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EXTENDED REPORT
ABSTRACT
Objective Participants in the Atherosclerosis Prevention
in Paediatric Lupus Erythematosus (APPLE) trial were
randomised to placebo or atorvastatin for 36 months.
The primary endpoint, reduced carotid intima medial
thickness (CIMT) progression, was not met but
atorvastatin-treated participants showed a trend of
slower CIMT progression. Post-hoc analyses were
performed to assess subgroup benet from atorvastatin
therapy.
Methods Subgroups were prespecied and dened by
age (> or 15.5 years), systemic lupus erythematosus
(SLE) duration (> or 24 months), pubertal status
(Tanner score 4 as post-pubertal or <4 as
pre-pubertal), low density lipoprotein cholesterol (LDL)
( or <110 mg/dl) and high-sensitivity C reactive
protein (hsCRP) ( or <1.5 mg/l). A combined subgroup
( post-pubertal and hsCRP1.5 mg/l) was compared to
all others. Longitudinal linear mixed-effects models were
developed using 12 CIMT and other secondary APPLE
outcomes (lipids, hsCRP, disease activity and damage,
and quality of life). Three way interaction effects were
assessed for models.
Results Signicant interaction effects with trends of
less CIMT progression in atorvastatin-treated participants
were observed in pubertal (3 CIMT segments), high
hsCRP (2 CIMT segments), and the combined high
hsCRP and pubertal group (5 CIMT segments). No
signicant treatment effect trends were observed across
subgroups dened by age, SLE duration, LDL for CIMT
or other outcome measures.
Conclusions Pubertal status and higher hsCRP
were linked to lower CIMT progression in
atorvastatin-treated subjects, with most consistent
decreases in CIMT progression in the combined
pubertal and high hsCRP group. While secondary
analyses must be interpreted cautiously, results
suggest further research is needed to determine whether
pubertal lupus patients with high CRP benet from
statin therapy.
ClinicalTrials.gov identier: NCT00065806.
(from the TFD to 10 mm proximal to the TFD) and the proximal 10 mm of the internal carotid artery (ICA) providing a set
of 12 CIMT measurement sites. All ultrasound scans were read
by a single experienced reader using Image Pro software (Media
Cybernetics, Bethesda, Maryland, USA). For each segment, both
near and far walls were measured, and maximum and mean
CIMT measurements recorded. The Ward R. Riley Ultrasound
Center supervised quality assurance procedures, including
central training and certication of all sonographers and the
reader as well as regular site visits and performance reviews.
For each measurement site, a maximum CIMT value dened
as the largest of the four angle-specic maximum CIMTs was
calculated. These 12 maximum CIMT values were then averaged to determine the meanmax CIMT over near and far walls
of the right and left CCA, carotid bifurcation and ICA. For each
of the four measurement sites in the CCA, a mean CIMT value
dened as the average of the four angle-specic mean CIMTs
was also calculated. The four mean CIMT values were then
averaged to determine the meanmean common CIMT. Other
CIMT outcomes, including an overall meanmean and other
segment/wall-specic meanmax or meanmean CIMT measures were computed accordingly.
Other assessments including fasting lipid levels, modied
Safety of Oestrogens in Lupus Erythematosus: National
Assessment version of the SLE Disease Activity Index (SELENA
SLEDAI),17 Systemic Lupus International Collaborating Clinics/
ACR Damage Index,18 and PedsQL 4.019 and PedsQL
Rheumatology module 3.020were obtained as previously
reported.15 21
Denition of subgroups
All subgroups were determined prior to performing secondary
analyses. Subgroups were dened by ve variables as follows.22
Participants 15.5 years of age were compared to younger participants. The selected age threshold represents the mean age of
the APPLE cohort. Participants with SLE duration 24 months
were compared to those with more recently diagnosed disease.
Pubertal status was assessed using a validated, patient reported
measure.23 Participants were given a standardised series of drawings with explanatory text to assess pubertal development. Girls
were given line drawings of the ve stages of breast and female
pubic hair development with appropriate written descriptions
accompanying the drawings. Boys were given line drawings of
boys showing the ve stages of pubic hair development with
appropriate written descriptions. Each participant was asked to
select the drawing best representing his or her own development.23 Prepubertal status was dened as Tanner stage <4 in
breast (for female) or genital (for male). Participants with a
baseline LDL<110 mg/dl were compared to those 110 mg/dl.
This LDL cut point was chosen based on National Cholesterol
Education Program recommendations for children and adolescents.24 Those with hsCRP<1.5 mg/l were compared to those
1.5 mg/l. The hsCRP cut point represents the 75th percentile
for healthy US females aged 1619 years 25 and falls within the
average risk range for the general adult population (1.0
3.0 mg/l) dened by the American Heart Association.
After reviewing the results for the ve predened subgroup
variables, we then dened an additional subgroup based on the
combination of post-pubertal status plus elevated baseline
hsCRP (1.5 mg/l) versus all others.
Outcome measures
The primary and secondary longitudinal CIMT outcomes from
the APPLE trial were used as outcomes for the subgroup
Ardoin SP, et al. Ann Rheum Dis 2013;0:110. doi:10.1136/annrheumdis-2012-202315
Statistical analysis
Baseline characteristics were summarised using descriptive statistics with categorical data presented as percentages and continuous data presented as means, SDs and medians. Baseline
characteristics between subgroups were compared using the 2
test, Fishers exact test, or the non-parametric Wilcoxon test.
The primary efcacy analysis for APPLE compared rates of
meanmean common CIMT progression between treatment
groups based on a test of two-way interaction between treatment
group and time in a longitudinal linear mixed effects model
under data missing at random assumptions.10 From this model,
the effect of treatment can be estimated as the difference in
mean progression rates between participants assigned to atorvastatin and placebo treatment groups, with negative differences
indicating progression for the atorvastatin group was slower
than for the placebo group. Similar models were used to assess
other CIMT and non-CIMT outcomes.
To examine heterogeneity of treatment effects across subgroups, the efcacy model used in the primary APPLE analysis
was extended to include an indicator variable for subgroup as
well as two- and three-way interactions between subgroup, treatment group and time. From these models, we provide estimated
mean progression rates with 95% CIs for each combination of
subgroup and treatment group. Finally, the three-way interaction
between subgroup, treatment group and time provides a test of
whether treatment effects in terms of progression rate differ signicantly between subgroups. Initially, models were t examining one subgroup variable at a time.
All statistical analyses were two-sided with the level of signicance set at 0.05. With ve subgroup variables, 12 different
CIMT outcomes and 11 other outcomes plus the combined subgroup and 12 different CIMT outcomes, we performed a total
of 127 tests of three-way interactions in these exploratory analyses. If all of these tests were independent, we would expect
approximately six tests to achieve statistical signicance due to
chance alone. These results should be interpreted cautiously as
hypothesis generating and not hypothesis testing. Analyses were
performed with SAS V.9.2.
Duration of lupus
Pubertal status
Variable
<15.5 years
15.5 years
<24 months
24 months
Pre-pubertal
Post-pubertal
91/110
13.6
49/110
27/110
23.5
22.6
88/110
4.7
36/107
46/109
27/110
102.2
15.5
0.2
41/107
2.7
0.28
7.2
154.7
46.4
85.7
116.0
21.4
0.468
0.574
0.582
93/111 (83.8%)
17.9 (1.6)*
65/111 (58.6%)*
27/111 (24.3%)
25.3 (5.3)*
39.3 (32.1)*
74/111 (66.7%)*
4.8 (4.2)
37/107 (34.6%)
45/111 (40.5%)
29/110 (26.4%)
99.3 (30.2)
15.6 (8.2)
0.2 (0.2)
43/106 (40.6%)
4.3 (17.6)
0.29 (1.61)
7.7 (3.2)
155.6 (39.7)
46.2 (13.8)
87.0 (31.6)
112.0 (60.7)
24.8 (27.6)
0.468 (0.042)
0.592 (0.058)*
0.587 (0.051)
90/106 (84.9%)
14.9 (2.3)*
59/106 (55.7%)
27/106 (25.5%)
24.4 (5.2)
9.0 (6.4)*
87/106 (82.1%)*
5.1 (4.4)
31/101 (30.7%)
35/105 (33.3%)*
24/106 (22.6%)
100.3 (26.9)
14.7 (7.7)
0.2 (0.2)*
38/101 (37.6%)
2.4 (8.1)*
0.57 (1.48)*
7.8 (3.3)
157.4 (40.8)
46.1 (12.3)
86.9 (34.1)
125.2 (78.0)*
22.7 (27.6)
0.464 (0.045)
0.572 (0.058)*
0.574 (0.060)
94/115 (81.7%)
16.5 (2.7)*
55/115 (47.8%)
27/115 (23.5%)
24.4 (5.5)
51.2 (25.8)*
75/115 (65.2%)*
4.4 (4.2)
42/113 (37.2%)
56/115 (48.7%)*
32/114 (28.1%)
101.1 (30.9)
16.4 (11.1)
0.1 (0.2)*
46/112 (41.1%)
4.7 (17.7)*
0.02 (1.52)*
7.2 (2.8)
153.0 (35.0)
46.5 (13.2)
85.8 (28.7)
103.5 (51.2)*
23.6 (26.2)
0.472 (0.040)
0.593 (0.053)*
0.587 (0.054)
61/72 (84.7%)
13.7 (2.1)*
29/72 (40.3%)*
16/72 (22.2%)
23.1 (5.4)*
26.6 (30.6)*
54/72 (75.0%)
5.0 (4.8)
21/72 (29.2%)
26/72 (36.1%)
31/72 (43.1%)
16/72 (22.2%)
102.4 (27.3)
14.7 (7.7)
0.2 (0.2)
30/69 (43.5%)
3.2 (7.8)
0.10 (1.53)
7.4 (3.5)
154.6 (35.6)
45.5 (12.3)
85.6 (31.6)
117.4 (53.3)
20.4 (24.2)
0.466 (0.045)
0.574 (0.060)
123/148
16.7
84/148
38/148
25.1
33.3
107/148
4.6
52/141
53/147
60/147
40/147
99.9
15.9
0.2
54/144
3.8
0.37
7.5
155.4
46.7
86.8
112.1
24.6
0.469
0.587
(82.7%)
(1.5)*
(44.5%)*
(24.5%)
(5.3)*
(21.3)*
(80.0%)*
(4.3)
(33.6%)
(42.2%)
(24.5%)
(27.7)
(11.0)
(0.2)
(38.3%)
(8.5)
(1.44)
(3.0)
(36.4)
(11.7)
(31.3)
(71.9)
(26.0)
(0.043)
(0.052)*
(0.058)
(83.1%)
(2.3)*
(56.8%)*
(25.7%)
(5.2)*
(27.3)*
(72.3%)
(4.0)
(36.9%)
(36.1%)
(40.8%)
(27.2%)
(29.9)
(10.5)
(0.2)
(37.5%)
(16.2)
(1.52)
(2.9)
(39.3)
(13.1)
(31.5)
(72.3)
(28.0)
(0.041)
(0.054)
DISCUSSION
APPLE is the largest randomised, double blind placebo controlled trial in paediatric lupus and the only clinical trial to
examine efcacy of safety of statin use in children and adolescents with SLE. Importantly, the APPLE trial demonstrated that
CIMT progressed in the placebo group in all but one CIMT
segment and at a faster rate than expected in the general paediatric population.10 Thus, the premature atherosclerosis of SLE is
present even in children and adolescents, highlighting the need
to identify particularly high risk individuals who may benet
from aggressive prevention strategies. Although the APPLE trial
did not show signicant benet of atorvastatin treatment in the
primary endpoint, a signal of reduced CIMT progression in the
atorvastatin group was evident across multiple CIMT segments,
raising the question of whether subgroups of the study population may have beneted from statin therapy.10 The current post
hoc secondary analyses were performed in order to identify
high risk subgroups that may benet from statin therapy with
clinically signicant reduction in CIMT progression.
Trends towards reduced CIMT progression were observed in
the atorvastatin-treated high hsCRP (two CIMT segments) and
in the post-pubertal subgroups (three CIMT segments).
Interestingly, the effect of puberty was not mediated by age
4
LDL
hsCRP/pubertal status
Variable
<1.5 mg/l
1.5 mg/l
<110 (mg/dl)
110 (mg/dl)
1.5 mg/l
post-pubertal
119/144 (82.6%)
15.7 (2.7)
78/144 (54.2%)
37/144 (25.7%)
23.6 (4.4)
28.3 (26.8)
107/144 (74.3%)
4.7 (4.0)
47/139 (33.8%)
52/143 (36.4%)
60/143 (42.0%)
34/143 (23.8%)
98.7 (27.3)
15.5 (10.4)
0.2 (0.2)
54/140 (38.6%)
0.5 (0.4)*
1.04 (0.92)*
7.3 (2.8)
157.1 (40.2)
48.0 (13.0)*
87.2 (32.5)
109.5 (59.6)
24.4 (29.5)
0.467 (0.043)
0.582 (0.058)
47/59 (79.7%)
15.9 (2.6)
27/59 (45.8%)
17/59 (28.8%)
25.7 (6.3)
35.8 (30.5)
40/59 (67.8%)
5.0 (4.9)
18/58 (31.0%)
20/59 (33.9%)
24/59 (40.7%)
18/59 (30.5%)
105.6 (33.1)
16.1 (7.9)
0.2 (0.2)
25/56 (44.6%)
11.0 (24.4)*
1.55 (1.07)*
7.9 (3.6)
152.0 (32.1)
42.9 (11.8)*
85.7 (28.2)
117.0 (49.5)
20.9 (20.0)
0.474 (0.041)
0.587 (0.051)
134/163 (82.2%)
15.7 (2.8)
94/163 (57.7%)*
41/163 (25.2%)
24.1 (5.2)
29.8 (27.7)
121/163 (74.2%)
4.1 (3.5)*
44/157 (28.0%)*
59/162 (36.4%)*
30/163 (18.4%)*
101.8 (25.8)
15.3 (7.1)
0.2 (0.2)*
58/158 (36.7%)
4.2 (15.7)
0.25 (1.59)
7.4 (3.1)
140.0 (22.7)*
46.3 (13.3)
73.0 (18.5)*
103.6 (50.2)*
19.5 (21.0)*
0.469 (0.043)
0.585 (0.057)
0.583 (0.057)
39/47 (83.0%)
15.6 (2.3)
17/47 (36.2%)*
13/47 (27.7%)
24.7 (5.2)
31.4 (28.1)
33/47 (70.2%)
6.9 (5.5)*
21/47 (44.7%)*
26/47 (55.3%)*
22/46 (47.8%)*
96.6 (38.4)
16.4 (15.8)
0.3 (0.2)*
23/45 (51.1%)
1.4 (1.9)
0.39 (1.28)
7.9 (2.9)
207.4 (33.9)*
46.8 (10.9)
132.7 (20.9)*
139.5 (67.4)*
36.3 (39.0)*
0.467 (0.041)
0.579 (0.055)
0.584 (0.050)
157/189 (83.1%)
15.5 (2.6)*
96/189 (50.8%)
42/189 (22.2%)
24.1 (5.2)
30.2 (29.4)
142/189 (75.1%)
4.7 (4.2)
62/183 (33.9%)
68/188 (36.2%)
78/188 (41.5%)
49/188 (26.1%)
99.7 (28.6)
15.5 (10.0)
0.2 (0.2)
71/182 (39.0%)
1.5 (5.0)*
0.66 (1.27)*
7.5 (3.1)
156.1 (39.2)
47.0 (13.1)
86.4 (32.3)
115.7 (70.5)
23.3 (28.0)
0.468 (0.043)
0.583 (0.057)
27/32 (84.4%)
17.3 (2.4)*
18/32 (56.3%)
12/32 (37.5%)
26.5 (5.6)
35.4 (22.1)
20/32 (62.5%)
4.9 (4.5)
11/31 (35.5%)
11/32 (34.4%)
13/32 (40.6%)
7/32 (21.9%)
106.4 (31.2)
16.0 (7.5)
0.1 (0.1)
13/31 (41.9%)
14.3 (31.3)*
1.72 (1.16)*
7.4 (2.7)
149.7 (30.0)
42.8 (10.2)
86.0 (26.2)
104.9 (35.7)
22.2 (19.7)
0.466 (0.038)
0.584 (0.050)
An Intervention Evaluating Rosuvastatin ( JUPITER) trial randomised 17 000 adults without cardiovascular disease who had
normal LDL but high hsCRP (>2.0 mg/dl) to rosuvastatin or
placebo.14 The rosuvastatin treatment group had lower rates of
myocardial infarction, stroke and death, prompting early discontinuation of the trial. On the other hand, the Heart
Protection Study randomised more than 20 000 adults without
cardiovascular disease to simvastatin or placebo, stratifying
them by hsCRP levels.36 The risk of developing cardiovascular
events after 5 years of treatment was reduced in the statin
group but did not differ according to hsCRP status. Use of
statins as primary prevention has not been explored in the
general paediatric population but is effective in preventing
CIMT progression in children with familial hypercholesterolaemia. In the population-based Bogalusa Heart Study, hsCRP
levels did not predict CIMT progression in healthy young
adults over a relatively short follow-up period (2.4 years).37 It
is important to note that results from healthy cohorts and
adults are difcult to extrapolate to adolescent and young adult
lupus patients who have a unique cardiovascular risk prole.
Taken together, the results of these analyses do not provide a
mandate for use of statins for primary prevention in pubertal
adolescents and young adults with SLE who have elevated
hsCRP, but suggest that this group may benet from statin
therapy and, according to APPLE trial safety data, are unlikely
to experience harm.
5
6
Pre-pubertal
Pubertal
CIMT
measurements
Interaction
p value
p Value
p Value
Meanmean
common
Meanmax
Meanmean
Meanmax
common
Meanmax internal
Meanmean
internal
Meanmax
bifurcation
Meanmean
bifurcation
Meanmax far wall
Meanmean far
wall
Meanmax near
wall
Meanmean near
wall
0.149
0.684
0.061
0.101
0.056
0.440
0.828
0.579
0.609
0.014
0.014
0.544
0.063
0.186
0.795
0.613
0.006
0.124
0.100
0.817
0.014
0.019
0.441
0.004
0.500
0.359
0.569
0.750
0.057
0.049
0.027
0.223
0.038
0.021
0.140
0.058
The interaction p value assesses differences in the progression rate for atorvastatin/placebo and subgroups. The p values in the pre-pubertal and pubertal groups assess differences in the progression rate for atorvastatin/placebo groups.
CIMT, carotid intima media thickness.
Comparison of atorvastatin and placebo treatment effects on CIMT progression in subgroups defined by pubertal status
Table 3
Comparison of atorvastatin and placebo treatment effects on CIMT progression in subgroups defined by hsCRP
hsCRP<1.5 mg/l
Interaction
p value
Meanmean
common
Meanmax
Meanmean
Meanmax
common
Meanmax internal
Meanmean
internal
Meanmax
bifurcation
Meanmean
bifurcation
Meanmax far wall
Meanmean far
wall
Meanmax near
wall
Meanmean near
wall
0.049
0.413
0.093
0.710
0.879
0.919
p Value
p Value
0.795
0.029
0.357
0.633
0.769
0.117
0.021
0.801
0.114
0.277
0.231
0.412
0.232
0.445
0.056
0.176
0.435
0.035
0.831
0.858
0.143
0.155
0.489
0.258
0.087
0.796
0.062
0.011
0.370
0.014
The interaction p value assesses differences in the progression rate for atorvastatin/placebo and subgroups.
The p values in the hsCRP<1.5 mg/l and hsCRP1.5 mg/l groups assess differences in the progression rate for atorvastatin/placebo groups.
CIMT, carotid intima media thickness; hsCRP, high sensitivity C reactive protein.
CIMT
measurements
hsCRP1.5 mg/l
Table 4
8
Not (pubertal and hsCRP1.5 mg/l)
CIMT
measurements
Interaction
p value
Meanmean
common
Meanmax
Meanmean
Meanmax
common
Meanmax internal
Meanmean
internal
Meanmax
bifurcation
Meanmean
bifurcation
Meanmax far wall
Meanmean far
wall
Meanmax near
wall
Meanmean near
wall
0.005
0.156
0.008
0.194
0.121
0.159
p Value
p Value
0.946
0.002
0.296
0.530
0.613
0.050
0.002
0.231
0.251
0.488
0.032
0.071
0.382
0.161
0.129
0.023
0.347
0.005
0.790
0.259
0.177
0.200
0.401
0.082
0.029
0.921
0.016
0.002
0.621
0.002
The interaction p value assesses differences in the progression rate for atorvastatin/placebo and subgroups. The p values in the not (pubertal and hsCRP1.5 mg/l) and pubertal and hsCRP1.5 mg/l groups assess differences in the progression rate
for atorvastatin/placebo groups.
CIMT, carotid intima media thickness; hsCRP, high sensitivity C reactive protein.
Comparison of atorvastatin and placebo treatment effects on CIMT progression in subgroups defined by pubertal status and hsCRP
Table 5
19
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Advance online articles have been peer reviewed, accepted for publication, edited and
typeset, but have not not yet appeared in the paper journal. Advance online articles are
citable and establish publication priority; they are indexed by PubMed from initial
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