati, OH, USA; 12Masonic Children’s Hospital, University of Minnesota,
Minneapolis, MN, USA 13 Hospital for Special Surgery, Weill Cornell Medical College,
New York, NY, USA
Correspondence: Kabita Nanda
Background
There has been rapid development in new treatments for systemic juvenile idiopathic
arthritis (SJIA) but there is no consensus on when and how to withdraw medications.
There are validated criteria for clinical inactive disease (CID) in juvenile idiopathic
arthritis (JIA); however, as SJIA is considered an autoinflammatory disease there
may be additional criteria to consider. The SJIA CARRA workgroup sought to obtain
opinions on CID in SJIA and how physicians approach withdrawal of medications.
Methods
An anonymous electronic survey using REDCap was sent to 100 randomly selected voting
members of CARRA. The survey elicited physicians’ opinions on CID in SJIA and physicians’
current approaches to withdrawal of medications in CID. Descriptive statistics were
used to analyze the data.
Results
Eighty-three of the 100 surveyed CARRA members completed the survey including 7 members
that opted out, as they are not involved in clinical care of SJIA. The vast majority
of participants (88%) agreed with the current criteria for CID in SJIA. Stated reasons
for dissent included lack of ferritin and other inflammatory markers in the criteria,
presence of uveitis in the criteria, preference for extending duration of morning
stiffness, preference for changing duration of time required for CID, imprecision
of physician global score and lack of patient/parent-reported outcomes. Ninety-three
percent agreed with the current definition for clinical remission on medications (CRM)
in SJIA. Disagreement was due to preference for 1 year (not 6 months) of inactive
disease to meet CRM. Most felt it was necessary to meet CRM (78%) before tapering
medications other than steroids, but others stated preferences for withdrawing other
therapy before 6 months of CID. Most members (76%) reported using the CARRA SJIA consensus
treatment plans always or the majority of the time. All members reported that they
weaned steroids first in SJIA patients on combination therapy, 47% reported waiting
greater than 6 months before tapering additional medications, and 37% preferred waiting
only 2-6 months. An equal number of members (35% each) reported tapering methotrexate
over more than 6 months and 2-6 months; however a higher proportion (39%) preferred
tapering anakinra, canakinumab and tocilizumab more quickly over 2-6 months and favor
spacing the dosing interval for canakinumab and tocilizumab. When patients are on
combination therapy with methotrexate and biologics, 58% preferred tapering methotrexate
first while most others would consider patient/family preference and adverse effects
to guide their choice.
Conclusion
Most CARRA members surveyed are using previously published consensus treatment plans
for SJIA and agreed with validated definitions of CID and CRM. There was also agreement
with tapering steroids first in SJIA, but there was considerable variability with
all other medications. Further work will need to be done to develop consensus in withdrawal
plans for medications in SJIA.
Ethics Approval
The study was approved by Seattle Children’s Hospital’s Internal Review Board, ID:
STUDY00000532, and Hospital for Special Surgery’s Internal Review Board, ID: 2017-0276.
P33 The lupus cohort in the New CARRA Registry: 10 months of enrollment
Mary Beth Son1, Stacy P. Ardoin2, Aimee O. Hersh3, Deborah Levy4 for the CARRA Registry
Investigators
1Boston Children’s Hospital, Boston, MA, USA; 2Nationwide Children’s Hospital, Columbus,
OH, USA; 3University of Utah, Salt Lake City, UT, USA; 4Hospital for Sick Children,
Toronto, Canada
Correspondence: Mary Beth Son
Background
The New CARRA Registry has enrolled patients with systemic lupus erythematosus (SLE)
and related conditions since March 2017. We sought to describe the population enrolled
thus far and to demonstrate the breadth and utility of the data generated by the New
CARRA Registry.
Methods
We requested de-identified counts of several fields collected from the case report
forms for subjects with SLE. Patients were eligible for enrollment in the New CARRA
registry if they were diagnosed with SLE or had a flare of lupus nephritis within
two years of the baseline visit. IRB approval was not required for this data request.
Results
To date, 102 patients (pts) have been enrolled; 88 (86%) are female. There are 30
black pts, 28 Hispanic pts, 27 white pts, 7 Asian pts and 6 pts were >1 race. Over
half the pts have private health insurance (n=57, 56%) and 35 pts (34%) have Medicaid.
96 pts were ANA positive. The distribution of autoantibodies documented at the baseline
visit is shown in Table 1. At the baseline visit, the mean Systemic Lupus Erythematosus
Disease Activity Index (SLEDAI, n=98) score was 6.6 ± 6.5, median =6 (range 0-37).
The mean Systemic Lupus International Collaborating Clinic Damage Index (SLICC DI,
n=86) score was 0.4, median=0 (range 0-4). Nearly 85% of pts were prescribed corticosteroids
at the baseline visit. A quarter of pts (n=26) were being treated for lupus nephritis
at the time of the baseline visit. Manifestations of SLE at the baseline visit were
varied (Table 2) but serologic disease, mucocutaneous disease and active nephritis
were the most prevalent.
Conclusions
Over a hundred SLE pts have been enrolled in the New CARRA Registry to date. This
is a multi-racial cohort with moderate disease activity and varied disease manifestations.
Further enrollment will continue to build a robust data source to study disease course
and outcomes in an incipient pediatric SLE cohort.
Table 1
(abstract P33). Auto-Antibody Data Documented at Baseline Visit (n=102)
Positive Auto-Antibodies
N (%)
ANA
96 (94%)
Anti-Smith
50 (49%)
Anti-dsDNA
61 (60%)
Anti-RNP
53 (52%)
Anti SSA
32 (31%)
Anti SSB
17 (16.7%)
Anti β2 glycoprotein I IgG
6 (5.9%)
Anti Cardiolipin IgG
18 (17.7%)
Lupus anti-coagulant
15 (14.7%)
Table 2
(abstract P33). Components of SLEDAI Present Within 30 days of Baseline Visit (n=98)
SLEDAI Component
N (%)
Seizure
1 (1%)
Psychosis
1 (1%)
Organic Brain Syndrome
0
Visual Disturbance
1 (1%)
Cranial Nerve Disorder
0
Lupus Headache
4 (3.9%)
Cerebrovascular Accident
0
Vasculitis
2 (2%)
Arthritis
16 (15.7%)
Myositis
5 (4.9%)
Urinary Casts
18 (17.6%)
Hematuria
9 (8.8%)
Proteinuria
9 (8.8%)
Pyuria
8 (7.8%)
Rash
21 (20.6%)
Alopecia
7 (6.9%)
Mucosal Ulcers
15 (14.7%)
Pleurisy
0
Pericarditis
0
Low Complement
45 (44.1%)
Increased DNA Binding
34 (33.3%)
Fever
7 (6.9%)
Thrombocytopenia
4 (3.9%)
Leukopenia
13 (12.7%)
P34 Towards a better understanding of childhood Sjögren syndrome: evaluation of the
2016 ACR/EULAR classification criteria for use in diagnosing Sjögren syndrome in children
Sara Stern1, Jay Mehta2, Scott Lieberman3 for the International Childhood Sjögren
Syndrome Workgroup
1Department of Pediatrics, University of Utah Health Sciences Center, Salt Lake City,
UT, USA; 2Department of Pediatrics, University of Pennsylvania Perelman School of
Medicine, Philadelphia, PA, USA; 3Stead Family Department of Pediatrics, University
of Iowa, Iowa City, IA, USA
Background
Clinical presentation of Sjögren syndrome in children differs from that in adults:
dryness symptoms are more common in adults, while parotitis is more common in children.
Criteria developed for adult classification have demonstrated low sensitivity when
applied to pediatric populations, and no child-specific criteria have been established.
The latest adult classification criteria have not yet been evaluated for use in children.
Our objective was to evaluate the applicability of these new criteria for use in children.
Methods
Retrospective chart reviews were conducted to collect individual patient level data
for children diagnosed with Sjögren syndrome (based on clinical diagnosis at age <18
years). Data including clinical features, laboratory values, imaging studies, and
test items in the 2016 ACR/EULAR criteria were collected, and de-identified data were
entered into a REDCap database. This study was approved by the Institutional Review
Boards or equivalent regulatory bodies at individual affiliate institutions.
Results
To date, 94 children with Sjögren syndrome were included from 12 institutions across
4 countries–data collection is ongoing. This constitutes the largest childhood Sjögren
syndrome patient series to date. The majority of children (90%) were female with a
mean age of 11.6 years at diagnosis (range 1–17.8 years). Fourteen children (15%)
also had another autoimmune disease (9 with SLE, 2 with uveitis, 1 with MCTD, 1 with
myositis/overlap, 1 with subacute cutaneous lupus). Frequency of clinical features
were as follows: 53% with dry eyes, 52% with dry mouth, 50% with parotitis, 44% with
arthralgias without arthritis, 24% with lymphadenopathy, 27% with arthritis, 14% with
cytopenias, 15% with fevers, 12% with cutaneous vasculitis, and ≤10% each with weight
loss, recurrent vaginitis, myositis, pulmonary, renal, or neurologic manifestations.
Only 6 children had testing for all 5 items included in the 2016 ACR/EULAR criteria.
Most children (95%) had testing for anti-SSA antibodies, but fewer underwent minor
salivary gland (MSG) biopsy (53%), Schirmer testing (53%), unstimulated whole saliva
flow (UWSF, 16%), or ocular surface staining (OSS, 20%). While most children studied
(94%) were missing at least one data point, 32 of 94 children (34%) met the 2016 ACR/EULAR
classification criteria for Sjögren syndrome. Of these 32 children: 29 (91%) had positive
anti-SSA antibodies; 21 (66%) had positive MSG biopsy; 25 (78%) had positive Schirmer
test; 3 (9%) had positive UWSF; and 1 (3%) had positive OSS. Of the 62 children not
meeting criteria: 39 (63%) had positive anti-SSA antibodies; 7 (11%) had positive
MSG biopsy; 8 (13%) had positive Schirmer test; and 3 (5%) had positive UWSF.
Conclusions
Criteria items from the 2016 ACR/EULAR criteria are not routinely assessed in children
diagnosed with Sjögren syndrome making formal retrospective assessment of criteria
difficult. Prospective study of these criteria along with defining child-specific
normal values and adding child-specific criteria items (such as recurrent parotitis)
are warranted. Establishing criteria for childhood Sjögren syndrome is a key step
toward better understanding this condition.
P35 Consenting for Biological specimens collection: the healthcare provider and research
coordinator perspective
Y. Ingrid Goh1,2, Lauren A. Henderson3, Jennifer M.P. Woo4, Marsha Malloy5, Mary Ellen
Riordan6, CARRA Research Coordinator Advisory Committee (RCAC), CARRA Translational
Research and Technology Committee (TRTC) Biobanking Workgroup
1Division of Rheumatology, The Hospital for Sick Children, Toronto, Ontario, Canada;
2Child Health Evaluative Sciences, SickKids Research institute, Toronto, Ontario,
Canada; 3Division of Immunology, Boston Children’s Hospital, Boston, Massachusetts,
USA; 4Division of Pediatric Rheumatology, UCLA Mattel Children’s Hospital, Los Angeles,
California, USA; 5Division of Rheumatology, Medical Center of Wisconsin, Milwaukee,
Wisconsin, USA; 6Department of Pediatric Rheumatology, Hackensack Meridian Health,
Joseph M. Sanzari Children’s Hospital, Hackensack, New Jersey, USA
Correspondence: Y. Ingrid Goh
Background
Biological specimens are important as they enable researchers to elucidate the links
between biological pathways and disease manifestation. Specimens can be used to provide
insight about why things happen; who is at risk; how it happens; understand what happens
in the body; and how to improve diagnosis and treatment. The knowledge garnered through
these specimens can ultimately lead to personalized medicine.
Biological specimen collection for Childhood Arthritis and Rheumatology Research Alliance
(CARRA) started in 2017. To date, specimens have been collected from over 60 unique
pediatric patients with rheumatologic disease residing in North America who were initiating
medications.
Recruiting newly diagnosed pediatric patients can be a challenging feat as this is
an emotional and psychologically taxing time for patients and their family. The objective
of this project was to identify best practices that can be used by CARRA clinicians
and research coordinators when consenting patients to donate biological specimens
for research.
Methods
Members of the CARRA Translational Research and Technology Committee (TRTC) Biobanking
Workgroup were asked to identify key points that are commonly discussed during the
biological specimen consent process. They were also asked to provide examples of specific
language used during the consent process. These items were collectively reviewed and
discussed during a series of conference calls with TRTC Biobanking Workgroup and the
CARRA Research Coordinator Advisory Committee (RCAC). A single document containing
the items was prepared and underwent a final review by the TRTC Biobanking Workgroup
and RCAC.
Results
Key points were received from CARRA TRTC biobank subgroup and RCAC members representing
five unique CARRA sites. After reviewing, discussing, and consolidating, 14 main topics
were identified as important items to address during the consent process. In addition
to these themes, it was thought to be beneficial, and at some institutions required,
to have a member of the healthcare team introduce the study prior to consent in order
to establish rapport. It was unanimously agreed that it is important to spend time
educating patients and their families about what research is and what it could potentially
mean for them and future patients. It was deemed important to use clear and approachable
language that patients and their families could understand when explaining the requirements
of the proposed research.
Conclusion
The key elements identified by the CARRA TRTC Biobanking Workgroup and RCAC have been
made available to CARRA members on the CARRA Coordinator internal webpage. The key
points will be reviewed with the wider CARRA Research Coordinator Network during the
2018 CARRA meeting. We anticipate that this information will be beneficial to less
experienced teams or teams that are experiencing difficulty recruiting patients to
participate in biological specimen collection.
P36 Validation of synovial fluid biomarkers for prediction of extension in oligoarticular
juvenile idiopathic arthritis
AnneMarie C. Brescia1, Megan M. Simonds2, Suzanne M. McCahan2, H. Timothy Bunnell2,
Kathleen E. Sullivan3, Carlos D. Rose1
1Nemours/AI DuPont Hospital for Children, Wilmington, DE, USA; 2Nemours Biomedical
Research, Wilmington, DE, USA; 3Pediatric Immunology, Children’s Hospital of Philadelphia,
PA, USA
Correspondence: AnneMarie C. Brescia
Background
Our goal is validation of synovial biomarkers to predict which children with oligoarticular
juvenile idiopathic arthritis (JIA) will have persistent vs. extended course. We previously
identified 5 candidate biomarkers from gene expression data of fibroblast-like synoviocytes
(FLS) of 12 P and 7 E patients1. In the current study, we are expanding the pool of
potential biomarkers using antibody array.
Methods
As part of an ongoing IRB approved protocol, remnant synovial fluid was obtained from
patients undergoing medically indicated arthrocenteses. Using our clinical database,
JIA samples were separated into two groups: (1) oligoarticular JIA with persistent
course (P), (2) oligoarticular JIA with extended course, prior to extension (E). Using
synovial fluid samples from 4 P and 4 E patients, RayBiotech Membrane-based Antibody
Arrays were completed for expression of 89 cytokines, chemokines, and other inflammatory
proteins and intensity measured using ImageJ. Twenty proteins were differentially
expressed between P and E. We chose 6 biologically relevant differentially expressed
proteins identified in synovial fluid by antibody arrays (angiogenin, IL-5, VEGF,
IL-1α, IL-6 and IL-3) to add to our already identified group of candidate biomarkers
from our gene expression data (MBP, ANKRD44, HSPBAP1, KLHL13, and CD14). To translate
these differences into a clinically testable biomarker panel, we tested the corresponding
synovial fluids for protein levels by ELISA. We conducted extensive chart review to
identify as yet untested samples for biomarker validation testing (exclusions included,
but were not limited to: prior injection, medications besides non-steroidal anti-inflammatory
medications, already extended at time of sample, co-morbid conditions with associated
arthropathy). We tested synovial fluid from 14 P and 8 E, which had been blinded by
an honest broker. Using statistical cutoffs for each protein as determined by ELISA,
each blinded sample was assigned to a group, P or E.
Results
We have completed this validation for 5/11 of the candidate biomarkers so far. The
performance of each protein to correctly assign an E sample (sensitivity) and as not
likely to extend (remain P, specificity) is shown in Table 1. There was reasonable
specificity for all the biomarkers, however, CD14 was the most specific. IL-6 was
the most sensitive for accurately predicting which synovial fluid came from patients
who would ultimately extend.
Conclusion
We have been able to demonstrate differential synovial fluid protein expression from
JIA patients who remained P vs those who are destined to extend, demonstrating detectible
difference early in disease that may be useful for prediction. We are now looking
to validate these potential biomarkers on a new larger validation cohort from outside
our institution.
Ethics Approval
The study was approved by Nemours Internal Review Board, (84709, 82053).
Table 1
(abstract P36). Sensitivity and Specificity of each biomarker to assign blinded samples
to the correct group, extended or persistent
Sensitivity
Specificity
CD14
29%
86%
IL-1alpha
14%
50%
IL-5
57%
64%
IL-6
71%
71%
IL-3
14%
71%
Reference
1 Pediatric Rheumatol 2018 Jan 8;16(1):3. 10.1186/s12969-017-0217-6.
P37 Chondrocyte conditioned media influences TGFβ and BMP signaling pathways in both
normal and juvenile idiopathic arthritis fibroblast-like synoviocytes
Amanda R. Schlefman1, Megan M. Simonds2, Kathleen E. Sullivan3, Carlos D. Rose1 and
AnneMarie C. Brescia1
1Nemours/Thomas Jefferson University, Wilmington, DE, USA; 2Nemours Biomedical Research,
Wilmington, DE, USA; 3Department of Pediatrics, University of Pennsylvania, Philadelphia,
PA, USA
Correspondence: Amanda R. Schlefman
Background
Juvenile Idiopathic Arthritis (JIA) is complicated by localized growth disturbances
including condylar bony hypertrophy. Fibroblast-like synoviocytes (FLS) are one of
the main cell types in the joint lining and, based on their role in cartilage damage
in adult rheumatoid arthritis, may play a role in the growth alteration seen in JIA.
Our prior work has shown that JIA FLS (JFLS) have a chondrocyte-like phenotype, possibly
due to dysregulated TGFβ and BMP signaling, which may contribute to bony overgrowth.
This study was designed to investigate the influence of chondrocytes (Ch) on FLS,
relative to TGFβ and BMP signaling.
Methods
Three JFLS samples were selected from our IRB-approved tissue and fluid repository.
We purchased a normal Ch line and three control FLS (CFLS) cell lines. At confluence,
the Ch culture media was replaced with fresh Ch growth media and Ch grew untreated
for 48 hours. Confluent JFLS and CFLS cells were then trypsinized and resuspended
in Ch conditioned media. After plating, cell media and cell lysates were collected
at 6 and 24 hours. RNA was isolated from cell lysates and analyzed using GeneChip
Whole Transcriptome Expression Analysis. Quantitative PCR (Q-PCR) was used to validate
microarray findings. Ingenuity Pathway Analysis (IPA) software was used to identify
significant differentially expressed genes in the TGFβ and BMP signaling pathways.
Results
Differentially expressed probe sets were identified among CFLS (1145 probe sets) and
JFLS (847 probe sets), both exposed to Ch conditioned media, with an FDR of 5%. A
set of 10 genes was chosen for validation from the following comparisons based on
most significant p-values: CFLS 6 h vs. 24 h, and JFLS 6 h vs. 24 h. Q-PCR analysis
confirmed that these genes were either upregulated or downregulated in CFLS (Figure
1A) or JFLS (Figure 1B), in accordance with what was seen on microarray.
Using gene lists generated in IPA for TGFβ and BMP signaling pathways, we identified
21 significant overlapping differentially expressed genes within our microarray comparisons
(Figure 2A and 2B). SMAD6, SKI and BMPR1a were all upregulated over the time course
in both CFLS and JFLS. SMAD9 and BMP1 expression increased by 2-fold and 1.5-fold,
respectively, in CFLS at 24 h compared to 6 h. SOS1 had a 1.6-fold higher expression
level in JFLS at 24 h compared to 6 h. SMAD3 was downregulated over time in both CFLS
and JFLS. BMPR1b and TGFβ3 expression decreased by 1.5-fold and 2-fold, respectively,
in CFLS at 24 h compared to 6 h. SMURF1 had a 1.3-fold lower expression level in JFLS
at 24 h compared to 6 h.
Conclusion
Ch influence TGFβ and BMP signaling in FLS in vitro. Hypertrophic Ch lead to bony
overgrowth. Significant differences in gene expression were identified when comparing
6 h and 24 h samples from CFLS and JFLS exposed to Ch conditioned media. Upregulation
of inhibitors such as SMAD6 and SKI suggest an overall decrease in canonical TGFβ
signaling. Downregulation of SMAD3 and TGFβ3 also support this conclusion. Higher
expression of SMAD9 and BMP1 suggest that BMP signaling is favored. SOS1, a member
of the non-canonical TGFβ signaling pathway, is of interest as it was significantly
expressed in JFLS.
Ethics Approval
This study was approved by Nemours Institution’s Internal Review Board, approval #2001-013.
Fig. 1
(abstract P37). Genes selected for validation by Quantitative PCR from microarray
analyses. Top 10 significantly expressed genes, based on p-values, from (A) 6 h and
24 h CFLS samples exposed to Ch conditioned media and (B) 6 h and 24 h JFLS samples
exposed to Ch conditioned media.
Fig. 2
(abstract P37). Differentially expressed genes derived using IPA software from (A)
CFLS and (B) JFLS, both exposed to Ch conditioned media over 24 h, in the TGFβ and
BMP signaling pathway.
P38 Comparison of pediatric localized scleroderma (LS) to healthy pediatric controls
utilizing RNA sequencing for differentially expressed genes (DEGs)
Roosha Mandal1,2, Emily Mirizio1, Qi Yan1, William Horne1, Kaila Schollaert-Fitch1,
Kathryn S. Torok1
1University of Pittsburgh, Pittsburgh, PA, USA; 2Carnegie Mellon University, Pittsburgh,
PA, USA
Background
Pediatric localized scleroderma (LS) is a disfiguring autoimmune disease of the skin
and underlying tissue. Smoldering disease activity leads to fibrosis and atrophy,
causing physical and psychological disability that continues throughout childhood
into adulthood. Available therapies for LS have had variable effects and are associated
with morbidity themselves. A better understanding of the pathophysiology of LS, especially
during the active inflammatory phase, would lead toward more directed and efficacious
therapies.
RNA sequencing (RNAseq) technology provides a new approach for investigating disease
operation and cellular influence by probing the genetic expression seen in direct
samples. This technique also provides utility for existing paraffin-embedded skin
tissue from patients that can be used to extract RNA for the investigation of differential
gene expressions (DEGs) relating to the immunophenotype of the disease.
Methods
RNAseq was performed on skin (n = 3 LS, n = 1 Healthy Child) and corresponding peripheral
blood (n = 2 LS, Healthy Child =1) samples. Fastq files (4 reads per sample) from
sequencing were analyzed via CLC Genomics software identifying DEGs between groups
by value of 2.5 log2fold change and p-values < 0.05. String-db opensource database
networks and Cytoscape networks were generated based on probable significant gene
lists resulting from Cluster 3.0 hierarchical clustering and CLC Genomics analyses.
Results
Genes of interferon inducible cytokines such as CXCL9, CXCL10, CXCL11, as well as
IFN-γ itself, were significantly upregulated with an absolute log2fold >2.5 in both
the peripheral blood and skin of LS subjects compared to healthy (Figure 1). String-db’s
gene ontology (GO) organization indicated groupings of biological processes involved
with the IFN-γ and TH1cellular response, such as CXCR3 receptor binding related CXCL9,
CXCL10, and CXCL11, and T-helper 1 type immune response, showed absolute log2fold
changes >7 in the LS skin samples and log2fold change values >2.55 in the peripheral
blood compared to control.
Conclusion
In this pilot study of LS skin and peripheral blood RNA Seq analyses a signature of
TH1 and IFN-γ - related genes were upregulated and were found to be networking with
other genes associated with these biological processes, such as chemokine-mediated
signaling pathway and regulation of T cell activation. These findings underscore the
potential importance IFN-γ and TH1-related interactions in the skin and the blood
of LS subjects. Evaluating a larger sample size and cross validating results from
CLC genomics in R is underway.
Fig. 1
(abstract P38). Log2fold change comparison for IFN-γ and TH-related DEGs in LS blood
vs. LS skin
Acknowledgements
This study received funding from the Nancy Taylor Foundation for Chronic Diseases
Inc. and the Children’s Hospital of Pittsburgh Pediatric Scleroderma Fund.
P39 High dimensional single-cell mass cytometry demonstrates distinct immune phenotypic
and functional signatures in pediatric SLE and malaria patients
Ryan Baxter, Josselyn Garcia Perez, Daniel Kong, Sidney Ogolla, Brianne Coleman, Conner
Jackson, Xuhong Zhang, Debashis Ghosh, John Cambier, Rosemary Rochford, Elena Hsieh
University of Colorado Denver, Aurora, Colorado, USA
Correspondence: Ryan Baxter
Background
A long-standing paradox is the reduced incidence of autoimmune diseases in areas of
the world where parasitic diseases are common. In both disorders, SLE and malaria,
patients are exposed to chronic antigen stimulation and both develop similar immunophenotypes,
with increased frequency of atypical and transitional B cells, hypergammaglobunemia,
the presence of autoantibodies, and a robust systemic inflammatory response. However,
mechanisms as to why chronic antigen exposure leads to the development of autoimmunity
in SLE versus autoantibodies alone in malaria are not understood. We applied mass
cytometry to evaluate the immune phenotypic and functional differences between children
with autoantibodies and SLE, versus those with autoantibodies induced by malaria infection,
to help elucidate what drives the transition to autoimmune disease.
Methods
Peripheral whole blood samples from 12 pediatric SLE (new diagnosis, flare, and inactive
states) from the US, and 12 pediatric malaria patients from Kenya (acute infection
and convalescent period) were analyzed by mass cytometry to simultaneously assess
surface marker expression (phenotype) and cytokine production (function). Healthy
age and gender-matched control samples from the US and Kenya were also similarly analyzed.
All human donors were enrolled under a study protocol approved by the Institutional
Review Board of the Research Compliance Office at the University of Colorado.
Results
CD14hi monocytes from every pediatric SLE patient studied expressed a unique cytokine
signature characterized by increased levels of monocyte chemoattractant protein-1
(MCP1), macrophage inflammatory protein-1β (Mip1β), and interleukin-1 receptor antagonist
(IL-1RA), compared to malaria-infected patients, and age and gender-matched healthy
controls. Pediatric malaria-infected patients demonstrated an expansion of T follicular
helper cells and effector memory T cells during acute infection timepoints only, compared
to pediatric SLE patients and age and gender-matched healthy controls. These distinct
and unique immune phenotypic and functional signatures were conserved between children
of the same disease group, suggesting that genetic predisposition (risk alleles) rather
than environmental variation programs the response profile to chronic antigen stimulation.
Conclusion
These tightly regulated immune phenotypic and functional signatures provide clues
into specific pathways that lead to the development of autoantibodies in autoimmunity
versus autoantibodies induced by infection. This experimental approach can be applied
to uncover immune dysregulation defects in autoimmunity and infection.
P40
This abstract is not included here as it has already been published.
P41 Variations in zinc finger protein gene might impact expression of transient receptor
potential channel and receptor tyrosine kinase genes contributing to inflammasome
dependent inflammatory response and development of clavicular cortical hyperostosis
Lovro Lamot1,2, Kristina Gotovac1, Antonela Blažeković1, Danka Grčević1, Mirta Lamot2,
Mandica Vidović2, Fran Borovečki1, Miroslav Harjaček1,2
1University of Zagreb School of Medicine, Zagreb, Croatia; 2Clinical Hospital Center
Sestre Milosrdnice, Zagreb, Croatia
Correspondence: Lovro Lamot
Background
Unilateral painful swelling of the clavicle might be the first symptom of chronic
nonbacterial recurrent multifocal osteomyelitis (CNO/CRMO), but when lacking other
inflammatory sites and recurrence, it might also be regarded as clavicular cortical
hyperostosis (CCH), separate condition of unknown etiology. To elucidate underlying
mechanisms of this disorder we performed various genome, transcriptome and proteome
analysis.
Methods
Total RNA was isolated from whole blood of 18 new-onset CCH patients and 8 healthy
controls, while DNA was extracted from three patients. Targeted exome sequencing was
performed using the Nextera Rapid Capture Exome Kit (Illumina). The extracted variants
were annotated and filtered using the Variant Studio software (Illumina) and Variant
Interpreter (Illumina). DNA microarray gene expression was performed in five CCH and
four control patients along with bioinformatical analysis of retrieved data. Carefully
selected differentially expressed genes (TRPM2, TRPM3, TRPM7, CASP2, MEFV, STAT3,
EIF5A, ERBB2, TLR4, NLRP3, CD24, MYST3) were additionally analyzed by qRT-PCR in all
participants. In one patient, the blood cells were processed with cytosine for immunofluorescence
microscopy (IF) using TRPM3 and TRPM7 antibody.
Results
Exome sequencing identified 428 shared identical variants among affected individuals.
Thirty of these variants were not associated with a gene, 121 were in ZNF717 gene
and 277 were distributed in 63 other genes. One heterozygous variant in CTBP2 gene,
one in HYDIN gene and six in ZNF717 were classified as likely pathogenic. Microarray
results and bioinformatical analysis revealed 974 differentially expressed genes,
while qRT-PCR analysis showed significantly higher expression of TRPM3 and TRPM7,
and lower expression of ERBB2. IF showed high signal of TRPM3 in blood cells of CCH
patient.
Conclusion
Broad investigation of genetic contribution in CCH patients revealed likely pathogenic
variants in ZNF717 gene which encodes a Kruppel-associated box (KRAB) zinc-finger
protein from the large group of transcriptional regulators and probably influences
observed gene expression patterns. Diligent analysis of those patterns indicated majority
of differentially expressed genes were involved in various inflammatory processes,
while further investigation confirmed aberrant expression in additional number of
patients. Most significant expression divergence was detected in TRPM3 and TPRM7 genes
which encodes transient receptor potential channels that are multimodal sensors able
to regulate inflammasome and ERBB2 gene which encodes widely expressed cell surface
growth factor receptor capable to protect cells during inflammation. Moreover, TRPM3
protein was abundant in blood cells of CCH patient confirming the increased function
of this gene. Consequently, our results along with the results of previous studies
imply CCH could be a new (auto)inflammatory bone disease entity in which ZNF717 variations
could contribute to TRP channel overexpression and abundancy, inflammasome activation
and reduced protection during inflammation.
Ethics Approval
The study was approved by Clinical Hospital Center Sestre Milosrdnice Institutional
Review Board (IRB).
P42 Transcription factor set binds multiple juvenile idiopathic arthritis genetic
susceptibility loci
Halima Moncrieffe1,2, Leah C. Kottyan1,2, Xiaoting Chen1, Mario Pujato1, John B. Harley1,2,3,
Matthew T. Weirauch1,2 and Susan D. Thompson1,2
1Center of Autoimmune Genomics and Etiology (CAGE), Cincinnati Children’s Hospital
Medical Center, Cincinnati, OH, USA; 2Department of Pediatrics, University of Cincinnati
College of Medicine, Cincinnati, OH, USA; 3US Department of Veterans Affairs Medical
Center, Cincinnati, OH, USA
Correspondence: Halima Moncrieffe
Background
Juvenile idiopathic arthritis (JIA) genetic association studies have identified 17
loci (p<5×10-8) and 21 additional loci with suggestive evidence of association (p<1×10-6).
As the majority of these genetic associations are located in non-coding regions of
the genome, we tested the hypothesis that specific transcription factors (TFs) bind
DNA at multiple JIA-associated genetic loci.
Methods
We defined a locus as those variants that had disequilibrium at r2>0.8 with the most
significant genotyped marker at the locus. We assembled a large collection of publically
available datasets, including 1,544 chromatin immunoprecipitation with next generation
sequencing (ChIP-Seq) datasets, and “Active Chromatin” maps generated from combinations
of histone marks in 221 different cell and tissue types. We developed a simulation
test called RELI (Harley et al., Nature Genetics, in press) to assess the statistical
significance of the number of JIA loci that intersect with each ChIP-seq dataset.
Bonferroni corrected P-values (pc) were estimated for each ChIP-seq dataset evaluated. We
focused our analysis on TF data sets where DNA was bound in ≥3 JIA genetic loci and
pc<0.01. The ToppGene web portal was used to characterize functional annotations and
protein interactions between TFs.
Results
Forty-three JIA loci were defined in this analysis. 129 of 1,544 ChIP-seq datasets,
containing 63 unique TFs, had DNA bound in ≥3 JIA genetic loci and had pc<0.01. Cell
populations identified in these 129 ChIP-seq datasets implicate several immune cell
types in JIA pathogenesis, including CD4+ T cell subsets such as Th17, CD8+ T cells,
CD56+ NK cells, and B cells. Ten TFs identified have a role in Th17 cell differentiation
(pc <10-8). The top result involves NFKB1 binding at 20/43 (46.5%) of JIA loci (pc<10-14).
Two vitamin D receptor (VDR) ChIP-seq datasets are also highly significant (pc<10-10)
and each intersects with at least 6 JIA loci. The viral TF Epstein-Barr nuclear antigen
2 (EBNA2) intersects with 17/43 (39.5%) JIA loci.
Conclusion
These data are consistent with common transcriptional control mechanisms operating
across multiple JIA risk loci in a shared intracellular environment. Notably, most
GWAS loci have small odds ratios (usually <1.2). If there are coordinated mechanisms
across loci that alter disease risk with larger effect sizes, including viral TFs,
then shared gene regulatory mechanisms such as these are important in generating disease
risk.
P43 Anti-transthyretin antibody positivity in pediatric patients with rheumatic disease
Janet E. Orrock1, Cristina C. Clement2, Marco Vigano3, Tamar B. Rubinstein1, Laura
Santambrogio2
1The Children’s Hospital at Montefiore, Bronx, NY, USA; 2Albert Einstein College of
Medicine, Bronx, NY, USA; 3Istituto Ortopedico Galeazzi, Milan, Italy
Correspondence: Janet E. Orrock
Background
Juvenile idiopathic arthritis (JIA) is composed of 7 subtypes, differentiated by clinical
characteristics and serologic markers; however, there is much unknown about pathophysiology,
and subtypes currently classified under the umbrella of JIA may be distinct diseases.
This supposition is particularly relevant to systemic JIA (SJIA), a disease process
with autoinflammatory, instead of autoimmune, features.
Transthyretin (TTR) is a serum protein implicated in the pathogenesis of amyloid diseases
such as senile systemic amyloidosis. TTR functions normally as a transport protein
in a homotetramer conformation. Each monomer is rich in β-sheet structures, which
can lead to misfolding and aggregation, increasing immunogenicity. Preliminary investigations
of TTR in adults with rheumatic disease have found evidence of anti-TTR antibody positivity
in patients with rheumatoid arthritis (RA) and osteoarthritis (OA). There has been
only 1 prior study of anti-TTR antibody positivity in juvenile arthritis, prompting
our current investigation into patients with JIA, including the subgroups of SJIA
versus all other types of JIA, and pediatric systemic lupus erythematosus (pSLE).
Methods
Serum samples were obtained from pediatric rheumatology clinic patients as well as
from 2 biorepositories. There were a total of 45 patients with SJIA, 29 patients with
other JIA, 36 patients with pSLE, 32 adults with osteoarthritis, and 11 healthy pediatric
controls.
Anti-TTR antibody levels were measured by ELISA. Data were normalized to account for
total serum protein levels, reported in optical density (OD) per milligram (mg) of
protein. Statistical analyses comparing expression of anti-TTR antibody between the
different groups were performed using the ordinary one-way ANOVA followed by Tukey
multiple comparison test. A p value less than 0.05 was considered significant.
Results
Anti-TTR antibody levels were most elevated in the other JIA group (Figure 1). There
were statistically significant differences between other JIA versus SJIA groups, as
well as other JIA versus SLE groups and other JIA versus healthy controls groups.
Compared to healthy controls group, there was no significant difference of anti-TTR
antibody level for SJIA group.
Conclusions
Anti-TTR antibody levels were highest in the group of patients with JIA subtypes other
than SJIA and had statistically significant differences when compared to the levels
of patients with SJIA, pSLE, or healthy controls. This observation suggests an immune
response to TTR may be part of the pathogenesis of some types of JIA. Further investigation
with larger patient numbers of each JIA subtype is indicated to determine if anti-TTR
antibody positivity may be a useful diagnostic and/or prognostic test.
Fig. 1
(abstract P43). Anti-TTR antibody levels normalized by protein. Data are shown as
box plots. Lines inside the boxes represent the mean. Each box represents the standard
error of measurement. Lines outside the boxes represent the minimum and maximum values
detected. * means p less than 0.05. ** means p less than 0.005.
P46 Juvenile idiopathic arthritis mediated by defective GATA-binding Protein 3
Anna E. Patrick, T. Brent Graham, Thomas M. Aune, Jessica B. Duis
Vanderbilt University Medical Center, Nashville, TN, USA
Correspondence: Anna E. Patrick
Background
Juvenile inflammatory arthritis (JIA) is the most common inflammatory joint disease
in childhood, yet its etiology and pathogenesis remain poorly understood. Genetic
defects contribute to both pediatric and adult arthritis, including JIA and rheumatoid
arthritis (RA). Previous studies suggest that immune regulatory genes play an important
role in these conditions, particularly in early onset disease. GATA-binding protein
3 (GATA-3) is a key transcription factor that drives the differentiation of CD4+ T
cells along the Th2 pathway. GATA-3 suppresses other cellular pathways, including
the CD4+ Th1 and Th17 pathways. Importantly, patterns of CD4+ T cell function, including
an increase in Th1 and Th17 and a decrease in Th2 pathways, have been implicated in
various models of arthritis. Mutations in GATA3 cause a syndrome of hypoparathyroidism,
sensorineural deafness, and renal dysplasia (HDR syndrome) due to loss of GATA-3 function.
In genome wide associated studies, GATA3 has an association with RA and displays altered
levels of transcription in JIA. We report the novel case of a frameshift mutation
causing stop-gain and elongation of the C-terminus of the protein. Our work indicates
a previously undescribed mechanism of JIA.
Methods
Whole exome sequencing was performed on a clinical basis by GeneDx. Peripheral blood
mononuclear cells (pBMCs) were collected from the index patient and controls. Effector
Th1, Th2, and Th17 cells were produced by polarization and re-stimulation of pBMCs.
RNA was assessed by preparation of cDNA and analysis by polymerase chain reaction
(PCR), Sanger sequencing, and quantitative PCR. Western blot and ELISA were used to
assess intracellular and secreted proteins respectively. A mammalian expression vector
containing GATA-3 was altered by site-directed mutagenesis to make mutant GATA-3.
Constructs were expressed in Jurkat cell culture. The expressed GATA-3 or mutant ability
to bind a GATA site was examined by luciferase assay.
Results
Our index case has c.1201_1202delAT: p.Met401ValfsX106 in exon 6 of GATA3. The patient
has mutant GATA-3 that is expressed at both at the RNA and protein level, indicating
it can escape nonsense-mediated decay. In an ex vivo assay, the index patient has
polarized pBMCs that have decreased Th2 effector activity and increased Th1 and Th17
effector activity. In an in vitro expression assay the mutant GATA-3 is less able
to drive GATA-dependent luciferase expression.
Conclusions
We find that dominant-negative mutations in GATA3 cause an expanded spectrum of disease
that includes inflammatory arthritis, and in this case psoriatic JIA. GATA3 is a key
regulatory gene in immune cells. A reduction in GATA-3 activity by aberrantly produced
protein interferes with normal function causing dysregulation of T cell effector function,
including a decrease in Th2 activity with a concomitant increase in Th1 and Th17 activity.
This case demonstrates a link of GATA-3 function to psoriatic JIA. Moreover, these
findings reveal a potential role of GATA-3 in the pathogenesis of autoimmune disease.
Finally, this work suggests GATA-3 as a novel therapeutic target for patients with
JIA or RA.
Ethics Approval
The study was approved by the Vanderbilt University Institutional Review Board.
P45 Identification of optimal subcutaneous doses of tocilizumab in children with systemic
juvenile idiopathic arthritis
Hermine Brunner1, Nicolino Ruperto2 Daniel Lovell1, Gerd Horneff3, Maria Luz Gámir
Gámir4, Markus Hufnagel5, Joy Hsu6, Min Bao6, Wendy Douglass7, Navita L. Mallalieu6,
Chris Wells7, Christopher M. Mela7, Fabrizio de Benedetti8
1Pediatric Rheumatology Collaborative Study Group (PRCSG), Cincinnati Children’s Hospital
Medical Center, Cincinnati, OH, USA; 2Pediatric Rheumatology International Trial Organization
(PRINTO), Istituto Giannina Gaslini Pediatria II - Reumatologia, Genoa, Italy; 3Asklepios
Clinic Sankt Augustin, Sankt Augustin, University Hospital of Cologne, Cologne, Germany;
4Rheumatology, Hospital Ramon y Cajal Unidad de Reumatologia Pediatrica, Madrid, Spain
5Universitätsklinikum Freiburg, Freiburg, Germany. 6Roche Innovation Center, New York,
NY, USA; 7Roche Products Ltd, Welwyn Garden City, United Kingdom; 8IRCCS Ospedale
Pediatrico Bambino Gesù, Rome, Italy for the PRINTO and PRCSG Investigators
Correspondence: Fabrizio de Benedetti
Background
The efficacy and safety of intravenous (IV) tocilizumab (TCZ) were demonstrated in
patients with systemic juvenile idiopathic arthritis (sJIA) in the phase 3 TENDER
study1 (WA18221). Study WA28118 (ClinicalTrials.gov, NCT01904292) investigated dosing
regimens of subcutaneous (SC) TCZ in patients with sJIA by bridging to data for IV
TCZ to identify the optimal SC regimen.
Methods
This was a phase 1b multicenter, open-label study to evaluate the pharmacokinetics
(PK), pharmacodynamics (PD), and safety of TCZ SC in patients aged 1-17 years with
sJIA and inadequate response to glucocorticoids and nonsteroidal anti-inflammatory
drugs. Interim analysis was conducted after 24 patients had received TCZ SC for 14
weeks. Patients could be TCZ naive or could switch from TCZ IV to SC. TCZ SC was administered
for 52 weeks according to body weight: patients <30 kg received either 162 mg every
10 days before interim analysis or 162 mg every 2 weeks (Q2W) after interim analysis;
patients ≥30 kg received 162 mg every week (QW). The study objective was to characterize
the PK, PD, and safety of TCZ SC in patients with sJIA; efficacy was an exploratory
objective.
Results
In total, 51 patients were enrolled, including 25 weighing <30 kg (8 before and 17
after interim analysis) and 26 weighing ≥30 kg. Twenty-six patients (51%) were TCZ
naive and 25 (49%) switched from TCZ IV. Median steady state Cmin was similar for
patients <30 kg receiving TCZ 162 mg Q2W and those ≥30 kg receiving TCZ 162 mg QW,
and the range largely overlapped (Table 1). More than 95% (49/51) of patients treated
with TCZ SC had model-computed steady state Cmin higher than the 5th percentile achieved
with TCZ IV. The median and range of AUC2weeks were similar for both body weight groups
(Table 1). Changes in interleukin-6, C-reactive protein, and erythrocyte sedimentation
rate were similar for both body weight groups. Almost all patients had ≥1 adverse
event (AE; n = 50; 98.0%). Injection site reactions (ISRs) occurred in 21 patients
(41.2%); most were mild, and none led to treatment interruption or withdrawal. The
AE rate was 1200.3/100 patient-years (PY) (909.3/100 PY, excluding ISRs). The most
common AEs were viral upper respiratory tract infection (13; 25.5%), neutropenia (13;
25.5%), and cough (12; 23.5%). Nine serious AEs occurred in 7 patients (13.7%; 19.3/100
PY); 5 were infections, all in the <30 kg group. Two deaths occurred, both in the
<30 kg group. Median Juvenile Arthritis Disease Activity Score-71 improved (decreased)
from baseline to week 52 for TCZ-naive patients (<30 kg, –13.9; ≥30 kg, –12.4) and
was maintained or improved further for patients who switched from TCZ IV (<30 kg,
–0.7; ≥30 kg –0.2).
Conclusion
A PK-based strategy was successful in bridging TCZ SC to TCZ IV in patients with sJIA.
Dosing regimens of 162 mg Q2W in patients <30 kg and 162 mg QW in patients ≥30 kg
provided adequate exposure to support efficacy comparable to that of TCZ IV. Except
for ISRs, safety results were consistent with the known safety profile of TCZ in sJIA.
Reference
1. De Benedetti F et al. N Engl J Med. 2012;367:2385-2395.
Table 1
(abstract P45). See text for description
TCZ SC(WA28118)
TCZ IV(WA18221)
<30 kg TCZ162 mg Q2Wn = 25
≥30 kg TCZ162 mg QWn = 26
<30 kg TCZ12 mg/kg Q2Wn = 46
≥30 kg TCZ8 mg/kg Q2Wn = 43
Model-computed steady state PK parameters, median (range)
Cmin,ss μg/mL
64.2(16.6-135.9)
72.419.5-157.8)
65.9(19.0-135.5)
70.7(5.3-126.6)
Cmax,ss μg/mL
126.6(51.7-265.8)
89.8(26.4-190.2)
274.4(148.8-444.0)
253.0(119.6-404.3)
AUC2weeks,ss μg/mL×day
1298(539-2792)
1154(334-2370)
1734(840-2712)
1631(526-2779)
P46 Safety of tocilizumab in patients aged <2 years with active systemic juvenile
idiopathic arthritis treated for one year
Sunethra Wimalasundera1, Wendy Douglass1, Chris Wells1, Yukiko Kimura2, Carine Wouters3
1Roche Products Ltd, Welwyn Garden City, United Kingdom; 2Hackensack University Medical
Center, Hackensack, NJ, USA; 3University Hospital Gasthuisberg, Leuven, Belgium
Correspondence: Sunethra Wimalasundera
Background
The US Food and Drug Administration approved intravenous (IV) administration of tocilizumab
(TCZ) for the treatment of patients ≥2 years of age with systemic juvenile idiopathic
arthritis (sJIA) in 2011 based on results of the phase 3 TENDER study1 (WA18221).
This approval was associated with a postmarketing requirement to investigate the use
of TCZ in patients with sJIA <2 years of age (study NP25737; ClinicalTrials.gov, NCT01455701).
Results from the 12-week main evaluation period (MEP) have been reported.2 Safety
results following completion of the optional extension period (OEP) of NP25737 (until
52 weeks from baseline or 2 years of age, whichever was longer, was reached) are now
reported.
Methods
NP25737 was a multicenter, open-label, single-arm study to evaluate the pharmacokinetics
and safety of IV TCZ 12 mg/kg every 2 weeks for 12 weeks in patients aged <2 years
with active sJIA for ≥1 month whose treatment with corticosteroids and nonsteroidal
anti-inflammatory drugs failed and who were receiving stable background therapy. After
the 12-week MEP, patients could participate in the OEP and continue TCZ treatment
(without requirement for stable background therapy) to evaluate long-term safety.
Cumulative adverse events (AEs) over the entire study period are reported.
Results
Seven of 11 patients enrolled in the MEP continued to the OEP and received ≥1 dose
of TCZ. Across the entire study period (n = 11), the median number of TCZ doses was
11.0 (range, 2-26), and the median duration of exposure to TCZ was 22.1 weeks (range,
4.1-58.1). Most patients (10/11; 90.9%) had ≥1 AE; most AEs were mild or moderate
in intensity and unrelated to study drug. The most common AEs were upper respiratory
tract infection (6/11 patients; 54.5%), followed by hypersensitivity, neutropenia,
rash, viral upper respiratory tract infection, and vomiting (each in 3/11 patients;
27.3%). Seven serious AEs occurred in 5 of 11 patients (45.5%), of which 2 occurred
during the OEP (transaminases increased and histiocytosis hematophagic), 3 occurred
during the MEP (3 hypersensitivity events), and 2 occurred during the safety follow-up
of the MEP (sJIA flare and hand-foot-and-mouth disease). AEs leading to dose modification
occurred in 5 of 11 patients (1 in the MEP and 4 in the OEP) mostly because of infections,
neutropenia, and elevated liver enzymes, all mild or moderate in intensity. AEs leading
to withdrawal occurred in 5 of 11 patients (45.5%): during the OEP, 1 patient was
withdrawn because of a serious AE of increased transaminases; during the MEP, 3 patients
were withdrawn because of serious hypersensitivity reactions to TCZ, and 1 patient
was withdrawn because of thrombocytopenia. No deaths were reported during the study.
AE rates per 100 patient-years of exposure are reported in Table 1.
Conclusion
During the OEP of the study, long-term treatment with TCZ was well tolerated in sJIA
patients aged <2 years, and no additional safety signals were reported in the OEP
beyond those reported in the MEP or observed previously for patients with sJIA aged
>2 years.
References
1. De Benedetti F et al. N Engl J Med. 2012;367:2385-2395.
2. Mallalieu NL et al. Arthritis Rheumatol. 2017;69(suppl 10):abstract 2856.
Table 1
(abstract P46). Rates of AEs
TCZ 12 mg/kg IV every 2 weeks
Main Evaluation Periodn = 11
Optional Extension Periodn = 7
Entire Study Periodn = 11
Total patient-years at risk
2.3
5.1
7.4
Number of events (AE rate per 100 patient-years at risk)
Any AE
32 (1396.4)
47 (926.5)
79 (1072.7)
Serious AE
5 (218.2)
2 (39.4)
7 (95.1)
AE with fatal outcome
0
0
0
AE leading to withdrawal
4 (174.6)
1 (19.7)
5 (67.9)
AE leading to dose interruption
1 (43.6)
12 (236.5)
13 (176.5)
P47 Systemic Treatment of Uveitis in Children A Single Center Experience
Khaled Alsaeid1,2, Jasim Alfailakawi2, Hamid Alenezi2, Hazem Alsaeed2
1Kuwait University, Kuwait; 2Mubarak Alkabeer Hospital, Jabriya, Kuwait
Background
Uveitis is a condition frequently seen in children with juvenile idiopathic arthritis
(JIA). A proportion of children with uveitis do not respond to local treatment with
corticosteroid eye drops. Because of the risk of vision loss associated with uveitis
and the complications of prolonged local steroid treatment, patients with severe uveitis
are referred to the pediatric rheumatologist for systemic therapy. Traditional systemic
treatments may not be effective, are slow in onset of action (traditional DMARDs)
or are associated with unacceptable toxicity profile (corticosteroids). TNF alfa antagonists
have been found of benefit in uveitis. Adalimumab has been recently licensed in our
country for this indication. Herein we report our experience in treating uveitis in
the setting of a referral pediatric rheumatology center.
Methods
The files of children with uveitis referred from ophthalmology centers across Kuwait
were reviewed. All patients had systemic therapy with traditional DMARDs, corticosteroids
or biologic DMARDs (anti-TNF). All patients had bi-weekly to 4 weekly visits to the
ophthalmologist during therapy. Degree of improvement or worsening was reported in
percentage of change in Standardization of the Uveitis Nomenclature (SUN) classification
criteria. All children had a complete blood count with liver and renal function tests
every 6-8 weeks. All patients treated with a biologic agent had T-spot test prior
to starting treatment to rule out latent tuberculosis.
Results
20 patients with uveitis were included in this review. The underlying disease in 11
patients was JIA, one patient had Vogt-Koyonagi-Harada syndrome and 8 patients had
idiopathic uveitis. Four patients were excluded due to missing data. The mean age
of patients at diagnosis was 11 years. Six patients were treated with a traditional
DMARD alone (systemic corticosteroids, methotrexate, cyclosporine and or mycophenylate),
3 patients with adalimumab monotherapy and 7 patients were treated with adalimumab
and a DMARD. One patient with JIA on etanercept was switched to adalimumab once uveitis
had developed. Overall, 75% improvement after 3 months and 93.3% after 9 months was
reported. Signs of active uveitis were more likely to improve at 3 months and 9 months
in patients treated with adalimumab (monotherapy or combined with a DMARD) than patients
on DMARDs (78% and 100% improvement vs 66% and 81%). No serious adverse events or
tuberculosis developed during the study period.
Conclusion
Systemic treatment of uveitis refractory or dependent on high dose local corticosteroids
treatment is warranted and appears to be effective. Adalimumab appears to be more
effective than conventional DMARDs and safe in treating uveitis in children. Our experience
is consistent with the results of the Sycamore trial. The cooperation between pediatric
ophthalmologists and rheumatologists and early referral is paramount.
Ethics Approval
IRB Approval obtained reference number VDR/EC/3200, Kuwait University.
P48 Resilience and mental illness in children with arthritis in a national sample
of US youth
Tamar Rubinstein1, Danielle R. Bullock2, Kaveh Ardalan3, Wenzhu Mowrey1, Nicole Brown1,
Ruth E. Stein1
1Albert Einstein College of Medicine/Children’s Hospital at Montefiore, Bronx, NY,
USA; 2University of Minnesota/Masonic Children’s Hospital, Minneapolis, MN, USA; 3Northwestern
University Feinberg School of Medicine/Ann & Robert H. Lurie Children’s Hospital of
Chicago, Chicago, IL, USA
Correspondence: Tamar Rubinstein
Background
Resilience is the ability to recover from adversity or chronic stress and is associated
with psychological health in children with chronic illness. Emerging data show that
chronic stress may contribute to rheumatologic diseases and that children with these
diseases are particularly at risk for mental illness. However, the role resilience
plays in youth with rheumatologic diseases has not been examined. Our objective was
to investigate the relationship between resilience and mental illness among children
with arthritis.
Methods
Using data from the 2016 National Survey of Children’s Health (NSCH), we investigated
differences in personal and family resilience between children with arthritis, children
with other chronic acquired physical illnesses (CAPC)*, and children with neither.
The NSCH is a survey of sampled households with children <18 years conducted by the
National Center for Health Statistics at the Centers for Disease Control. Children
were determined to have current conditions, including arthritis, if their guardian
indicated yes to both “has a doctor or other health care provider ever told you that
this child has…” and “does this child currently have the condition?” We defined personal
resilience as high/moderate/low by responses of ‘definitely true’/‘somewhat true’/‘not
at all true’ to the following questions: does the child ‘bounce back quickly when
things do not go his or her way?’ (for children < 6 years old); or, do they ‘stay
calm and in control when faced with a challenge?’ (for children 6 years or older).
Family resilience was scored (range: 0-4) based on positive responses to the following
query: when faced with a problem do they 1) talk together 2) work together 3) know
their strengths 4) stay hopeful. Higher scores were indicative of greater resilience.
Bivariate analyses examined differences between the groups. We investigated whether
resilience was inversely associated with comorbid depression/anxiety among children
with arthritis in logistic regression models.
Results
Among 50,212 children included in the survey, 16,892 had CAPC and 138 had current
arthritis. There were fewer children with arthritis and high personal resilience compared
to children with other CAPC and children with neither (44% vs 51%, 61%, p<0.001).
Children with arthritis had the lowest mean family resilience scores (1.5 vs 1.8,
2.0, p=0.0001). More children with arthritis had anxiety/depression (34% vs 13%, 6%,
p<0.001). Personal resilience, but not family resilience, was inversely associated
with anxiety/depression among children with arthritis. A graded relationship was seen
between the level of personal resilience and the odds of having anxiety/depression,
which persisted after adjusting for age, sex, minority race/ethnicity, and poverty
(Table 1).
Conclusions
Children with arthritis exhibit lower personal and family resilience compared to peers.
Lower personal resilience is associated with higher odds of anxiety/depression among
children with arthritis. Further studies will help us understand whether resilience
building interventions may improve mental health among children with arthritis.
*Asthma, allergies, diabetes, and epilepsy.
Table 1
(abstract P48). Odds Ratios (OR) for Anxiety/Depression by Resilience Level in Children
with Arthritis
Unadjusted
Adjusted**
Resilience Level*
OR
Confidence Interval
p value
OR
Confidence Interval
p value
High
1
---
---
1
----
----
Moderate
3.13
1.40 – 7.01
0.005
2.69
1.13 – 6.41
0.025
Low
4.57
1.29 – 16.1
0.018
5.16
1.32 – 20.14
0.018
* Personal resilience defined in children <6 years old as ‘bounces back quickly when
things do not go his or her way’ and in older children as ‘stays calm and in control
when faced with a challenge’: ‘definitely true’ (high), ‘somewhat true’ (moderate),
or ‘not true’ (low).
** Adjusted for age, sex, minority race/ethnicity, and poverty status.
Ethics Approval
Approval for exemption was obtained from the Einstein-Montefiore Institutional Review
Board.
P49 Does anti-cyclic citrullinated peptide antibody positivity predict erosive disease
in polyarticular juvenile idiopathic arthritis jia patients? Experience from a tertiary
care medical center in the United States
Saumya V. Joshi1, Bipin Malla1, Yujuan Zhang1, Trevor Davis1
1Department Pediatric Rheumatology, Floating Hospital for Children, Tufts Medical
Center, Boston, MA, USA
Correspondence: Saumya V. Joshi
Background
The primary hypothesis of this study is that anti-CCP antibodies measured in the serum
of subjects with polyarticular juvenile idiopathic arthritis(JIA) are associated with
increased risk of bony erosions. We further hypothesize that anti- anti-cyclic citrullinated
peptide (CCP) antibody positivity is an independent risk factor for severe bone involvement
in both rheumatoid factor (RF) positive and RF negative polyarticular JIA.
Methods
Extensive chart review of Floating Hospital for Children’s electronic medical records
(EMR) identified 58 subjects between January 2011 through December 2017 (7 years)
with polyarticular RF positive or polyarticular RF negative JIA who had at least one
RF and CCP value tested. Subjects with a diagnosis of enthesitis related arthritis,
juvenile psoriatic arthritis, chronic unspecified arthritis or extended oligoarticular
arthritis were excluded. Further EMR review within these subjects identified those
with bony erosions on the available radiographs read by staff radiologists trained
in pediatric musculoskeletal radiography. We defined positive CCP and RF above 20
units/ml and 15 units/ml respectively based on our lab standards. Subjects with either
two consecutive positive values or a single positive value, not checked again, were
considered positive for this study. Subjects with a single or multiple negative serum
values or subjects with an initial positive but the subsequent negative CCP or RF
were considered negative for this study. We evaluated the statistical significance
of the association between CCP positivity and erosive disease as well as RF positivity
and erosive disease.
Results
The mean subject age at the time of the chart review was 18.2 years-old, age range
4 to 58 years. 81% subjects were females and 76% white. About 28% subjects had erosive
disease in all (16/58). Out of these 16 subjects, 10 had both RF and CCP negative,
4 had both positive, 1 subject had CCP positive but RF negative and another one had
CCP negative but RF positive. Eight subjects were positive for anti-CCP antibodies,
out of which 5 subjects had evidence of erosive bony disease on radiographs (p value
significant at 0.03 on Fischer test). Anti-CCP antibodies had a specificity of 92.8%
(CI 80.5% to 98.5%) and a sensitivity of 31.2% (CI 11.0% to 58.6%). Out of 10 RF positive
subjects, 5 had erosions and 5 did not. Interestingly RF positivity was not significantly
correlated with erosive disease (p value 0.1). However, with this small sample size,
we would only be able to detect a difference of about 70% erosion rate between the
two groups (Power 80%, 95% CI). RF had similar sensitivity (31.2%, CI 11.0-58.6) but
poorer specificity (88.1%, CI 74.3-96.0) compared to anti-CCP antibodies.
Conclusions
This study provides preliminary evidence that CCP is a biomarker of more aggressive
disease in JIA. These findings support inclusion of anti-CCP antibody positivity in
the diagnostic criteria for polyarticular JIA in any future revisions of ILAR criteria,
but these findings must be validated by future larger scale studies.
Ethics Approval
The study protocol underwent exempt review by the IRB.
P50 Is the patient global health assessment reliable in juvenile idiopathic arthritis?
Cindy M. Wang1, Rebecca Trachtman1, Jackie Szymonifka2, Karen B. Onel1
1Hospital for Special Surgery/Weill Cornell Medicine, New York, NY, USA; 2Hospital
for Special Surgery, New York, NY, USA
Background
Juvenile idiopathic arthritis (JIA) is a chronic autoimmune disease that poses many
challenges in monitoring and management. There is increasing recognition of the importance
of patient-reported outcomes (PROs), because they reflect the patient's own view of
their rheumatic illness. Although newer PROs are being developed and more widely utilized
both in clinical care and in research, their performance and reliability remain unclear. This
study seeks to evaluate: (1) performance of the patient global health assessment (PGA)
compared to standard disease activity measures in children with JIA, (2) correlations
of the PGA with socioeconomic status (SES) in children with JIA, and (3) relationship
between PGA and physician global health assessment in children with JIA.
Methods
A convenience sample of patients with JIA (N = 47) aged 2-18 were recruited from a
single center. Patients aged ≥ 10 years completed the questionnaire, and parents of
patients aged 2-9 completed a proxy questionnaire on their child’s behalf. Correlations
between (1) the PGA and disease activity, as measured by the Juvenile Disease Activity
Score-71 (JADAS-71), (2) the PGA and physician global health assessment, and (3) the
physician global health assessment and the JADAS-71 were evaluated using Spearman
correlation coefficients. PGAs were compared by age, sex, insurance status, race,
and ethnicity using Wilcoxon rank-sum tests. Differences between PGA and physician
global health assessments were compared using Wilcoxon rank-sum tests.
Results
16 parents and 31 patients completed the patient global assessments (Table 1). There
was a moderate correlation between PGA and JADAS-71 (r= 0.503, p<0.001), and PGA and
physician global health assessments (r= 0.503, p= 0.002). There was a stronger correlation
between physician global health assessments and JADAS (r= 0.612, p<0.001). PGA median
scores and IQRs appeared to be higher among patients with Medicaid insurance, non-white
race, and Hispanic ethnicity, with the greatest difference seen in the category of
race (Table 2). There were no differences between patient and physician assessments
across all groups except among patients with Medicaid (difference median =-1.25) and
Hispanic patients (difference median = 2) (Table 3).
Conclusion
Our results demonstrate that physician global health assessment had a stronger correlation
with standard disease activity measures than the PGA. These scores were higher in
patients who were non-White race, Hispanic, and had Medicaid insurance; however, these
were not statistically significant. These data indicate that the PGA is fairly stable
across groups, and can be used reliably for disease monitoring. Further validation
using data from other centers and patient cohorts is needed prior to implementation
in routine clinical care.
Table 1
(abstract P50). Patient Characteristics
Patients and Parents(N = 47)
Patients(n = 31)
Parents(n = 16)
Age, years(median, IQ range)
12.4[8.6, 15.0]
14.2[12.4, 15.8]
4.3[3.3, 9.0]
Sex
Male
17 (36.2%)
14 (45.2%)
3 (18.8%)
Race
Caucasian/White
38 (80.9%)
24 (77.4%)
14 (87.5%)
Asian
3 (6.4%)
3 (9.7%)
0 (0.0%)
Other
6 (12.7%)
4 (12.9%)
2 (12.5%)
Ethnicity
Hispanic
8 (17.0%)
5 (16.1%)
3 (18.8%)
Insurance
Medicaid
8 (17.0%)
4 (12.9%)
4 (25.0%)
Private
39 (83.0%)
27 (87.1%)
12 (75.0%)
BMI, kg/m2
(median, IQ range)
18.3[15.6, 22.3]
21.3[18.2, 23.8]
15.5[15.0, 16.8]
Table 2
(abstract P50). Comparison of Patient Global Assessments by age, sex, insurance status,
race and ethnicity
Patient global median [IQR]
P-value
Age
Patient completed
2 [0, 5]
0.892
Parent completed
2 [0.05, 4.5]
Sex
Male
2 [0, 5]
0.679
Female
2 [0, 4]
Insurance
Medicaid
2.5 [1, 5,]
0.313
Private
2 [0, 4]
Race
White
1.5 [0, 4]
0.266
Non-white
4 [2, 5]
Ethnicity
Hispanic
2.5 [2.5, 5]
0.134
Non-Hispanic
1 [0, 4]
Table 3
(abstract P50). Discordance of patient and physician assessments by age, sex, insurance
status, race, and ethnicity
Difference median** [IQR]
P-value
Age
Patient completed
0 [-1, 2]
0.370
Parent completed
0 [-2.25, 1]
Sex
Male
0 [-2, 2]
0.731
Female
0 [-2, 1]
Insurance
Medicaid
-1.25 [-4.5, 1.0]
0.226
Private
0 [-2, 1]
Race
White
0 [-2, 1]
0.957
Non-white
0 [-2, 2]
Ethnicity
Hispanic
2 [-0.5, 2.25]
0.127
Non-Hispanic
0 [-2, 1]
**Differences between patient and physician global assessments were calculated as
patient global – physician global
Ethics Approval
This study was approved by the Hospital for Special Surgery IRB.
P51 Stepping it up: the use of physical activity monitors as an outcome measure in
juvenile myositis
Emily Brunner1, Laura Tasan1, Kathryn S. Torok1, Kimberly Francis1, Emily Mirizio1,
Kaila Schollaert-Fitch1, Chester Oddis2, Rohit Aggarwal2
1Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, PA, USA; 2UPMC, Pittsburgh,
PA, USA
Background
Clinical trials in juvenile myositis (JM) are limited, partly until recently due to
lack of validated longitudinal outcome measures. More robust, objective and continuous
functional assessments should supplement currently validated outcome measures in JM.
The use of physical activity monitors (PAM), which effectively quantify movement,
may enhance assessment of disease activity and complement the current core set measures
(CSM) as established by Pediatric Rheumatology International Trials Organization (PRINTO)
and International Myositis Assessment and Clinical Studies Group (IMACS). We examined
the use of variables obtained from a commercially available PAM device, Fitbit® One,
as outcome measures in patients with JM.
Methods
JM patients from age 5-17 years were enrolled from rheumatology clinics with an ongoing
enrollment. Following evaluations were performed in each patient at baseline, 1, 3
and 6 months: a) PRINTO and IMACS CSMs including Manual Muscle Testing (MMT) and Childhood
Myositis Assessment Scale (CMAS), b) Patient/Parent Reported Outcome measures (PRO):
Patient-Reported Outcome Measurement Information System Mobility Short Form (PROMIS-SF)
and Childhood Health Assessment Questionnaire (CHAQ), and office functional tests:
Sit-to-Stand (STS), Timed Up and Go (TUG) and Six Minute Walk Distance (6MWD). A waist-based
Fitbit® One was worn by patients for 7 consecutive dates every month for 6 months
and average daily step counts were assessed. Spearman’s correlation coefficient was
used to evaluate the relationship between Fitbit® step counts as compared to current
IMACS and PRINTO CSMs, PROs and functional tests. Patients were characterized as active
and stable disease based on PRINTO criteria and MD assessment, and ability of Fitbit®
average daily steps to differentiate between the two groups were assessed.
Results
As data collection and analysis are ongoing, the following results represents the
cross-sectional analysis at baseline. A total of 17 out target of 25 JM participants
have been enrolled, including 5 active and 12 stable, 76% female, 94% White with mean
(SD) age of 11.5 years (3.4). Spearman’s correlation analyses demonstrated a moderate
to strong correlation between Fitbit® average daily step counts and baseline MMT8,
patient/parent global, PROMIS-SF and CHAQ (Table 1), but not with CMAS, MD Global
and functional tests. Fitbit average daily step counts, most CSMs and physical functional
variables were different between active vs. stable patients at baseline visit (Table
2), however, p values not calculated due to small sample size.
Conclusion
The number of steps recorded by Fitbit® in the free-living environment had moderate
to strong correlation with key JM CSMs except CMAS, supporting further study of the
potential for the use of the Fitbit® steps as outcome measures in JM. Continued analysis
of longitudinal data will help to determine the utility of a commercially available
PAM as an outcome measure in JDM.
Funding
This study received funding from Cure JM.
Ethics Approval
This study was approved by the Institutional Review Board at the Children’s Hospital
of Pittsburgh of University of Pittsburgh Medical Center PRO16110410.
Table 1
(abstract P51). Spearman’s correlation analyses of Fitbit® steps in free-living environment
with CSMs1, PROs1 and functional tests
Average Fitbit® stepsRho (p value)
CHAQ1
-0.68 (0.007)
Patient/Parent Global
-0.49 ( 0.07)
PROMIS-SF1
0.49 ( 0.08)
MD global
-0.18 ( 0.5)
CMAS1
0.15 ( 0.6)
MMT81
0.76 ( 0.002)
STS1
-0.07 ( 0.84)
TUG1
0.11 ( 0.71)
6MWD1
0.21 ( 0.44)
1Core Set Measures (CSM), Patient Reported Outcomes (PROs), Childhood Health Assessment
Questionnaire (CHAQ), Patient-Reported Outcome Measurement Information System Mobility
Short Form (PROMIS-SF), Manual Muscle Testing (MMT), Childhood Myositis Assessment
Scale (CMAS), Sit-to-Stand (STS), Timed Up and Go (TUG), Six Minute Walk Distance
(6MWD).
Table 2
(abstract P51). Baseline differences in CSM1 and functional tests in active versus
stable patients. Median (IQR1)
Variables
Active (n=5)Median (IQR)
Stable (n=12)Median (IQR)
CHAQ1
0.63 (0.5 - 0.875)
0 (0 - 0.1875)
Patient/Parent Global
6 (6 - 6.5)
0.25 (0 - 1.125)
PROMIS SF1
29 (28 - 32)
32 (31.75 - 32)
MD Global
5.5 (3 - 6)
0 (0 - 0.065)
CMAS1
45 (35 - 49)
49 (46.75 - 51.25)
MMT81
139 (133 - 146)
149.5 (147.5 - 150)
STS1
14 (14 - 16)
15.5 (13.75 - 18.25)
TUG1
7 (6 - 7)
7 (7 - 8)
6MWD1
368 (336 - 410)
403 (345.75 - 428)
Average Fitbit® Steps
4197.5 (3415.5 - 5744)
7135 (5460 - 8863)
1Core Set Measures (CSM), Interquartile Range (IQR), Childhood Health Assessment Questionnaire
(CHAQ), Patient-Reported Outcome Measurement Information System Mobility Short Form
(PROMIS-SF), Manual Muscle Testing (MMT), Childhood Myositis Assessment Scale (CMAS),
Sit-to-Stand (STS), Timed Up and Go (TUG), Six Minute Walk Distance (6MWD).
P52 Analyze myositis with ultrasound and exercise (AMUSE) kids - analysis of baseline
data
Laura Tasan1, Emily Brunner1, Rohit Aggarwal2, Chester Oddis2, Emily Mirizio¹, Kaila
Schollaert-Fitch1, Kim Francis¹, Judith Squires1, Amisha Shah1, Kathryn Torok1
1Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, PA, USA; 2University of Pittsburgh
Medical Center, Pittsburgh, PA, USA
Correspondence: Laura Tasan
Background
Pediatric Rheumatology International Trials Organization (PRINTO) and International
Myositis Assessment and Clinical Studies Group (IMACS) have validated core set outcome
measures (CSM) in Juvenile Myositis (JM). However, given some limitations of these
CSMs, there is an unmet need for more dynamic yet objective outcome measures for JM.
The aim of this pilot study is to test the reliability, validity and responsiveness
of advanced ultrasound (US) modalities as dynamic imaging outcome measures in JM patients.
Methods
This prospective observational cohort study includes JM subjects consecutively recruited
from a rheumatology clinic for the collection of clinical, functional and US data
at baseline, 3 and 6 months follow up. Clinical and functional variables include:
demographics, clinical characteristics, PRINTO/IMACS defined CSMs, Sit To Stand (STS),
Time Up and Go (TUG), and 6 Minute Walk Distance (6MWD). US modalities to evaluate
muscle consistency and perfusion include: Gray Scale with Echogenicity (EI) and Muscle
thickness (MT), Power Doppler (PD), 2D Shear wave© Elastography (SWE) and Contrast
Enhanced US with Lumason© (CEUS) performed on unilateral proximal (vastus lateralis)
and distal muscle (medial gastrocnemius) groups. At each study visit, US is performed
before and after all functional measures and exercise to stress the muscles of interest.
Spearman’s correlation coefficient was utilized to evaluate the relationship of US
measures with CSMs and functional tests, specifically using Manual Muscle testing
(MMT8) as the primary CSM outcome for validation of US measures.
Results
We have enrolled 9 JM patients currently out of our goal of 20 JM patients and 10
healthy controls. Patients enrolled in this pilot study are 89% Non-Hispanic females
with a mean age of 11.5 and a mean disease duration of 36 months. Several US measures
had moderate to strong correlations with JM CSMs (MMT, MDAS, CMAS), including Echogenicity,
Power Doppler, CEUS blood flow measurements (Time to Peak (Tp) and Peak Intensity
(Ip)) and CEUS blood volume measurement (area under the curve (AUC)), both pre- and
post-exercise, with most associations being stronger post-exercise (Table 1, rs >0.35
bolded). Importantly, the US parameters EI, PD, CEUS, correlate moderately to strongly
with the MMT8, the pre-defined primary outcome measure for this study.
Conclusions
Preliminary results demonstrate that US measures of Echogenicity, Power Doppler and
CEUS (both blood flow and blood volume) correlate moderately to strongly with core
JM outcome measures of functionality at baseline, supporting their potential to serve
as supportive outcome measures in JM studies. The stronger correlations in the blood
flow and blood volume CEUS variables post exercise likely reflect the increased blood
perfusion in muscles, reflecting normal muscle function. Whereas the stronger negative
correlation with Power Doppler reflects increased blood flow secondary to active muscle
inflammation. Further longitudinal analysis is underway to examine which modality
is more sensitive and specific to changes over time.
Table 1
(abstract P52). Baseline Spearman Correlations of US muscle measures, *Core Set Measures,
and Functional
Test in all JM Patients (n=9)
*CHAQ SDI
*Pt/Parent Global
PROMIS SF Pt/Parent
*MDAS
*MD global
*CMAS
*MMT8
STS
TUG
6MWD
Echogencity Pre
0.30
0.30
-0.21
0.38
0.45
-0.52
-0.84
-0.17
-0.43
-0.36
Echogencity Post
0.34
0.34
-0.28
0.45
0.50
-0.56
-0.84
-0.10
-0.43
-0.30
Muscle thickness Pre
0.01
0.04
0.04
0.08
-0.08
0.32
-0.20
-0.47
0.08
0.10
Muscle thickness Post
-0.02
-0.01
-0.19
0.19
0.11
0.25
-0.19
-0.54
-0.10
0.28
Elastography Pre
0.05
0.03
-0.18
0.10
0.12
-0.24
0.27
-0.34
0.15
-0.34
Elastography Post
0.01
-0.04
0.39
0.29
0.20
-0.06
0.22
-0.66
0.05
-0.02
Power doppler Pre
0.29
0.29
-0.45
0.41
0.42
-0.41
-0.41
0.28
-0.22
0.14
Power doppler Post
0.00
0.00
0.00
0.33
0.40
-0.13
-0.78
-0.09
-0.78
0.00
CEUS Tp Pre
-0.47
-0.51
-0.20
-0.10
-0.06
0.17
0.57
-0.05
-0.22
0.57
CEUS Tp Post
-0.27
-0.29
-0.30
-0.76
-0.60
0.19
0.43
0.00
0.55
0.14
CEUS Ip Pre
-0.33
-0.33
0.04
0.21
0.16
0.00
0.39
0.15
-0.49
-0.04
CEUS Ip Post
0.09
0.09
0.27
0.71
0.70
-0.09
-0.09
-0.29
-0.68
0.03
CEUS AUC Pre
-0.15
-0.15
0.10
-0.36
-0.29
-0.11
-0.11
0.33
0.16
0.07
CEUS AUC Post
-0.09
-0.09
-0.27
-0.37
-0.43
-0.26
0.60
0.90
0.68
-0.37
Bold rs values >0.35, *Core Set Measures, Pre (Pre exercise), Post (Post exercise),
CEUS (Contrast Enhanced Ultrasound), Tp (Time to Peak), Ip (Peak Intensity), AUC (Area
Under the Curve), CHAQ (Childhood Health Assessment Questionnaire), Pt (Patient),
Patient-Reported Outcome Measurement Information System Mobility Short Form (PROMIS-SF),
MDAS (Myositis Disease Activity Score), CMAS (Childhood Myositis Assessment Scale),
MMT8 (Manual Muscle Testing 8), STS (Sit to Stand), TUG (Time Up and Go), 6MWD (6
Minute Walk Distance).
Funding
This study received funding from Cure JM and Children’s Hospital of Pittsburgh Radiology
Department.
Ethics Approval
University of Pittsburgh Medical Center IRB was obtained and approved for this study
following protocol #17020677.
P53 Patients with pediatric onset systemic lupus erythematosus in South Africa
Laura B. Lewandowski1, Christiaan Scott2
1Systemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal
and Skin Diseases, National Institutes of Health, Bethesda, MD, USA; 2Paediatric Rheumatology,
Red Cross War Memorial Children’s Hospital and University of Cape Town, Cape Town,
South Africa
Background
Systemic lupus erythematosus (SLE) is a systemic autoimmune disease which can be fatal.
While African ancestry is a risk for severe disease and poor outcomes, less is known
about SLE on the African continent. Our group recently reported that pediatric onset
SLE patients (pSLE) in South Africa(SA) have higher disease activity at presentation
and suffer more organ damage than North American counterparts, but was limited to
one geographical area. The aim of this study is to describe organ involvement, organ
damage, renal survival and overall survival in a larger, more geographically diverse
South African cohort.
Methods
We conducted a retrospective chart review of pediatric and adult rheumatology and
nephrology patients seen at 3 centers in Cape Town and one center in Johannesburg,
South Africa from 1988-2017 meeting American College of Rheumatology criteria for
pSLE. Patient age, gender, race, presenting features, treatment, and outcomes were
recorded. All calculations were performed using R statistical software.
Results
The South Africa Cohort includes 170 patients; mean age 11.2 years, 91% female. The
larger cohort continues to have high rates of organ system involvement. The current
cohort has a 56% rate of renal disease and 35% rate of central nervous system (CNS)
SLE. Of those with lupus nephritis, 54% underwent renal biopsy. The majority (60%)
of those that underwent biopsy had class III or class IV lupus nephritis. Twenty-two
percent of all patients had acute renal failure (ARF) at enrollment, and 9% went on
to develop end-stage renal disease (ESRD). The cohort had a high SLE Systemic Lupus
International Collaborating Clinics Damage Index (SLICC-DI) score at enrollment.
Conclusions
SA patients from a larger, more geographically diverse cohort present at a young age
with multisystem involvement. They have high rates of renal and CNS involvement, and
a high mortality rate. These differences may be due to access to diagnosis and treatment,
genetic predisposition, or a combination of factors. Further research is required
to determine identify risk factors for damage and death in this high-risk population.
Table 1
(abstract P53). Demographic and clinical features at enrollment
South African Cohort (N=151)
Age at diagnosis, years median (SD)
11.2 (3.2)
% female
91
% African descent
90.5
% ANA positive
97
% lupus nephritis
56
% CNS SLE
35
Table 2
(abstract P53). Renal features, outcomes, and organ damage
South African Cohort (N=151)
% renal biopsy
54
Class III/IV
60
Class V
13
% ARF
22
% ESRD
9
% Dialysis
10
% Transplant
4
% Death
9
SLICC-DI median, (SD)
1.537 (1.6)
P54 Development of the treatment and education approach for childhood-onset lupus
(TEACH) intervention for adolescents and young adults
Natoshia Cunningham1,2, Erin Moorman1, Lauren Fussner1, Pinar Ozge Avar Aydin1, Allen
Watts1, Onengiya Harry1, Susmita Kashikar-Zuck1,2, Hermine Brunner1,2
1Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA; 2University
of Cincinnati College of Medicine, Cincinnati, Ohio, USA
Correspondence: Natoshia Cunningham
Background
Childhood-onset lupus (cSLE) has been linked to significant impairment in health-related
quality of life including increased fatigue, depressive symptoms, and pain. To date,
a customized psychological intervention to meet the unique needs of adolescents and
young adults (AYA) with cSLE (e.g., adjustment to diagnosis, sleep hygiene) has not
been developed. Thus, the current study tested the feasibility and initial effectiveness
of a tailored cognitive behavioral treatment for AYA with cSLE (Treatment and Education
Approach for Childhood Onset Lupus; TEACH) with the goal of improving fatigue, depressive
symptoms, and pain.
Methods
TEACH consists of six one-hour individual treatment sessions administered by a psychologist.
Separate protocols were developed for adolescents and young adults. Both protocols
consist of psychoeducation, cognitive strategies and behavioral skills training adapted
for AYA with cSLE. To qualify, patients were required to meet clinical cut offs for
fatigue (PROMIS Pediatric Fatigue- short form; cut off: ≥20/40), depressive symptoms
(youth < 18 years: Children’s Depression Inventory 2; cut off: ≥14/56; youth ≥ 18
years: Beck Depression Inventory-II; cut off: ≥ 14/63), or pain intensity (Visual
Analog Scale; cut off: ≥4/10). All measures were completed before and immediately
following treatment. Participants also provided feedback on the content and structure
of TEACH via a semi-structured interview.
Results
Sixteen patients are enrolled for participation in the study (recruitment is ongoing).
Of these, 2 failed to begin and 2 discontinued treatment early. Eleven female participants
(mean age 16.4 years) completed the intervention and 1 participant is in treatment.
Wilcoxon signed-rank tests indicated that treatment completers <18 years (n = 8) experienced
significant reductions in fatigue (M∆=4.37, Z=-2.52, p=<05) and depressive symptoms
(M∆=4.29, Z=-2.38, p=<05), but not pain. Treatment completers ≥ 18 years (n = 3) experienced
reductions in fatigue (M∆=11.33), depression (M∆=10.00), and pain (M∆=1.50). Participants
reported they enjoyed the intervention content and format, and reported increased
confidence and self-efficacy.
Conclusion
Reductions in fatigue and depressive symptoms were reported among treatment completers.
Young adult treatment completers experienced reduction in pain. Participants felt
the intervention was beneficial and practical. TEACH may be a feasible and effective
method to help AYA manage symptoms related to cSLE.
Ethics Approval
The study was approved by Cincinnati Children’s Hospital Medical Center’s Internal
Review Board, approval number 2016-0802.
P55 Living with Childhood-onset Systemic Lupus Erythematosus: A Focus Group with Caregivers
Onengiya Harry, Angela C. Combs, Brooke Hater, Emily Roemisch, Aimee W. Smith, Lauren
M. Fussner, Rhyanne McDade, Leslie Favier, Najla Aljaberi, Allen Watts, Jennifer L.
Huggins, Lori E. Crosby, Avani C. Modi
Cincinnati Children’s Hospital Medical Center
Correspondence: Onengiya Harry
Background
Non-adherence in childhood-onset systematic lupus erythematosus (cSLE) is estimated
to be between 40-50% [1, 2]. In patients with cSLE, non-adherence results in a significant
health care burden with increased hospitalizations, preventable disease damage, disease
flares, and higher health care costs [1]. There are no published data regarding caregivers’
perspectives on management of cSLE including barriers to treatment adherence for adolescents
with cSLE. The aim of this study is to characterize caregivers’ perspective on the
management of cSLE and its impact on family life.
Methods
Nine caregivers (100% mothers; 67% White; 33% Black) of adolescents diagnosed with
cSLE (N=10, 100% female; 70% White; 30% Black; mean age = 15.5± 3.03 years) were recruited
from a pediatric rheumatology clinic and its cSLE registry to participate in focus
groups. Two group sessions were led by trained facilitators to discuss topics around
living with cSLE and its management. The sessions were audio-taped, transcribed, and
coded for themes by three independent coders.
Results
Preliminary analysis revealed six major themes: 1) Barriers/Facilitators of treatment
adherence, 2) Symptoms Impacting Daily Life, 3) Lack of Understanding/Knowledge about
cSLE, 4) Need for School Advocacy, 5) Sense of Normalcy/Disruption of Family Schedule,
and 6) Worry about the Future. Adherence barriers included the number, taste, timing
and side effects of oral medications. Facilitators of adherence were desire to avoid
being sick/in pain/hospitalized, use of pill boxes, reminder apps, and storage location
of pills. Fatigue, pain, and mood significantly impacted daily life. Caregivers expressed
difficulty with balancing adolescents’ autonomy with treatment supervision. All caregivers
emphasized need for school advocacy regarding absenteeism due to symptoms and hospitalizations,
in-school accommodations, and healthcare providers helping increase schools’ awareness
and understanding of cSLE. Worry about the future involved insurance coverage, quality
of life, transition to college, and job opportunities.
Conclusion
While adherence was identified as a significant problem, caregivers also noted beneficial
strategies related to self-management. Caregivers’ desired increased knowledge/understanding
from the public regarding cSLE, especially aimed at school advocacy. Important next
steps are to identify themes from our adolescent and young adult focus groups, with
the long-term goal of developing interventions to improve management of cSLE for adolescents
and young adults.
Ethics Approval
This study was approved by the Cincinnati Children's Hospital IRB Medical Center board
(IRB # 2017-5659).
References
1. Feldman, C.H., et al., Medication Nonadherence Is Associated With Increased Subsequent
Acute Care Utilization Among Medicaid Beneficiaries With Systemic Lupus Erythematosus.
Arthritis Care Res (Hoboken), 2015. 67(12): p. 1712-21.
2. Bugni, V.M., et al., Factors associated with adherence to treatment in children
and adolescents with chronic rheumatic diseases. J Pediatr (Rio J), 2012. 88(6): p.
483-8.
P56 Safety of belimumab in patients with adult- and pediatric-onset neuropsychiatric
systemic lupus erythematosus
Meiqian Ma1, Suhas K Ganguli1, Barbara Anne Eberhard1, Joyce S Hui-Yuen1*, Anca Askanase2*
1Pediatric Rheumatology, Cohen Children’s Medical Center and Hofstra University School
of Medicine, NY, USA; 2Division of Rheumatology, New York-Presbyterian Hospital/Columbia
University Medical Center, NY, USA
Background
Belimumab (Benlysta) is a human monoclonal antibody that inhibits soluble B-lymphocyte
stimulator. It was approved by the FDA in 2011 for treatment of adults with active,
autoantibody-positive, systemic lupus erythematosus (SLE). To date, data are scarce
on the use of belimumab in patients with neuropsychiatric lupus (NPSLE).
Methods
Retrospective study of SLE patients treated with belimumab who either had NPSLE prior
to start of belimumab, or developed NPSLE symptoms while under treatment with belimumab.
Data were collected on clinical features, laboratory results, disease course, and
treatment response. Descriptive statistics were used where appropriate.
Results
We previously reported a cohort of 195 patients treated with belimumab from 10 academic
centers. Twenty-one of these patients, from 8 centers, had NPSLE prior to starting
belimumab and 5 developed NPSLE while on belimumab. The mean age at start of belimumab
was 34.7 (+/- 10.9) years; the median disease duration was 8 years. All 26 patients
were female, 9.5% Black, 62% Caucasian, 4.7% Asian, 4.7% Alaskan, and 23% other/unknown.
All patients were taking other background medications prior to initiation of belimumab
(85.7% hydroxychloroquine, 81% prednisone mean daily dose of 18.8±12.1mg prednisone/equivalent,
19% azathioprine, 52.3% mycophenolate mofetil). Indications for initiation of belimumab
included rash, arthritis, renal, hematologic abnormalities, serositis, and worsening
serologic activity (low complement and increasing anti-dsDNA). The mean duration of
belimumab therapy was 22.7 +/- 13.9 months. Belimumab was discontinued in 5 patients
after a mean of 14.3 +/- 15.6 months due to neuropsychiatric symptoms such as headache,
stroke-like symptoms, or worsening NPSLE. Of the 5 patients who developed NPSLE symptoms
while on belimumab therapy, 3 had pediatric-onset SLE (pSLE, diagnosed before 19th
birthday). Symptoms included seizures, stroke, and severe migraines.
Of note, 1 pSLE patient was started on belimumab for peripheral neuropathy and serologic
abnormalities. Her clinical symptoms stabilized and her complement and anti-dsDNA
levels trended toward normal. In addition, another pSLE patient without NPSLE in the
past, developed cognitive impairment on treatment with belimumab and was diagnosed
with CNS vasculitis.
Conclusion
We report 26 patients who developed or had worsening NPSLE while on treatment with
belimumab. This is the first study describing neuropsychiatric outcomes and adverse
effects in patients treated with belimumab. Our data are consistent with the observed
effects of neuropsychiatric symptoms from the randomized trials, with 8-10% of patients
treated with belimumab developing NPSLE symptoms. We are also the first to describe
the use of belimumab to treat peripheral neuropathy. Thus, we remain cautious about
the use of belimumab in patients with NPSLE. Further studies with larger populations
and longer follow up will be beneficial to elucidate the role of belimumab in NPSLE.
Ethics Approval
This study was approved by the Columbia University Internal Review Board.
P57 Cutaneous Scarring in Neonatal Lupus: A Retrospective Cohort Study
Lauren Briggs1, Rebecca Levy2, Earl Silverman2, Elena Pope1,2, Irene Lara-Corrales1,2
1Faculty of Medicine, University of Toronto, Toronto, ON, Canada; 2Hospital for Sick
Children, Toronto, ON, Canada
Correspondence: Lauren Briggs
Background
Neonatal Lupus Erythematosus (NLE) is a rare autoimmune condition occurring in newborns
secondary to trans-placental passage of maternal autoantibodies during pregnancy.
Cutaneous rashes are among the most common manifestations of NLE seen in up to 50%
of patients. Lesions are classically described as annular, erythematous plaques favoring
periorbital and photo-distributed sites. Traditionally thought to be self-resolving,
some literature suggests that cutaneous sequelae may persist in a subset of patients.
Objective
To explore the clinical features of cutaneous NLE, and characterize the presence of
cutaneous sequelae, including atrophic scarring.
Methods
A retrospective cohort study of pediatric patients diagnosed with cutaneous NLE, and
born between January 1980 and May 2017, was carried out at a tertiary pediatric referral
center. 106 patients met inclusion criteria. All patients in the study were at least
6 months of age at last follow-up. Data were summarized using descriptive statistics;
a regression analysis was used to explore risk factors for atrophy. Statistical analysis
was performed using STATA 14.0, Texas, US.
Results
57% of patients were female. Known maternal connective tissue disease was noted in
65% of cases. The antibodies most frequently present included anti-Ro, anti-La with
frequencies of 93% and 68% respectively. The rash was most often described as papulosquamous
(72%) and annular (71%). Sites of involvement included head and neck only (39%), body
only (8%), or widespread (54%). At last follow up, 34% of patients had cutaneous sequelae
from the NLE rash. Of these, 13% of patients had residual telangiectasia, 17% had
dyspigmentation and 9% had atrophic scarring. Mean duration of follow-up was 3.8 years
+/- 4.3 (0.2-18.5), and mean age at last follow-up was 4 +/- 4.3 (0.5-18.7). Atrophic
scarring was significantly associated with both maternal anti-Ro antibodies (Pearson
Chi2 9.7, P=0.0002) and topical treatment of NLE lesions (Pearon Chi2 5.5, P=0.02).
Conclusion
The results of this study suggest that NLE can result in cutaneous sequelae, including
atrophic scarring, telangiectasia, hyperpigmentation and hypopigmentation. Anti-Ro
antibodies may signify increased propensity of cutaneous scarring. This suggests the
importance of ensuring accurate diagnosis of cutaneous NLE, in conjunction with long-term
monitoring.
Ethics Approval
This study was approved by the Hospital for Sick Children’s Internal Review Board,
approval number 1000055474.
P58 Childhood primary angiitis of the central nervous system: deciphering a rare disease
through international collaboration
Marinka Twilt1, Shehla Sheikh2, Courtney Moore2, Anastasia Dropol1, Ana Sepulveda1,
Susanne Benseler1, on behalf of the BrainWorks investigators
1Alberta Children’s Hospital, University of Calgary, Calgary, Alberta, Canada; 2Sickkids,
Toronto, Ontario, Canada
Correspondence: Marinka Twilt
Introduction
Childhood Primary Angiitis of the central nervous system (cPACNS) is an increasingly
recognized inflammatory brain disease with potentially devastating neurological deficits.
Early recognition and initiation of treatment has led to dramatically improved mortality
and decreased morbidity. Immunosuppressive treatment is tailored to the disease subtype.
Three distinct subtypes have been recognized and are based on the size of the brain
vessel involved. Large vessel cPACNS, angiography positive, includes two subtypes;
progessive (P-cPACNS) and non-progressive cPACNS (NP-cPANCS). Small vessel, angiography
negative cPACNS (AN-cPACNS) is confirmed by brain biopsy. BrainWorks is an international
registry for inflammatory brain diseases, endorsed by CARRA initiated to collect these
rare cases. The aim of this study is to describe the presentation, course and outcome
of children with cPACNS in BrainWorks.
Methods
Consecutive patients with inflammatory brain diseases age < 18 years at the time of
diagnosis were prospectively enrolled in the BrainWorks study since 2007. BrainWorks
is a multicenter collaborative cohort study of all subtypes of inflammatory brain
diseases. Children were included if they had a confirmed diagnoses of P-cPACNS, NP-cPACNS,
or AN-cPACNS according to modified Calabrese criteria. Demographics, clinical features,
inflammatory markers, and standardized functional assessments were extracted from
BrainWorks. Informed consent was obtained, following approval from the respective
Research Ethics Boards.
Results
To date, a total of 445 patients have been enrolled in BrainWorks. Of these, 257 patients
(58%) were diagnosed with cPACNS. Of these, large vessel vasculitis was diagnosed
in 158 patients (61%) including NP-cPACNS in 121 and P-cPACNS in 37. Small vessel
cPACNS was diagnosed in 99 (39%). more Children with large vessel disease more commonly
presented with hemiparesis (NP-cPACNS: 105/121, 87%, P-cPACNS: 20/37, 54% versus AN-cPACNS:
36/99, 36%) and speech impairment (NP-cPACNS: 66/121, 54%, P-cPACNS: 17/37, 46% versus
AN-cPACNS: 39/99, 39%). Seizures (general, focal and status) were seen most frequently
in the AN-cPACNS: 85/99, compared to large vessel vasculitis (25/121 NP-cPACNS: 21%,
P-cPACNS:24%). Interstingly, behavioral changes and cognitive impairment were seen
most frequently in AN-cPACNS (38/99, 38% and 41/99, 41%) and P-cPACNS patients (8/37,
22% and 12/37, 32%). The Pediatric Stroke Outcome Score was available for 191 patients
(P-cPACNS: 22, NP-cPACNS: 96, AN-cPACNS: 73) and the average score was 1.25 (P-cPACNS:
1.6 , NP-cPACN: 0.9, AN-cPACNS: 1.75), the highest and therefore the largest functional
burden was documented in children with small vessel vasculitis.
Conclusion
The BrainWorks study determined the clinical phenotypes and outcomes of children with
cPACNS: the large vessel cohort presented primarily with hemiparesis and speech impairment,
while small vessel CNS vasculitis results in seizures, cognitive dysfunction and behavioral
abnormalities. At the one-year-follow-up, children with cPACNS demonstrated a moderate
functional impairment, most significantly in the AN- and P-cPACNS cohorts.
P59 Descriptive analysis of pediatric patients with systemic vasculitis admitted to
the intensive care unit of a tertiary care hospital: 10-year experience
Ellen Go1, Alicia Teagarden2, Courtney M. Rowan2, Stacey Tarvin1
1Division of Pediatric Rheumatology, Indiana University School of Medicine, Riley
Hospital for Children, Indianapolis, IN, USA; 2Division of Critical Care, Indiana
University School of Medicine, Riley Hospital for Children, Indianapolis, IN, USA
Correspondence: Ellen Go
Background
Primary systemic vasculitis (PSV) is a heterogeneous group of disease with diverse
clinical symptoms. The non-specific clinical manifestation frequently leads to a delay
disease diagnosis. Therefore, patients often present with complications such as severe
hypertension, heart failure, kidney injury or a neurological event requiring intensive
care unit admission. We aim to describe patient characteristics and interventions
required for patients with PSV admitted to a tertiary care hospital pediatric intensive
care unit (PICU).
Methods
A retrospective cohort study of all patients diagnosed with PSV who were referred
to pediatric rheumatology at Riley Hospital for Children from January 2007 to December
2017 was conducted. We investigated PICU admission, clinical characteristics, and
critical care intervention.
Results
142 PSV patients were seen by pediatric rheumatology at Riley Hospital for Children.
Henoch-Schonlein purpura (HSP) (n=100, 70.4%) was the most common PSV diagnosis, followed
by refractory Kawasaki disease (KD) (n=17, 12%), anti-nuclear cytoplasmic antibody
(ANCA)-associated vasculitis (n=12, 8.5%), Takayasu’s arteritis (n=8, 5.6%), polyarteritis
nodosa (n=3, 2.1%) and primary central nervous system (CNS) vasculitis (n=2, 1.4%).
There were 18 patients (12%) with PSV and who required PICU admission (Table 1). Highest
rate of PICU admissions were Takayasu’s arteritis (62.5%) and primary CNS vasculitis
(50%). For critical care characteristics (Table 2), rule out sepsis was the leading
cause of admission and more than half required respiratory support with at least a
third received vasoactive agents. No mortality seen in PICU PSV cohort.
Conclusions
This is one of the first descriptive cohort of pediatric patients with PSV requiring
critical care. Generally patients with HSP and refractory KD are unlikely to have
severe enough disease to require specific PICU intervention. While HSP is the most
frequent, the PICU admission rate is highest in chronic systemic vasculitides like
Takayasu arteritis. Further diagnosis subgroup data analysis is ongoing.
Ethics Approval
This study was approved by Indiana University’s Institutional Review Board, approval
number 1711175931.
Table 1
(abstract P59). Patient Characteristics
PICU PSV Cohort (n=18)
Median age, years (IQR)
9.5 (5.9-13.7)
Male/Female, n (%)
7 (38.9)/11 (61.1)
Diagnosis, n (%)
Refractory Kawasaki disease
6 (33.3)
Takayasu’s arteritis
5 (27.8)
ANCA-associated vasculitis
4 (22.2)
Henoch-Schonlein purpura
2 (11.1)
Primary CNS Vasculitis
1 (5.6)
Others
0 (0)
Diagnosis during hospital admission, n (%)
15 (83.3)
Treatment during hospitalization
Glucocorticoids
15 (83.3)
IVIg
7 (38.9)
Aspirin
5 (27.8)
Cyclophosphamide
4 (22.2)
Disease modifying anti-rheumatic drugs
2 (11.2)
Biologics
1 (5.6)
Median hospital length of stay, days (IQR)
8.5 (4.0-18.8)
Table 2
(abstract P59). Characteristics of PICU Stay
Reason for PICU admission, n (%)
Rule out sepsis
6 (33.3)
Hypertension
2 (11.1)
GI bleeding
2 (11.1)
Others
8 (44.5)
PICU interventions, n (%)
Vasoactive agent
7 (38.9)
Invasive ventilation
6 (33.3)
High flow nasal cannula
4 (22.2)
Non-invasive ventilation
2 (11.1)
Dialysis
1 (5.6)
Plasmapheresis
1 (5.6)
Median PICU length of stay, n (%)
0-2 days
9 (50)
3-7 days
5 (27.8)
>7 days
4 (22.2)
PICU Mortality, n (%)
0 (0)
Abbreviations: ANCA=anti-neutrophil cytoplasmic antibody; CNS=central nervous system;
GI = gastrointestinal; IVIg=intravenous immune globulin; PICU= pediatric intensive
care unit
P60
This abstract is not included here as it has already been published.
P61 Prevalence of Psychiatric Disorders in a Transition Clinic of Adolescents with
Rheumatic Diseases in México
Nadina E. Rubio-Pérez1, Ana C. Arana-Guajardo2, Marcia D. Torres Made1, Fernando García-Rodríguez1,
Ana V. Villarreal-Treviño1, Antonio López-Rangel3, María E. Corral-Trujillo4, Dionicio
A. Galarza-Delgado2
1Pediatric and; 2Adult Rheumatology Services; 3Psychiatry Department; and 4Clinical
Psychologist. Autónoma de Nuevo León University. Hospital Universitario "Dr. José
Eleuterio González", Monterrey, Mexico
Background
The adolescence is a critical period when different process are made, as identity,
cognitive changes, enhance of autonomy, and emotional, physical and sexual development.
Besides that, an adolescent with rheumatic disease has to front facing the disease
acceptance. The recognition of psychiatric disorders is of utmost importance in order
to achieve a healthy transition to adult-centered health care services.
Objective
To describe prevalence of psychiatric disorders in adolescents who attended our Transition
Clinic.
Methods
We included rheumatologists, psychiatrist, clinical psychologist, nurse and social
services. We included patients with established rheumatic diseases older than 16 years
old, who attended the Transition Clinic in the period between July and December 2017.
We used MINI KID assessment tool to characterized psychiatric disorders in our patients.
Each patient performs an interview with both a clinical psychologist and a pediatric
psychiatrist to confirm diagnosis. We use descriptive statistics with measures of
central tendency or frequencies depending on variable characteristics.
Results
Nineteen patients had already seen at the clinic, most of them are female (79%) and
with mean age of 18 years old. The most frequent diagnosis were juvenile idiopathic
arthritis (48%) and systemic lupus rythematosus (26%).
After a screening assessment with MINI KID tool, 14 (74%) patients shown an abnormal
result. Those patients were later evaluated finding agoraphobia (21%), depression
(26%), specific phobias (21%) and social anxiety disorder (26%) as the most prevalent
diseases (Table 1 and Figure 1).
Conclusion
Transition from pediatric to adult health-care is a transcendental step in life, especially
when a chronic disease is present. In this pilot study, we shown a high prevalence
of psychiatric problems among adolescents.
These results encourage the need of an organized, specialized, multidisciplinary,
and integrated clinic in which the patient could adapt to adult care centers.
References
1. Oen K. Comparative epidemiology of rheumatic diseases in children. Curr Opin Rheumatol
2000;12:410.
Table 1
(abstract P61). Psychiatric diagnosis in the patients using MINI KID tool. Each patient
could have more than one diagnosis
Diagnosis
Number of patients
%
Agoraphobia
4
21
Anxiety
1
5
Separation anxiety disorder
3
16
Depression
5
26
Mild Intellectual Disability
1
5
Dysthymia
2
11
Specific Phobias
4
21
Social Anxiety Disorder
5
26
Oppositional defiant disorder
1
5
Obsessive-Compulsive Disorder
2
11
Past suicide risk
1
5
Attention-deficit/hyperactivity disorder
1
5
Fig. 1
(abstract P61). Psychiatric diagnosis in the patients using MINI KID tool. Each patient
could have more than one diagnosis
P60 Leveraging a patient-powered research network to understand the impact of adverse
childhood experiences and resilience on children with rheumatic diseases
Danielle R. Bullock1, Kaveh Ardalan2, Tamar Rubinstein3
1University of Minnesota/Masonic Children’s Hospital, Minneapolis, MN, USA; 2Northwestern
University Feinberg School of Medicine/Ann & Robert H. Lurie Children’s Hospital of
Chicago, Chicago, IL, USA; 3Albert Einstein College of Medicine/Children’s Hospital
at Montefiore, Bronx, NY, USA
Correspondence: Danielle R. Bullock
Background
Adverse Childhood Experiences (ACEs), such as violence, abuse, neglect, scarcity,
and household dysfunction, are associated with chronic disease and worse health. Studies
in children suggest that resilience, defined as the ability to recover from adversity,
can mitigate health effects of ACEs. While an association between ACEs and autoimmune
diseases in adults has been described, a relationship between ACEs and childhood-onset
rheumatic diseases has not yet been examined in detail. We performed preliminary explorations
of the relationships between arthritis, ACEs, and resilience using data from the 2016
National Survey of Children’s Health (NSCH). Further prospective data is needed in
order to better understand the relationships between ACEs, resilience, and childhood-onset
rheumatic diseases. Our objectives are: 1) to engage the CARRA community and stakeholders
in eliciting feedback on a project studying ACEs and resilience in youth with rheumatic
diseases; 2) to assess the acceptability among patients and parents of collecting
data on ACEs and resilience during CARRA Registry visits at selected sites.
Methods
We propose a project leveraging the Patients, Advocates and Rheumatology Teams Network
for Research and Service (PARTNERS) consortium to engage children with rheumatic diseases
and their parents in the design of a survey to collect preliminary data on ACEs, resilience,
patient-reported outcomes in juvenile idiopathic arthritis, systemic lupus erythematosus,
and juvenile dermatomyositis populations. We also propose collecting data on the acceptability
of administering these measures during CARRA Registry visits to families of patients
enrolled in the CARRA Registry. Because assessing ACEs can involve sensitive topics
and has implications for patient and family safety, it is important to represent patient/family
voices in the design of this study.
Results
Knowledge gained from this project will improve our understanding of a relationship
between ACEs, resilience, and patient-reported outcomes in childhood-onset rheumatic
diseases and will help determine whether collecting data on ACEs and resilience will
be acceptable to families participating in the CARRA Registry. Future projects could
include a pilot study of CARRA Registry participants to assess the feasibility of
collecting this data, the rate of missingness, and perceptions of the usefulness of
collecting such data more broadly for all registry patients in future iterations of
the CARRA Registry.
Conclusions
ACEs and resilience may help explain differential outcomes among patients with pediatric
rheumatic diseases. A greater understanding of these factors can guide the development
and testing of novel resilience-building interventions for improving clinical and
patient-reported outcomes. Engaging families in the design of studies of ACEs and
resilience will help ensure that data is collected in a manner that is acceptable
to patients and parents.
Ethics Approval
Prior to initiation of any data collection, the necessary IRB approval will be obtained.
P63 Getting a HEEADSSS in psychosocial screening: use of standardized clinic note
templates for psychosocial screening in a pediatric rheumatology clinic
Erin Brennan Treemarcki, Jackie Szymonifka, Alexa Adams, Nancy Pan, Sarah Taber, Karen
Onel
Hospital for Special Surgery, New York, New York, USA
Correspondence: Erin Brennan Treemarcki
Background
Children and adolescents with rheumatic diseases are at risk for psychosocial challenges
related to illness, treatment, and normal development and should receive psychosocial
screening. Psychosocial assessments have been successfully utilized in other pediatric
specialties, including oncology and gastroenterology. A common psychosocial screening
tool is the HEEADSSS (home environment, education/employment, eating, activities,
drugs, sexuality, suicide/depression, and safety). This tool is easy to remember,
quickly administered, and modifiable for younger children. We conducted a quality
improvement project aimed to increase psychosocial screening by providers in a single
pediatric rheumatology clinic by instituting standardized follow up templates for
juvenile idiopathic arthritis (JIA) and systemic lupus erythematosus (SLE) including
the HEEADSSS assessment.
Methods
The quality improvement intervention evaluated in this study involved the creation
of disease specific follow up note templates inclusive of the HEEADSSS assessment
and introduction of the templates to the pediatric rheumatology fellows’ clinic. Charts
of patients with an ICD-10 diagnosis of JIA or SLE were reviewed during a 3 month
window prior to (February-April 2017) and after (October-December 2017) the intervention.
Charts were reviewed for presence of 2 elements of the HEEADSSS assessment documented
within the previous 12 months: smoking exposure (all patients) and sexual activity
(ages 11 years and up). The proportion of patients with completed HEEADSSS assessment
components pre- and post-intervention were compared using Fisher’s exact test.
Results
Chart review included 36 patients pre- and 42 post-intervention (Table 1). There was
an increase in assessment of both measures in the period immediately following the
intervention. Assessment of smoking exposure increased from 0.0% to 21.4% (p=0.003)
with greater but not significant improvement in SLE versus JIA patients (29.4% versus
16.4%, p=0.45). Assessment of sexual activity in patients 11 years and older increased
from 13.0% to 37.5% (p=0.09), although this comparison may be underpowered due to
decreased sample sizes.
Conclusion
Introduction of standardized note templates with the HEEADSSS assessment has resulted
in preliminary improvement in psychosocial screening by providers in a single pediatric
rheumatology clinic as demonstrated by improved rates of screening for smoking exposure
and a trend towards improved screening rates for sexual activity. Additional studies
are needed to confirm these findings, and future studies will assess whether the improvement
seen is sustained and whether usage of this template can be expanded to other pediatric
patient populations.
Table 1
(abstract P63). Documentation status pre- and post- implementation of standardized
follow up templates for providers
Pre-Intervention
Post-Intervention
p-value
Smoking assessed
Overall
0/36 (0.0%)
9/42 (21.4%)
0.003
JIA
0/20 (0.0%)
4/25 (16.0%)
0.12
SLE
0/16 (0.0%)
5/17 (29.4%)
0.04
Sexual Activity (11+) assessed
Overall
3/23 (13.0%)
9/24 (37.5%)
0.09
JIA
1/9 (11.1%)
2/8 (25.0%)
1.00
SLE
2/14 (14.3%)
7/16 (43.8%)
0.14
Abbreviations: JIA=juvenile idiopathic arthritis; SLE=systemic lupus erythematosus
P64 A collaborative approach to diagnosis and treatment of hematophagocytic lymphohstiocytosis
and macrophage activation syndrome: a single center’s approach to the development
of evidence-based guidelines
Olha Halyabar1,2, Margaret H. Chang1,2, Michelle Schoettler1,3, Marc A. Schwartz1,3,
Leslie Benson1, Catherine M. Biggs4, Fatma Dedeoglu1, Mark Gorman1, Leslie Lehmann1,3,
Mindy S. Lo1, Peter A. Nigrovic1,2, Craig D. Platt1, Gregory P. Priebe1, Jared Rowe1,3,
Robert P. Sundel1, Neeraj K. Surana1, Katja Weinacht5, Barbara A. Degar1,3, Melissa
M. Hazen1*, Lauren A. Henderson1*
1Boston Children’s Hospital and Harvard Medical School, Boston, MA, USA; 2Brigham
and Women’s Hospital and Harvard Medical School, Boston, MA, USA; 3Dana-Farber Cancer
Research Institute and Harvard Medical School, Boston, MA, USA; 4British Columbia
Children’s Hospital, Vancouver, BC, Canada; 5Lucile Packard Children’s Hospital Stanford,
300 Pasteur Drive, Stanford, CA, USA
Correspondence: Olha Halyabar
Background
Historically, primary hemophagocytic lymphohistiocytosis (HLH) and macrophage activation
syndrome (MAS) were thought of as distinct diseases and management was divided between
hematology/oncology and rheumatology with little communication between the two specialties.
It is now evident that the underlying pathophysiology of these entities is closely
related, underscoring the need to develop a multidisciplinary approach to HLH/MAS.
We utilized quality improvement methods to develop consensus on the diagnosis and
treatment of patients with HLH/MAS at our hospital.
Methods
For support, we leveraged the Evidence Based Guideline (EBG) Initiative, which is
administered through the Quality Improvement Program of the Department of Medicine.
An EBG is a clinical algorithm constructed from available evidence in the literature
and expert opinion of locally involved clinicians. The guideline is created through
prescribed steps that are designed to build consensus and ensure successful implementation.
Clinical outcomes are measured and evaluated to allow for improvement and additional
iterations of the EBG.
As per the EBG protocol, we gathered a multidisciplinary workgroup of specialists
with expertise in HLH/MAS. A series of face-to-face meetings was held monthly from
March 2016 to December 2017 and the meeting format was based on nominal group techniques.
The goals of the group included: 1) increased communication across specialties; 2)
development of a diagnostic and treatment algorithm for HLH/MAS based on evidence
in the literature and expert opinion; 3) establishment of a clinical response team.
Once the diagnostic and therapeutic pathway for HLH/MAS was developed, the EBG was
presented to the wider hospital community and revisions were made based on feedback.
Quality metrics were selected to monitor outcomes and the EBG was implemented.
Results
Entry criteria for the EBG, fever and ferritin ≥ 500 ng/mL in a hospitalized patient,
is broad and designed to capture as many patients with HLH/MAS as possible. The rheumatology
consult team serves as the initial point of contact if HLH/MAS is suspected, and performs
patient triage and provides recommendations for additional laboratory testing and
consultations. The rest of the core HLH/MAS team is involved through emails sent to
HLH/MAS distribution list, which serves as an open platform for patient discussion.
An HLH/MAS order set is available to facilitate the recommended diagnostic work up
and treatment guidelines. The treatment algorithm includes suggested medications and
doses based on the acuity of illness and risk of concurrent infection (Fig 2). Quality
metrics to be tracked prospectively and compared to the 2 years prior to EBG implementation
include, time to initiation of treatment, fever duration, length of hospital stay,
time to normalization of laboratory markers, and mortality.
Conclusion
HLH and MAS are increasingly considered to be a spectrum of related conditions and
joint management across subspecialties will likely improve patient outcomes. Our experience
in creating a multidisciplinary approach to HLH/MAS management based on consensus
can serve as a model at other institutions.
P65 The role of food in the self-management of pain in teens with juvenile arthritis:
gender and ethnic differences
Kimberly A. Lewis1,2,3, Amanda Mabry-Flynn3, Ruy Carrasco4, Lauren Nielson2
1The University of Texas at Austin, Austin, TX, USA; 2Ascension Texas, Nursing Research,
Austin, TX, USA; 3The University of Illinois at Urbana-Champaign, Urbana, IL, USA;
4Dell Children’s Medical Center, ‘Specially for Children Pediatric Rheumatology Clinic,
Austin, TX, USA
Correspondence: Kimberly A. Lewis
Background
The complex emotional interplay between chronic pain and familial and cultural norms
about food could lead to the development of disordered eating and obesity in Juvenile
Arthritis (JA) patients. JA is a collection of inflammatory joint diseases with symptom
onset prior to age 16 that accounts for over $285 mil in annual healthcare costs.
Joint pain leads to stiffness, loss of fine motor skills, immobility, or fatigue,
and requires daily self-management. Weight gain can result from a sedentary lifestyle
or increased appetite and fluid retention from immunosuppressant medications. The
negative physical and psychological consequences (i.e. low self-esteem and bullying)
may present a challenge for adolescents at a developmental stage in which the pressure
to maintain a particular body image is communicated at all levels, from peers to mass
media, and is more likely to be internalized resulting in unhealthy behaviors and
distorted self-image.
The purpose of this study is to explore the meanings adolescents diagnosed with JA
place on food choice in the context of pain, and how messages teens receive about
food from interpersonal to mass mediated communication may influence their nutritional
self-care beliefs and practices.
Methods
The cross-sectional, inductive qualitative study was guided by the social-ecological
model. Diverse focus groups of teens aged 13-17 (total sample N=46) were recruited
from a clinic in Austin, Texas, using a two (Hispanic ethnicity, white) by two (male
or female) array. An experienced moderator led the discussion using a semi-structured
interview guide. The recorded transcripts were systematically analyzed following an
established protocol from previous literature.
Results
The preliminary sample from three focus groups (n=9) was 56% female, 33% Hispanic
ethnicity, and 22% overweight or obese (body mass index percentile >85). All participants
described the multiple levels of interplay between food and pain: individual, familial,
community, and societal. Communication at multiple levels (relational, cultural, and
mass-media) was a source of influence in all groups for varying reasons. Food choices
centered on individual, familial, and peer preferences and beliefs about how the food
would make them feel. Hispanic males and females were more likely to mention a spiritual
component; consume different foods; and minimize symptoms in order to avoid distressing
family members. Peer relationships and societal influences (school, commercials, social
media) both positively and negatively affected food choices and pain.
Conclusion
Findings from this study indicate similarities and differences based on gender and
ethnicity in a sample of adolescents with JA when they communicate about food and
pain. These findings have implications for clinical practice to address the dietary
needs of this population in a developmentally appropriate, gender-specific, and culturally
sensitive way. The communication influence at multiple levels (relational, cultural,
and mass-media) is a novel consideration in designing interventions and policy recommendations
to promote the best outcomes. Further research is warranted to confirm these findings.
Ethics Approval
This study received Institutional Review Board Approval (CR-15-036) from the Seton
Institutional Review Board in Austin, Texas prior to enrollment and research activities.
All participants and parents provided informed assent and consent prior to participating
in the research activities.
Acknowledgements
The authors would like to acknowledge Dr. Tracie Harrison, PhD, RN, FAAN, for her
role as faculty sponsor for the project. The study was funded by a grant from the
Health Communications Scholars Program through the Moody College of Communication,
The University of Texas at Austin, Austin, Texas, USA.
P66 Increasing adult rheumatology fellows’ confidence and competence in providing
transition care to transferring young adult rheumatology patients
Rebecca E. Sadun, Gary R. Maslow, Richard J. Chung, Lisa G. Criscione-Schreiber
Duke University, Durham, NC, USA
Correspondence: Rebecca E. Sadun
Background
The transition from pediatric to adult healthcare is a vulnerable time for adolescents
and young adults (AYA) with chronic conditions. EULAR and the Paediatric Rheumatology
European Society (PReS) jointly published expert opinions regarding transition care
of AYA with juvenile-onset rheumatic diseases, and the ACR recently developed a transition
toolkit. However, there are no published curricula for teaching transition guidelines,
skills, or utilization of existing tools. We therefore designed and evaluated a workshop
to help adult rheumatology fellows learn key skills for providing effective transition
care to transferring young adult patients.
Methods
A 1-hour skills-based workshop on transition and transfer best practices was developed
alongside an objective standardized clinical examination (OSCE) station in which trainees
welcomed a young adult with lupus – and her parent – to a first visit in an adult
clinic. Adult rheumatology fellows (n=19) from 5 institutions were asked to self-asses
their ability to perform 10 transition/transfer skills pre- and post-workshop on a
Likert scale from 1-4, with 1 being “not at all prepared” and 5 being “completely
prepared.” The OSCE evaluation rubric assessed 5 transition/transfer skills on a Likert
scale of 1-5, with 5 being the best performance. Twelve fellows were tested with the
OSCE de novo, whereas 7 were tested with the OSCE after participating in the workshop.
Aggregated pre- and post-workshop survey responses were compared using Fisher’s exact
test, and OSCE scores were compared using an unpaired t-test. To assess skill retention,
second year fellows will be re-tested with the OSCE transfer station twelve months
after the initial workshop.
Results
After participating in the workshop, fellows felt more confident in their ability
to perform 8 of the 10 transition/transfer skills (Table 1). In addition, OSCE performance
(Table 2) was significantly better among the fellows who participated in the OSCE
after the workshop than among those who took the OSCE de novo. Twelve-month-post-workshop
data, establishing the degree of skill retention, will be collected January 2018 and
will be analyzed in time for presentation at the 2018 CARRA Meeting.
Conclusion
This brief educational intervention successfully increased adult rheumatology fellows’
confidence with many transition/transfer skills as well as increasing fellows’ ability
to employ transition best practices in an OSCE setting. It will be important to measure
skill retention 1 year following the workshop to ensure long-term impact of the curriculum.
Next steps include the development of a complementary workshop for pediatric rheumatology
fellows; this workshop will focus on skills that are key to helping young adult rheumatology
patients prepare for the transfer to adult care.
Table 1
(abstract P66). Impact of workshop on fellows’ confidence in ten transition and transfer
skills
Self-Assessed Preparedness Increased
Self-Assessed Preparedness Not Increased
Orient young adult to adult rheumatology care (p<0.01)
Establish rapport and trust with young adult patients (p=0.13)
Provide expectations of the young adult patient (p<0.01)
Speak w/ pediatric providers re transferring patients (p=0.07)
Explain differences between pediatric & adult care (p<0.01)
Assess young adult self-management skills (p<0.0001)
Assure young adult of confidentiality (p<0.001)
Ask parent to leave the room for social history (p=0.01)
Take a transition-focused adolescent social history (p<0.01)
Identify barriers to transition and adherence (p<0.05)
Table 2
(abstract P66). Impact of workshop on fellows’ competence in 5 core transition and
transfer skills
Explaining differences between pediatric and adult care
Placing the AYA patient in the primary role (parent for corroboration)
Assessing self-management skills
Performing a confidential adolescent social history
Assessing barriers to transition & adherence
Total score / Average score
Pre-workshop (n=12)
3.5
4.3
3.8
2.8
2.3
16.7/3.3
Post-workshop (n=7)
4.6
5.0
4.4
4.7
2.6
21.3/4.3
p-value
<0.01
<0.05
0.18
0.01
0.86
0.01
Ethics Approval
This study received exemption from the Duke University Internal Review Board.
P67 The value of ethnography in understanding burden of disease and designing better
care delivery systems in pediatric care
David C. McDonald1, Matt Bradley1, Brian Shakley1, Hermine Brunner2, Teresa A. Simon3
1LIFT 1428, Chattanooga, TN, USA; 2Division of Rheumatology, Cincinnati Children’s
Hospital Medical Center, Cincinnati, OH, USA; 3Bristol-Myers Squibb, Princeton, NJ,
USA
Correspondence: David C. McDonald
Background
Qualitative measures of care delivery and disease burden include patient (pt)-reported
measures of satisfaction; post-care experience; and social, physical, and mental functioning.
Parents’ and patients (pts)’ emotional distress derived from family systems, cultural
beliefs, or other unique situations may not be captured using traditional qualitative
methods. The purpose of this study is to evaluate the impact of ethnography in understanding
burden of disease.
Methods
Interviews (INTs) are conducted by a healthcare ethnographer. Ethnographers use a
formal INT guide (IG) with parents/pts to better understand their lived experience
and clinical environment experiences. INTs are audio- and video-recorded, and audio
recordings are transcribed verbatim. A code book is developed for each study; transcripts
are analyzed and coded to identify common themes related to guiding the research question
and the key topics we investigated (e.g. lived experience, individual/cultural belief
systems and pt/parent journey).
This method has been used in several pediatric settings. We describe 2 here: a study
of pediatric urgent care delivery environments (A) and a study of juvenile idiopathic
arthritis (JIA)pts (B, ongoing). In A, a bilingual semi-structured IG was used for
exit INTs with parents within clinical point of care. Post-exit INT, participants
could continue being observed and interviewed by an ethnographer (lived [in-home]
environment). In B, JIA pts and their parents are being observed and interviewed (lived
environment) by an ethnographer using an IG designed to understand individual pt beliefs/behavioral
drivers related to the realities of transitioning from a pediatric care environment
to an adult care environment, measure impact of beliefs/behavioral drivers on the
individual/family via pt-reported experiences, and leverage learning to implement
self-management tools into care delivery environments.
Results
In A: 38 unique INTs were conducted among 19 clinical staff members (intake staff,
healthcare providers) and 19 parents (parents/grandparents); 162 hours were spent
observing/interviewing participants in clinical and/or lived environment(s). Four
major themes emerged: healthcare is a layered emotional journey for parents/pts and
clinicians; there are many opportunities to provide a more meaningful experience;
parents/pts can be difficult to manage; and communication creates connection. We also
uncovered that the parent paradigm is informed along 4 categories among the 4 themes
(Table 1). For B, a sample of 5 pt/parent pairs will be interviewed; preliminary results
are planned at time of presentation.
Conclusion
There are innate challenges in providing meaningful qualitative insights to help frame
a better care delivery experience and improve the current care delivery model. The
integration of ethnography, an important tool to gain meaningful insights into the
human condition, into patient care may improve the accuracy and comprehensiveness
of burden of disease measurements and improve healthcare transactions.
Table 1
(abstract P67). Parent Perspectives on Patient-Reported Measures of Lived Experience
and Burden of Disease
Category
Issues
Sensory overload throughout the journey
▪ Fitting event into activity of daily living▪ Difficulty suppressing anticipatory
anxiety▪ Difficulty managing logistics▪ Situation can be psychologically distressing
Multiple determinants of anxiety
▪ Severity of the child’s injury/illness▪ Day-to-day life circumstance▪ Mood▪ Experience
level▪ Family and work–life dynamics
General feeling of being overwhelmed
▪ The perception/belief that ”life is not fair”▪ The reality that life is a battle▪
Multiple healthcare challenges in same family unit
Sensitivities to cultural barriers can lead to a positive or negative experience
▪ Socioeconomic circumstances▪ Language barriers▪ Cultural/ideological values▪ Healthcare
providers may generalize experiences based on spoken language
Trial Registration
Not applicable.
Ethics Approval
Study A was performed for a healthcare system and all participants were consented
at the time of the study. We have received the appropriate IRB approval for the research
involved in this submission for Study B.