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R E S E A R C H A R T I C L E Open Access
Systematic review of published trials: long-
term safety of topical corticosteroids and
topical calcineurin inhibitors in pediatric
patients with atopic dermatitis
Elaine C. Siegfried
1*
, Jennifer C. Jaworski
2
, Jennifer D. Kaiser
2
and Adelaide A. Hebert
3
Abstract
Background: Many clinicians have concerns about the safety of atopic dermatitis (AD) treatments, particularly in
children requiring long-term daily maintenance therapy. Topical corticosteroids (TCS) have been widely used for >5
decades. Long-term TCS monotherapy has been associated with adverse cutaneous effects including atrophy,
rebound flares, and increased percutaneous absorption with potential for adverse systemic effects. Topical
calcineurin inhibitors (TCIs), tacrolimus and pimecrolimus, available for 1–2 decades, are not associated with atrophy
or increased percutaneous absorption after prolonged use and have much lower potential for systemic effects.
However, since 2006 TCIs have carried a controversial Boxed Warning based on a theoretical risk of malignancy (eg,
skin and lymphoma) that has limited TCI use for standard-of-care maintenance therapy.
Methods: A comparative systematic search of PubMed was done for long-term (≥12 week) clinical trials of TCS or
TCI treatment in patients <12 years with AD. Citations were reviewed for inclusion based on MeSH terms, abstracts,
and relevant article text. Studies were excluded if they did not encompass subjects <12 years, or were <12 weeks’
duration, retrospective, meta-analyses, or limited to anecdotal case reports.
Results: Of 27 trials meeting criteria, 21 included 5825 pediatric patients treated with TCIs, and 6 included 1999
patients treated with TCS. TCS studies were limited to low- to mid-potency products, and all but one study lacked a
vehicle control. Eight TCI studies were vehicle-controlled, and safety data were well reported, with ≤5 % of patients
reporting discontinuation due to adverse effects (DAEs). Cutaneous and systemic adverse events (AEs) were similar
in TCI and vehicle groups, with no reports of lymphoma. Safety data in TCS trials were less well reported. DAE
incidence was addressed in just 2 trials, and systemic and cutaneous AEs were mostly unreported.
Conclusions: Data supporting long-term use of TCIs are robust, documenting safety and efficacy, while data
supporting long-term TCS use are limited to low- to mid-potency products. Our review identifies a lack of
information on the safety of commonly prescribed, long-term monotherapy with mid- to high-potency TCS in
pediatric AD, and supports standard-of-care maintenance therapy with TCIs and intermittent use of low- to
mid-potency TCS for flares.
Keywords: Atopic dermatitis, Long-term safety, Lymphoma, Pediatric, Pimecrolimus, Tacrolimus, TCS, TCI, Topical
calcineurin inhibitor, Topical corticosteroid
* Correspondence: esiegfri@slu.edu
1
Saint Louis University, Cardinal Glennon Children’s Hospital, 1465 South
Grand Avenue, St Louis, MO 63104, USA
Full list of author information is available at the end of the article
© 2016 Siegfried et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Siegfried et al. BMC Pediatrics (2016) 16:75
DOI 10.1186/s12887-016-0607-9
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
Background
Atopic Dermatitis (AD) is a chronic, pruritic inflamma-
tory skin disease that occurs most frequently in children.
It is the most common chronic pediatric inflammatory
skin disease, affecting 12.5 % of US children (aged 0–17
years) from 2009 to 2011, an increase of 5.1 % from
1997 to 1999 [1]. More than half of pediatric patients
with AD have mild disease [2], yet the majority of pedia-
tricians refer even their mild patients to dermatologists
after providing initial, limited care [3, 4]. This pattern of
referrals is due at least in part to questions about the
safety of using topical corticosteroids (TCS) and topical
calcineurin inhibitors (TCI) to treat AD, particularly in
pediatric patients. However, given the shortage of spe-
cialists and an increased emphasis on the accountable
care model, primary care physicians and pediatricians
will continue to play an important role in the manage-
ment of AD, both as a first-line contact and in regular
maintenance following consultation with a specialist.
TCS, which are considered to be first-line treatment
for AD flares, have been FDA-approved for a variety of
grandfathered indications since 1955. Their mechanism
of action, though not well understood, is multifaceted
and includes broad-spectrum impact on immune and
skin barrier function. Despite their demonstrated efficacy
in AD, TCS are associated with a known potential for
cutaneous atrophy-related adverse effects such as tel-
angiectasia, striae and purpura, as well as focal hypertri-
chosis, hypopigmentation and perioral dermatitis [5–9].
In addition, long-term and/or more than once-daily use
is associated with subclinical barrier disruption that can
result in rebound flares following discontinuation. Long-
term subclinical barrier disruption may also cause cu-
mulative increases in percutaneous absorption, with the
possibility of rare but insidious and difficult-to-quantify
systemic adverse events such as adrenal suppression,
poor growth, hypertension, hyperglycemia, insulin resist-
ance, and cataracts [10–14]. These safety concerns are
increased in pediatric patients, whose greater body sur-
face area-to-weight ratio is thought to cause increased
percutaneous absorption. This risk may be compounded
by concomitant use of corticosteroids for other atopic
comorbidities (asthma, allergic rhinitis).
In 2000–2001, TCIs were approved in the US for
“short-term and noncontinuous chronic treatment of
AD in nonimmunocompromised individuals who have
failed to respond adequately to other topical prescription
AD treatments”[15, 16]. Tacrolimus ointment is avail-
able in 2 concentrations: 0.03 %, approved for patients
over age 2, and 0.1 %, approved only for patients over
age 16 due to theoretical concerns. Pimecrolimus 1 %
cream is approved for patients over age 2. In 2006, the
FDA instituted a Boxed Warning for both TCIs based on
a theoretical risk of malignancy (including lymphomas)
that sparked a debate over their safety and appropriate
use [17].
Since then, no clear link has been demonstrated between
TCI use and lymphoma risk, despite almost a decade of
clinical and epidemiological studies, post-marketing sur-
veillance, and monitoring of reports to the FDA Adverse
Event Reporting System (AERS). Recent published reviews
and/or meta-analyses that assess lymphoma risk of TCIs
based on the last decade of clinical experience conclude
that there is no evidence that TCI use is associated with in-
creased risk of lymphoma (Table 1) [18–39]. Yet the Boxed
Warning remains, leaving many clinicians hesitant to pre-
scribe TCIs despite their potential benefit to some patients.
Unlike TCS, TCIs do not carry the risks of skin atrophy,
percutaneous absorption, or rebound flares, and have been
also been demonstrated to reduce TCS use in long-term
studies [40–48]. Therefore TCIs are potentially useful
as steroid-sparing agents, and as first-line topical anti-
inflammatory treatment on the face and in skin folds.
To assess the safety of TCS and TCI use in children,
we performed a comparative systematic literature search
for published, long-term clinical trials of TCS or TCI
treatment in pediatric patients with AD.
Methods
Systematic searches for published, long-term clinical trials
of TCI and TCS trials in pediatric patients
The search strategies we used to identify published, long-
term (≥12 week) clinical trials of TCI and TCS in pediatric
patients (<12 yrs of age) with AD are shown in Figs. 1 and
2. For TCI trials, PubMed was queried with the following
terms: (topical calcineurin inhibitor OR TCI OR pimecroli-
mus OR tacrolimus) AND (atopic dermatitis OR eczema).
Results were filtered for clinical trials to eliminate other
types of publications (eg, review articles, meta-analyses,
case reports) and minimize risk of bias. For TCS trials,
PubMed was queried with the terms: topical AND (gluco-
corticoid OR glucocorticosteroid OR corticosteroid OR
steroid OR hydrocortisone OR fluocinolone OR triamcino-
lone OR desonide OR prednicarbate OR fluticasone OR
mometasone) AND (atopic dermatitis OR eczema). Results
were filtered for clinical trials to eliminate other types of
publications (eg, review articles, meta-analyses, case re-
ports) and minimize risk of bias. For all citations obtained,
MeSH terms, abstracts, and when necessary the article
text, were reviewed. Citations were excluded if they were
not English-language or were duplicate PubMed entries; if
they reported trials in animals or in healthy subjects with-
out AD; if they included subjects with psoriasis, asthma,
or hand eczema; or if TCI, or TCS, were not the ac-
tive treatment being assessed. Meta-analyses/review
articles that did not present new, previously unpublished
data were excluded, as well as retrospective studies, case
reports, and studies of 10 or fewer patients.
Siegfried et al. BMC Pediatrics (2016) 16:75 Page 2 of 15
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Table 1 Summary statements from review articles that assess TCI lymphoma risk
a
Citation Evidence of lymphoma risk with TCIs? Lymphoma risk summary statement
Yes No
Berger 2006 [18]√…no causal proof that TCIs cause lymphoma…
Deleuran 2009 [19]√…no studies support that the use of topical immunosuppression increases the risk
of local or systemic cancer
b
.
Ehrchen 2008 [20]√…no data indicating that topical therapy in humans results in an increased risk for
lymphomas.
Fonacier 2005 [21]√…risk/benefit ratios of topical pimecrolimus and tacrolimus are similar to those of
most conventional therapies…
Langley 2007 [22]√…there is no clinical evidence to establish that treatment with pimecrolimus
cream 1 % increases the risk of malignancy.
Lebwohl 2006 [23]√…no causal relationship between the use of TCIs and the occurrence of
lymphoma…
Legendre 2015 [24]√…systematic literature review shows slightly increased risk of lymphoma in patients
with AD…role of topical steroids and TCIs is unlikely to be significant.
McNeill 2007 [25]√…low incidence of lymphoma and lack of temporal relationship points to a strong
safety profile thus far in regards to tacrolimus and lymphoma.
Munzenberger 2007 [26]√…no data that show that TCIs are associated with an increased risk of
lymphoproliferative disease…lymphoproliferative disease was induced only
when doses of TCIs well above the maximum recommended human doses were
used.
Orlow 2007 [27]√…no evidence to suggest that there is any increased risk of malignancy associated
with TCIs.
Ormerod 2005 [28]√…no evidence to date to suggest an increased risk of cutaneous or visceral cancer.
Ortiz de Frutos 2008 [29]√…with the current information, it cannot be associated to an increase of any type
of neoplasms
b
.
Patel 2007 [30]√…no established causal link between the topical immunomodulators tacrolimus
and pimecrolimus and…malignancy.
Ring 2008 [31]√…the potential risk of malignancy seems to be low.
Rustin 2007 [32]√…no evidence of a causal link between the use of tacrolimus ointment and the
rare cases of skin cancer that have been reported.
Sánchez-Pérez 2008 [33]√…there doesn’t exist scientific evidence of increase of skin cancer, lymphomas or
systemic immunosuppression in patients that use…topical tacrolimus
b
.
Spergel 2006 [34]√…studies from clinical trials, systemic absorption, and post-marketing surveillance
show no evidence for this systemic immunosuppression or increased risk for any
malignancy.
…no evidence of increased incidence of lymphoma with short-term or intermittent
long-term …tacrolimus and pimecrolimus…
Tennis 2011 [35]√…the hypothesis that pimecrolimus and tacrolimus cause malignancy…has not
been supported by the epidemiological studies to date…
Thaçi 2007 [36]√…current scientific data do not support increased concern for risk of malignancy.
Thaçi 2010 [37]√…no scientific evidence of an increased risk for malignancy due to a topical
treatment with calcineurin inhibitors.
Weischer 2007 [38]√…tumor risk of topical immunomodulators is lower than the FDA black box
warning may indicate.
Werfel 2009 [39]√…clinical studies with pimecrolimus have not shown any evidence of an increased
risk of malignancy…analysis of spontaneously reported adverse events has also
not shown any evidence of malignancy…
a
Review articles or meta-analyses that assess the lymphoma risk of TCIs were identified by querying PubMed with the terms (lymphoma OR neoplasm OR malignancy
OR cancer) AND (topical calcineurin inhibitor OR TCI OR pimecrolimus OR tacrolimus) AND (atopic dermatitis OR eczema), and filtering for meta-analysis, review, and
systematic review articles. Articles were excluded if lymphoma risk was not the main focus of the article, or if authors did not come to a conclusion regarding lymphoma
risk (or merely referenced conclusions from other papers)
b
Statement is quoted from the translated abstract of a foreign-language article
Siegfried et al. BMC Pediatrics (2016) 16:75 Page 3 of 15
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Finally, we excluded studies that did not include safety
data, were less than 12 weeks’duration, or did not in-
clude pediatric patients (<12 yrs of age).
Summary of safety data from TCI and TCS trials
Long-term safety data from the TCI and TCS trials that
met inclusion criteria were summarized descriptively;
statistical analyses were not performed due to the incon-
sistency in reporting of these data. We limited the focus
to safety data that we judged to be most relevant to
long-term AD treatment: discontinuations due to AEs,
cutaneous AEs (skin infection, atrophy), and systemic
AEs (infection, lymphoma, gastrointestinal [GI] events,
respiratory tract infections [RTIs]). We did not present
the incidence of minor application site reactions (burn-
ing, pruritus) that typically occur early in treatment and
resolve, potentially atopic or allergic events (allergies,
asthma, conjunctivitis) that are common in patients with
AD and are generally not related to treatment, or events
with unclear origin that are unlikely to be treatment-
related (cough, fever, headache, nasopharyngitis, rhinitis).
Results
Published trials included in safety summary
The PubMed queries resulted in 221 TCI citations and
487 TCS citations (Figs. 1 and 2). Of these, 21 TCI trials
(27 citations [41, 44–69]) met the inclusion criteria for
our safety summary and are presented in order of dur-
ation in Tables 2 and 3. All 21 TCI trials were published
after 2000, and more than half were published after the
Boxed Warning was issued in 2006. Six trials (6 citations
[50, 61, 70–73]) met inclusion criteria and are included
in the TCS safety summary (Table 4), 2 of which were
actually TCI trials with a TCS treatment arm as an active
comparator (both trials are also included in the TCI
safety summary [50, 61]). One long-term TCS trial in
pediatric patients was excluded from our summary
due to its retrospective design (n= 756) [74]. In this
study, patients using TCS of any potency were in-
cluded in the study, and no systemic safety data were
reported. All but 1 of the TCS trials included in our
summary were published after 2000, but only 1 was
published after 2006.
Study designs
Treatment varied according to individual study designs,
but typically a brief twice-daily regimen to control the
initial flare was followed by a maintenance period of
intermittent, as-needed treatment for flares (study treat-
ments during the maintenance phase are indicated in
bold in Tables 2, 3 and 4).
Fig. 1 Systematic search strategy for published long-term (≥12 weeks) TCI trials in pediatric patients (<12 years) with AD.
a
Exclusions were based on
review of MeSH terms, abstract, or (when necessary) the article text.
b
Meta-analyses and reviews were excluded if no new (previously unpublished)
data were presented
Siegfried et al. BMC Pediatrics (2016) 16:75 Page 4 of 15
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TCI trials
Three tacrolimus trials were double-blind, vehicle-
controlled (2 tacrolimus 0.03 % vs vehicle [51–54], 1 ta-
crolimus 0.1 % vs tacrolimus 0.03 % vs vehicle [49]), 1
was double-blind, active- and no treatment-controlled
(tacrolimus 0.03 % vs hydrocortisone vs no treatment
[50]), and 5 were uncontrolled, open-label [55–59]. Five
pimecrolimus studies were double-blind, vehicle-controlled
[41, 44–48], and 1 was double-blind, active-controlled
(pimecrolimus BID vs QD [60]). One study was open-label,
active-controlled (the Petite Study, pimecrolimus vs low-
or mid-potency TCS [61]), and 5 were uncontrolled, open-
label trials [62–69].
TCS trials
Two TCS studies were double-blind, active-controlled: 1
low-potency TCS (hydrocortisone) vs mid-potency TCS
(betamethasone valerate) [70], and 1 low-potency TCS
(desonide) vs low-potency TCS (hydrocortisone) [71].
One was an open-label, vehicle-controlled trial of mid-
potency TCS (fluticasone) vs vehicle [72], and another
was a meta-analysis of 2 previously unpublished, double-
blind, active-controlled trials of mid- or low-potency
TCS (fluticasone or hydrocortisone) [73].
Two additional studies that met inclusion criteria for
TCS safety summary were actually TCI studies in which
TCS treatment was an active comparator: one was a
double-blind trial of tacrolimus vs low-potency TCS
(hydrocortisone) vs no treatment [50], and the other was
the Petite Study, an open-label trial of pimecrolimus vs
low- or mid-potency TCS (hydrocortisone or hydrocorti-
sone butyrate) [61].
We did not identify any published long-term pediatric
trials of high-potency TCS.
TCS use in TCI studies
All except 3 of the tacrolimus studies prohibited TCS
use; 1 study permitted TCS use per protocol during
the first 4 weeks [55], 1 permitted TCS use for flares
not controlled by study medication [58], and 1 pro-
hibited TCS use but did not exclude an unspecified
number of patients that deviated from study protocol
and used TCS [59]. In 10 of the 12 pimecrolimus
studies, TCS use was permitted for flares not con-
trolled by study medication; in these studies, 28–72 %
of patients in any treatment group reported using a
TCS (2 trials did not report the incidence of TCS
use).
Fig. 2 Systematic search strategy for published long-term (≥12 weeks) TCS trials in pediatric patients (<12 years) with AD.
a
Exclusions were based
on review of MeSH terms, abstract, or (when necessary) the article text.
b
Meta-analyses and reviews were excluded if no new (previously unpublished)
data were presented
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Table 2 Study designs for long-term (≥12 weeks) tacrolimus trials in pediatric patients (<12 years) with AD
Trial Duration (wk)
a
Baseline AD severity Age, mean (range) TCS Use N Treatment
b
Controlled studies
Paller 2001 [49] 12 moderate to severe
(≥4.5 R&L)
6yr(2–15) None 118 tacrolimus 0.1 % BID (DB) for flares
117 tacrolimus 0.03 % BID (DB) for flares
116 vehicle BID (DB) for flares
Hofman 2006 [50] 28 moderate to severe
(≥4.5 R&L)
~6 yr (2–11) None 133 tacrolimus 0.03 % BID for 3 wk, then tacrolimus
QD + vehicle QD (DB) for flares
- 124 hydrocortisone ointment 1 % BID for head/neck
and hydrocortisone butyrate ointment 0.1 %
BID for trunk/limbs for 2 wk, then
hydrocortisone 1 % BID (DB) for flares
None 50 no treatment (patients did not have AD)
Paller 2008 [51]
Breneman 2008 [52]
42 moderate to severe
(mean EASI = ~11)
7yr(2–15) None 68 tacrolimus 0.03 % or alclometasone ointment
0.05 % BID for 4 d (DB), then BID (OL) for
2–16 wk until clearance; then tacrolimus 0.03 %
QD 3x/wk (DB) and tacrolimus BID for flares
36 tacrolimus 0.03 % or alclometasone ointment
0.05 % BID for 4 d (DB), then BID (OL) for
2–16 wk until clearance; then vehicle QD 3x/wk
(DB) and tacrolimus 0.03 % BID for flares
Thaçi 2008 [53]
Thaçi 2010 [54]
52 mild to severe
(≥3 R&L)
7yr(2–15) None 125 tacrolimus 0.03 % BID (OL) for 1–6 wk until
clearance, then tacrolimus 0.3 % 2x/wk (DB)
and tacrolimus 0.03 % BID (OL) for flares
125 tacrolimus 0.03 % BID (OL) for 1–6 wk until
clearance, then vehicle 2x/wk (DB) and
tacrolimus 0.03 % BID (OL) for flares
Uncontrolled studies
Kubota 2009 [55] 12 moderate to severe
(mean EASI = 13)
7yr(2–15) None
c
31 OL tacrolimus 0.03 % QD + TCS (strong or weak)
QD for 2 wk, then tacrolimus BID on weekdays
and tacrolimus QD + TCS QD on weekends for
2 wk, then tacrolimus BID (no TCS) for 2 wk
followed by tacrolimus BID (no TCS) for flares
Tan 2004 [56] 24 mild to severe 8 yr (2–15) None 82 OL tacrolimus 0.1 % BID until 1wk after
clearance, then tacrolimus 0.1 % BID for flares
Kang 2001 [57] 52 moderate to severe
(≥4.5 R&L)
8yr(2–15) None 255 OL tacrolimus 0.1 % BID for flares
Mandelin 2012 [58] 104 moderate to severe
(mean EASI = 11)
15 mo (3–24) NR
d
50 OL tacrolimus 0.03 % BID for 3 wk and then
QD until clearance; thereafter BID for flares
Hanifin 2005 [59] 156 (≤196 wk
exposure)
mild to severe (R&L) (2–15 yr) NR
e
391 OL tacrolimus 0.1 % BID for flares for 3 yr
(after 1 yr tacrolimus in unpublished lead-in study)
N= safety population
BID indicates twice daily, ddays, DB double-blind, EASI eczema area and severity index, mo months, NR not reported, OL open label, PSGA physicians static global
assessment, pts patients, QD once daily, R&L Rajka and Langeland, TCS topical corticosteroids, wk week(s), yr year(s)
a
For trials of <12 months: duration in weeks = 4 X total months of study. For trials ≥1 year: duration in weeks = 52 X total years of study
b
To differentiate the long-term study treatments from any short-term lead-in treatments, the long-term treatments are indicated in bold
c
TCS use per protocol was permitted during the first 4 weeks and prohibited for the remainder of the study
d
TCS use was permitted (for up to 2 weeks in any 3 months) to treat flares not controlled by study medication; information on the incidence and duration of TCS
use was NR
e
TCS use was not permitted, however an unspecfied number of patients deviated from protocol and used TCS; these patients were not excluded from
study summary
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Table 3 Study designs for long-term (≥12 weeks) pimecrolimus trials in pediatric patients (<12 years) with AD
Trial Duration (wk)
a
Baseline AD
severity
Age, mean
(range)
TCS Use N Treatment
b
Controlled studies
Ruer-Mulard 2009 [60] 22 mild to severe
(mean EASI = ~10)
7yr(2–17) NR
c
134 pimecrolimus 1 % BID (OL) for ≤6 wk until
clearance, then pimecrolimus BID (DB) for
flares
134 pimecrolimus 1 % BID (OL) for ≤6 wk until
clearance, then pimecrolimus QD + vehicle
QD (DB) for flares
Siegfried 2006 [44] 24 mild to severe
(mean IGA = 3)
59 mo (3–140) 40 % of pts 183 pimecrolimus 1 % BID (DB) for flares
62 mo (3–143) 55 % of pts 92 vehicle BID (DB) for flares
Zuberbier 2007 [47]
Zuberbier 2008 [48]
24 severe (R&L = 8.3) ~8 yr (2–17) 29 % of days 195 prednicarbate cream 0.25 % OL for 7–21 d,
then pimecrolimus 1 % BID (DB) until
clearance (≥7 d) and pimecrolimus BID for
flares
35 % of days 89 prednicarbate cream 0.25 % OL for 7–21 d,
then vehicle BID (DB) until clearance (≥7d)
and vehicle BID for flares
Sigurgeirsson 2008 [45] 26 mild to moderate
(IGA ≤1)
7yr(1–17) 41 % of pts 256 pimecrolimus 1 % BID (DB) for flares
72 % of pts 265 vehicle BID (DB) for flares
Kapp 2002 [41] 52 mild to severe
(mean EASI = ~12)
12 mo (3–23) 36 % of pts 204 pimecrolimus 1 % BID (DB) for flares
65 % of pts 46 vehicle BID (DB) for flares
Wahn 2002 [46] 52 mild to severe
(mean EASI = ~13)
8yr(1–17) 43 % of pts 474 pimecrolimus 1 % BID (DB) for flares
68 % of pts 237 vehicle BID (DB) for flares
Sigurgeirsson 2015 [61] 260 mild to moderate
(IGA = 2–3)
7mo(3–12) 64 % of pts 1205 pimecrolimus 1 % (OL) until clearance, and
then pimecrolimus as needed for flares
d
- 1213 hydrocortisone 1 % or hydrocortisone
butyrate 0.1 % (OL) until clearance and then
hydrocortisone as needed for flaresd
Uncontrolled studies
Kaufmann 2004 [62]
Staab 2005 [63]
20 mild to severe
(mean EASI = ~17)
(3–23 mo) NR
e
188 pimecrolimus 1 % or vehicle BID (DB) for
2–4 wk until clearance, then pimecrolimus
1 % BID (OL) for flares for 12 wks and 4 wks
with no treatment
Lübbe 2006 [64] 24 mild to severe 15 yr (<1–81) 53 % of pts 947 pimecrolimus 1 % BID (OL) for flares
Simon 2006 [65] 24 mild to severe 21 yr (<1–70) NR
c
109 pimecrolimus 1 % BID (OL) until clearance,
then pimecrolimus BID for flares
Whalley 2002 [66]
Langley 2008 [67]
26 mild to moderate
(IGA = 2–3)
~7 yr (<2–17) None 233 pimecrolimus 1 % BID (DB) for 6 wks, then
pimecrolimus BID (OL)
102 vehicle BID (DB) for 6wks, then
pimecrolimus BID (OL)
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Number of patients analyzed and duration of treatment
The TCI studies ranged in duration from 12 weeks to
5 years (260 weeks) and included 5825 pediatric patients
with mild to severe AD (tacrolimus studies = 1370,
pimecrolimus studies = 4455) (Fig. 3). Six TCS trials (in-
cluding 2 in which TCS treatment was an active com-
parator) included 1999 pediatric patients with mild to
severe AD. The only TCS study longer than 48 weeks
was the Petite study, in which TCS was an active com-
parator for pimecrolimus [61]; the 1213 TCS patients in
this study accounted for more than half of the total
number of TCS subjects in the analysis. In contrast,
there were 8 TCI trials of >2700 patients with durations
of more than 48 weeks [41, 46, 53, 54, 57–59, 61, 68, 69],
including a 2-year study (n=91), 4-year study (n=391),
and the 5-year Petite study (n= 1205).
Reporting of safety data in the published trials
Reporting of safety data was highly variable from study to
study, especially in the TCS studies. While TCI trials usu-
ally reported the cutaneous and systemic AEs that occurred
most frequently during the study, many TCS studies only
reported application-site events, and did not report the in-
cidence of systemic AEs. Further, instead of reporting any
AE that occurred frequently, regardless of severity or rela-
tion to study treatment, some TCS studies reported only
AEs that were classified as serious/severe and/or thought
to be treatment-related. Terminology and classification of
AEs was inconsistent across all the studies, with some
studies reporting incidences of specific AEs, and others
reporting incidences of general AE categories (eg, bacterial,
viral, or fungal infection). In the studies that reported the
incidenceofspecificAEs,theterminologyusedfortheAEs
was not consistent between studies.
Summary of safety data
Safety data are summarized in Table 5. Studies are listed
from shortest to longest duration, and divided by treat-
ment received: tacrolimus (N= 1370; 0.03 %, n=524;
0.1 %, n= 846), pimecrolimus (N= 4455), low-potency
TCS (N= 400), mid-potency TCS (N= 257), low- or
mid-potency TCS (N= 1342), vehicle + TCS rescue (TCS
was permitted to treat flares not controlled by study
medication, N= 729), vehicle (N=355), and no treatment
(N= 50; these subjects did not have AD).
To increase clarity and interpretability, AEs were cate-
gorized as either cutaneous events (bacterial infection,
viral, infection, fungal infection, or atrophy) or systemic
events (bacterial infection, viral infection, RTIs, GI
events, or lymphoma). A list of the AE terms that were
included in each category is provided in the footer of
Table 5. When multiple AEs in the same category were
reported, incidences are shown as a range. If the inci-
dence of an AE category was not reported in the pub-
lished study, it could not be assumed to be 0 and is
therefore shown as “●”. AE incidences of >1 % were
rounded to the nearest whole number.
Discontinuations due to adverse events
Fourteen of 21 TCI studies reported the incidence of
discontinuation due to AEs (DAEs, Table 5); in those
studies it was ≤5 %. About half of the DAEs were caused
by application-site events (with the exception of 1 tacro-
limus study in which all 9 DAEs in the vehicle group
were application-site events). In contrast, only 2 TCS tri-
als reported the incidence of DAEs; in those 2 studies,
the incidence was <5 %.
Cutaneous adverse events
The incidence of skin infections in TCI-treated pa-
tients was generally low (Table 5), and similar to those
reported by vehicle-treated patients. In all but one trial
of <1 year duration, ≤5 % of patients reported skin in-
fections (in a 24-week, uncontrolled, open-label tacro-
limus study, 13 % of patients reported impetigo [56]).
In most longer-term studies (≥1 year duration), skin
infection occurred in <10 % of patients. Varicella was
reported by 18 % of patients in a 2-year tacrolimus
study and 20 and 16 % of pimecrolimus and vehicle
patients, respectively in a 1-year study [41, 58]), and
impetigo was reported by 27 % of vehicle patients (but
just 8 % of pimecrolimus patients) in another 1-year
trial [46]. In the 5-year Petite study, rates of skin infec-
tion were similar in the pimecrolimus and TCS groups
Table 3 Study designs for long-term (≥12 weeks) pimecrolimus trials in pediatric patients (<12 years) with AD (Continued)
Papp 2005 [68]
Papp 2005 [69]
52 (≤104 wk
exposure)
mild to severe
(mean EASI = 5.8)
28 mo (18–41) 28 % of pts 91 pimecrolimus 1 % BID (OL) for flares for
1 yr (following 1 yr of pimecrolimus 1 %
BID [DB] or vehicle BID in lead-in study
[Kapp et al. 2002 [41]]
Nsafety population
BID indicates twice daily, ddays, DB double-blind, EASI eczema area and severity index, IGA investigator’s global assessment, mo months, NR not reported, OL open
label, pts patients, QD once daily, R&L Rajka and Langeland, TCS topical corticosteroids, wk week(s), yr year(s)
a
For trials of <12 months: duration in weeks = 4 X total months of study. For trials ≥1 year: duration in weeks = 52 X total years of study
b
To differentiate the long-term study treatments from any short-term lead-in treatments, the long-term treatments are indicated in bold
c
TCS use was permitted to treat flares not controlled by study medication; information on the incidence and duration of TCS use was not reported (NR)
d
Pimecrolimus and TCS dosing during acute and maintenance phases was per the study country’s label
e
It was not stated whether TCS use was permitted
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Table 4 Study designs for long-term (≥12 weeks) topical corticosteroid trials in pediatric patients (<12 years) with AD
Trial Duration
(wk)
a
Baseline AD severity Age, mean
(range)
TCS Potency
[87]
N Treatment
b
Controlled studies
Thomas 2002 [70] 18 mild to moderate
(mean SASSAD = ~8–14)
5yr(1–15) low (class 7–6) 104 hydrocortisone ointment 1 % BID (DB) for
7 d bursts “when required”
mild to moderate
(mean SASSAD = ~9–16)
6yr(1–15) mid (class 5–3) 103 alternating (DB) betamethasone valerate
ointment 0.1 % BID (3 d) and emollient BID
(4 d) for 7 d bursts “when required”
Jorizzo 1995 [71] 25 mild to moderate 5 yr (<1–12) low (class 7–6) 16 desonide ointment 0.05 % BID (SB)
low (class 7–6) 20 hydrocortisone ointment 1 % BID (SB)
Hanifin 2002 [72] 44 moderate to severe
(mean R&L = 7)
7 yr (<1–17) mid (class 5–3) 154 fluticasone propionate cream 0.05 % BID (OL)
for ≤4 wks until clearance; then fluticasone
propionate BID (DB) decreased over 20 wk to
QD 2x/wk; then fluticasone propionate QD
2x/wk (OL) for 20 wk
- 77 fluticasone propionate cream 0.05 % BID (OL) for
≤4 wks until clearance; then vehicle BID (DB)
decreased over 20 wk to QD 2x/wk; then
fluticasone propionate QD 2x/wk (OL) for 20 wk
Meta-analysis
Kirkup 2003 [73]
c
16 moderate to severe
(mean AD
d
= ~12
e
)
8yr(2–14) mid (class 5–3) 136 hydrocortisone 1 % cream BID for 1–2 wk, then
fluticasone propionate cream 0.05 % BID (DB)
for 2–4 wk and then “as required”for flares
low or mid
(class 7–3)
129 hydrocortisone 1 % cream BID for 1–2 wk, then
hydrocortisone 1 % or hydrocortisone
butyrate 0.1 % BID (DB) for 2–4 wk and then
“as required”for flares
TCS as active comparator
f
Hofman 2006 [50] 28 moderate to severe
(≥4.5 R&L)
~6 yr (2–11) - 133 tacrolimus 0.03 % BID for 3 wk, then tacrolimus
QD + vehicle QD (DB) for flares
low (class 7–6) 124 hydrocortisone ointment 1 % BID for head/neck
and hydrocortisone butyrate ointment 0.1 %
BID for trunk/limbs for 2 wk, then
hydrocortisone 1 % BID (DB) for flares
-50no treatment (patients did not have AD)
Sigurgeirsson 2015 [61] 260 mild to moderate
(IGA = 2–3)
7mo(3–12) - 1205 pimecrolimus 1 % (OL) until clearance, and
then as needed for flares
g
mild to moderate
(IGA = 2–3)
7mo(3–12) low or mid
(class 7–3)
1213 hydrocortisone 1 % or hydrocortisone
butyrate 0.1 %(OL) until clearance, and then as
needed for flares
g
N= safety population
AD indicates atopic dermatitis, BID twice daily, ddays, DB double-blind, EASI eczema area and severity index, IGA investigator’s global assessment, mo months, NR
not reported, OL open label, pts patients, QD once daily, R&L Rajka and Langeland, SASSAD Six area, six sign atopic dermatitis, TCS topical corticosteroids, wk
week(s), yr year(s)
a
For trials of <12 months: duration in weeks = 4 X total months of study. For trials ≥1 year: duration in weeks = 52 X total years of study
b
To differentiate the long-term study treatments from any short-term lead-in treatments, the long-term treatments are indicated in bold
c
Meta-analysis of 2 previously unpublished studies
d
AD Score (max 21) = Number of body areas affected (max 12) + Sum of erythema, excoriation, and lichenification scores (each graded 0–3) at target area (max 9)
e
After ‘run in’
f
TCS treatment was an active comparator arm in 2 TCI trials: Hofman et al. 2006 (also listed in Table 1) and Sigurgeirsson (also listed in Table 2)
g
Pimecrolimus and TCS dosing during acute and maintenance phases was per the study country’s label
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(impetigo was reported in 12 % of pimecrolimus and
10 % of low- or mid-potency TCS patients, and varicella
was reported in 25 and 23 %, respectively [61]). There
were no reports of skin atrophy in the TCI studies.
Besides the Petite study, the incidence of skin infection
in TCS patients was reported in just 2 studies, a 16-week
trial and a 28-week trial; the incidence was ≤2 % in those
studies. Three TCS studies used various methods to assess
skin for signs of atrophy. An 18-week study measured skin
thickness with an ultrasound scanner [70] and found that
8 and 12 % of patients using low- and mid-potency TCS,
respectively, had >25 % reduction in skin thickness. In a
25-week study of low-potency TCS [71], investigators
found no signs of atrophy using an 8x magnifying lamp.
In a meta-analysis of 2 16-week studies of low- or mid-
potency TCS [72], investigators visually assessed skin and
found no evidence of atrophy.
Systemic adverse events
The most frequently reported systemic AEs in the TCI
studies were common childhood infections that were
considered unrelated to treatment. Systemic infections
were reported in up to 20 % of patients in TCI studies
of <1 year duration; higher incidences were reported in
some longer studies. In one 1-year study, 27 and 25 %
of patients in the pimecrolimus and vehicle groups, re-
spectively, reported an RTI, and 28 and 26 % reported a
gastrointestinal (GI) event [41]. Almost half of patients
in a 4-year, open-label tacrolimus study reported a viral
infection [59], and in a 2-year, open-label tacrolimus
study up to 90 % of patients reported an RTI, and 38 %
reported a GI event [58].
In the 5-year Petite study, up to 17 % of pimecrolimus
and TCS patients reported some type of systemic bacter-
ial infection, and 17 % reported influenza-like illness
[61]. Up to 35 and 32 % of pimecrolimus and TCS pa-
tients, respectively, reported RTIs, and up to 32 and
31 % had GI events. Besides the Petite study, just 2 TCS
studies of 16- and 18-week durations reported inci-
dences of systemic AEs of ≤6 % [70, 73].
Effects on adrenal and immune system function
The Petite study investigated the effects of up to 5 years
of AD treatment on growth rate and immune system
function in a large population of infants, and found no
difference in growth rate between the pimecrolimus and
TCS treatment groups [61]. Similarly, immunologic in-
vestigation showed that infants in the pimecrolimus and
TCS groups developed antibody titers to common vac-
cine antigens that were similar to each other and to what
would be expected in the general population.
Prior to the Petite study, there were few published
studies that evaluated the effects of long-term TCS treat-
ment on immune system or HPA-axis function in
pediatric patients. In a 44-week study of mid-potency
TCS, 2 patients from a small cohort that were adminis-
tered a cosyntropin stimulation test (CST) had reduced
serum cortisol responses [72]. In a 28-week study, nei-
ther tacrolimus nor low-potency TCS interfered with
Fig. 3 Total subjects included in summary of long-term (≥12 weeks) pediatric trials by therapeutic agent and study duration.
a
Lighter shading
indicates the proportion of patients that received TCS treatment as an active comparator in studies of a TCI.
b
One of the trials was a 1-yr OL
extension of a 1-yr DB study. N=Numberofstudies. n= Number of subjects in respective treatment group
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Table 5 Adverse events reported in long-term (≥12 weeks) pediatric trials of TCI and TCS listed by duration
If trial duration was <1 year and reported in months, the number of weeks was calculated as follows: duration in weeks =4 X duration in months. If trial duration
was ≥1 year, the number of weeks was calculated as follows: duration in weeks = number of years X 52
Only incidences of adverse events (AEs) that were specifically reported to be “0”are indicated as such; AEs that were not a specified study outcome and/or were
not reported are indicated as “●”
Incidences of discontinuations due to adverse events (DAEs) and AEs >1 % are rounded to the nearest whole number; incidences are presented as a range when
multiple AEs within the same category were reported
a
AEs that may have been reported in the studies but are not shown include: application site reactions (burning, pruritus, etc.), potentially atopic or allergic events,
or events with unknown/unclear origin (asthma, conjunctivitis, coughing, fever/pyrexia, joint pain, nasal congestion, nasopharyngitis, pharyngitis,
rhinitis/coryza, rhinorrhea)
b
Cutaneous AE categories
Bacterial infection = abscess, bacterial infection, boil, cellulitis, eczema Infected/infection, erysipelas, folliculitis, furuncle, impetigo, infection, pustules,
staphylococcal Infection, streptococcal infection, or stye
Viral infe ction =chicken pox, eczema herpeticum, flat warts, herpes simplex, herpes virus infection, herpes zoster, Kaposi’s varicelliform eruption, molluscum, skin
papilloma, varicella, viral rash Candida, fungal infection, ringworm
Atrophy = antecubital fossae atrophy, atrophy, hypertrichosis, popliteal fossae atrophy, telangiectasia
c
Systemic AE categories
Bacterial infection = bacterial pneumonia, bronchitis, ear infection, external otitis, infection, laryngitis, sinusitis, Staphylococcus infection, Streptococcus
pharyngitis, tonsillitis
Viral infe ction = flu-like symptoms, influenza, influenza-like Illness, viral encephalitis
Respiratory tract infection (RTI) = otitis media, respiratory tract infection, upper respiratory tract infection, viral respiratory tract infection
Gastrointestinal infection (GI) = diarrhea, gastroenteritis, viral gastroenteritis, vomiting
d
Incidences of some viral infections were reported only for the combined tacrolimus group in the Paller study
e
Results for the 2 pimecrolimus treatment groups are combined in the Ruer-Mulard and Whalley/Langley studies
f
TCS treatment was received In the Hofman study as an active control for tacrolimus
g
Patients received either hydrocortisone 1 % (low-potency TCS) or hydrocortisone butyrate 0.1 % (mid-potency TCS)
h
TCS treatment was received in the Sigurgeirsson study as an active control for pimecrolimus
i
TCS was permitted to treat flares not controlled by study medication
j
Tacrolimus was permitted in the Paller/Breneman and Thaçi/Thaçi studies for flares not controlled by study medication
k
These subjects did not have AD
AE indicates adverse event, BID twice daily, BMV betamethasone valerate, DAE discontinuations due to AE, DES desonide, FTC, fluticasone propionate, GI
gastrointestinal, HB hydrocortisone butyrate, HYD hydrocortisone, mo months, PM pimecrolimus, pts patients, QD once daily, RTI respiratory tract infection, TC
tacrolimus, TCS topical corticosteroids, Tx treatment, URTI upper respiratory tract infection, VEH vehicle, wk, week(s), yr, year(s)
Siegfried et al. BMC Pediatrics (2016) 16:75 Page 11 of 15
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immune response following vaccination [50], and a third
study found that long-term (up to 2 years) treatment with
pimecrolimus did not interfere with the development of
systemic immune responses in young children [68].
Ocular risk
None of the TCI and TCS trials we identified in our sys-
tematic literature search assessed glaucoma or cataracts.
Lymphoma risk
There were no reports of lymphoma in any of the TCI
and TCS trials, including the 5-year Petite Study
(Table 5).
Discussion
Given the increasing frequency of AD, primary care phy-
sicians will continue to play an important role in its
management. Some clinicians, patients, and/or parents
have concerns about the safety of topical AD treatments,
especially in children who have an increased risk of per-
cutaneous absorption and systemic exposure. These
safety concerns are also increased with long-term daily
maintenance therapy.
We conducted a systematic search for safety data from
published pediatric TCI and TCS clinical trials of at least
12 weeks duration, and identified 27 clinical trials that
met our inclusion criteria. Twenty-one TCI studies in-
cluded 5825 pediatric patients, >2700 of whom were
followed for 48 weeks to 5 years. Six TCS studies were
limited to low- to mid-potency products and included
1999 pediatric patients, more than half of whom re-
ceived TCS as an active comparator in a study designed
to evaluate the safety of pimecrolimus. Most TCI studies
included a vehicle control group, while all but one TCS
study lacked a vehicle control.
Safety data were generally well reported in the TCI
studies, including the incidences of cutaneous and sys-
temic infections. Less than 5 % of patients in the TCI
studies discontinued due to AEs. Incidences of cutane-
ous AEs were similar in TCI and vehicle treatment
groups, and were within expected range given the pre-
disposition of the AD patient to cutaneous infections
[75]. Systemic AEs that occurred were common child-
hood infections and not considered to be related to
treatment; incidences were similar in treatment and ve-
hicle groups. Extracutaneous viral infections were re-
ported in 47 and 90 % of patients in 2 uncontrolled
tacrolimus studies; these incidences are not unex-
pected given that children under age 5 are expected to
have 3 to 6 respiratory infections per year [76, 77]. In
contrast, safety data in TCS trials were not as well
reported: systemic and cutaneous AEs were mostly
unreported, and DAE incidence was addressed in just
2 trials. None of the TCS studies assessed the inci-
dence of glaucoma or cataracts.
The inconsistency of safety data reporting in the trials
may be due to timing, as more than half of the TCI studies
were published after 2006, when the Boxed Warning for
TCIs increased the focus on their safety and appropriate
use. In contrast, only 2 TCS studies (including the Petite
Study) were published in or after 2006. More recent trials
tend to have improved protocols with standardized and
validated methods for assessing safety data. This is espe-
cially true following the establishment by the NIH in 2000
of a clinical trial registry (ClinicalTrials.gov), and FDA-
mandated expansions in 2007 of registry requirements, in-
cluding disclosure of study design. Further, journal criteria
for publication continue to become more rigorous, requir-
ing more clear and complete reporting of data as well as
clinical trial registration prior to publication.
According to current treatment guidelines, low-to-mid
potency TCS should be used as first-line, short-term
treatment of flares [3, 8, 78]. Choice of potency depends
on the severity, extent, and site of the flare; the least po-
tent TCS that can control the symptoms should be used.
No TCS is indicated for >4 consecutive weeks of use,
and few are approved for patients younger than 2 years
of age because of risk of atrophy and rebound effects.
For mild AD, long-term control is often possible with
intermittent TCS for flares and trigger avoidance, bleach
baths, and daily moisturizers. Moderate-to-severe AD
usually requires long-term daily maintenance therapy
with intermittent TCS or TCIs, which are most useful as
steroid-sparing agents. The regimen and choice of prod-
uct for maintenance therapy depends on factors includ-
ing patient preference, access to medications, cost, and a
careful evaluation of benefits versus risks.
Our review supports the long-term safety of TCIs and
low-to-mid potency TCS in pediatric patients with AD.
Long-term treatment with TCIs and intermittent use of
low-to-mid potency TCS was generally well tolerated in
27 trials of >5800 and >1900 pediatric patients, respect-
ively, with no evidence of cutaneous atrophy or cumula-
tive systemic exposure and no reports of lymphoma.
This reflects preclinical animal studies that detected ma-
lignancy signals only after systemic TCI exposure was
high enough to cause immune suppression. This expos-
ure was much higher than the negligible systemic expos-
ure detected after twice daily topical administration (the
highest blood concentrations reported for infants with
pimecrolimus 1 % range from 1.8 to 4.14 mg/ml, and the
average maximum concentration with tacrolimus 0.03 %
was 3 % of that observed in pediatric liver-transplant pa-
tients receiving oral tacrolimus) [17, 79–84].
Many recent meta-analyses and reviews have also con-
tributed to the body of evidence that has filed to detect
increased lymphoma risk with TCIs [18–39]. One study
Siegfried et al. BMC Pediatrics (2016) 16:75 Page 12 of 15
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
compared the incidence of TCI-associated malignancies
reported to multiple TCI AE databases and found a rate
similar to or lower than the expected rate of malignancy
in the general population [17], and another compared
incidences of lymphoma in health insurance claims data-
bases and did not find an increased risk among patients
treated with TCIs versus TCS [85]. And no increased risk
of malignancy was detected in 7457 children enrolled as
of May 2014 in the ongoing prospective 10-year obser-
vational cohort study of children with a history of AD and
pimecrolimus use (Pediatric Eczema Elective Registry,
PEER) [86].
A decade’s worth of clinical experience, epidemio-
logical data, postmarketing surveillance, and adverse
event database monitoring have failed to demonstrate a
causal relationship between TCI use and malignancy, yet
TCI labelling continues to include a Boxed Warning.
The biggest impact of the warning is to limit patient ac-
cess to the most well-studied medications for long-term
maintenance AD treatment, especially in children.
Conclusions
This comprehensive literature review supports the long-
term safety of TCI and low- to mid-potency TCS ther-
apy in children with AD, with no evidence of cutaneous
atrophy or cumulative systemic exposure and no reports
of lymphoma. We found comparatively limited data on
the long-term safety of mid- to high-potency TCS. Our
findings are not reflected by the current TCI labelling
and Boxed Warning; therefore we hope our review facili-
tates the rescindment of the Boxed Warning.
Abbreviations
AD: atopic dermatitis; AE: adverse event; BID: twice daily;
BMV: betamethasone valerate; d: days; DAE: discontinuation due to adverse
effect; DB: double-blind; DES: desonide; EASI: eczema area and severity index;
FTC: fluticasone propionate; GI: gastrointestinal; HB: hydrocortisone butyrate;
HYD: hydrocortisone; IGA: investigator’s global assessment; Mo: months;
NR: not reported; OL: open-label; PM: pimecrolimus; PSGA: physician’s static
global assessment; Pts: patients; QD: once daily; R&L: Rajka and Langeland;
RTI: respiratory tract infection; SASSAD: six area, six sign atopic dermatitis;
TC: tacrolimus; TCI: topical calcineurin inhibitor; TCS: topical corticosteroids;
Tx: treatment; URTI: upper respiratory tract infection; VEH: vehicle;
Wk: week(s); Yr: year(s).
Acknowledgments
There were no contributors to this paper beyond the individuals that are
listed as authors.
Funding
Financial support for the writing of this manuscript was provided by Valeant
Pharmaceuticals NorthAmerica LLC. Valeant Pharmaceuticals had no role in
the design of the literature searches, or analysis andpresentation of results.
Availability of data and materials
All data supporting our findings are contained within the manuscript;
therefore this published report serves as theaccessible record of the protocol
and findings of our systematic review. No identifying/confidential patient
data wereshared in this paper.
Authors’contributions
ES contributed to the concept of this paper, analysis of search results,
provided clinical perspective, and criticallyreviewed each draft. JCJ
contributed to the concept and preparation of this paper, design of the
literature searches,and analysis and presentation of results. JK was involved in
the design of the literature searches, backgroundresearch, analysis and
presentation of results, and drafting and coordinating the manuscript. AH
contributed to theconcept of this paper, analysis of search results, provided
clinical perspective, and critically reviewed each draft. Allauthors read and
approved the final manuscript as submitted.
Authors’information
TAG conceived of the study, participated in its design and coordination and
helped to draft the manuscript. PYuP carried out the investigation of
possible effects of NGF mimetics on the body weight of rats, performed the
corresponding statistical analysis, participated in the sequence alignment
and drafted the manuscript. TAA carried out all in vitro studies using cultures
and performed the corresponding statistical analysis. YuNF performed the
synthesis of dipeptide NGF mimetics. MAK carried out the investigation of
possible effects of NGF mimetics on pain sensitivity in rats and performed
the corresponding statistical analysis. SBS participated in the study design
and coordination. All authors read and approved the final manuscript.
Competing interests
Elaine C. Siegfried has participated in contract research with Astellas Pharma
(prior to 2001) and Novartis Pharmaceuticals Corporation (prior to 2004) for
which financial compensation was paid to her employer. She received travel
expenses for presentation of some of this contract research from Valeant
Pharmaceuticals North America LLC (in 2012). She has received consulting
fees from Novartis Pharmaceuticals (prior to 2006).
Jennifer Jaworski and Jennifer Kaiser are employees of Prescott Medical
Communications Group and participated in this manuscript with financial
support by Valeant Pharmaceuticals North America LLC.
Adelaide A. Hebert has received consulting fees, been a member of speakers’
bureaus, and/or served on Advisory Boards for Astellas Pharma US, Novartis
Pharmaceutical Corporation (prior to 2008), and Valeant Pharmaceuticals
North America LLC. She has also served as a member of data safety
monitoring boards for Valeant Pharmaceuticals North America LLC and
Novartis Pharmaceuticals Corporation. In addition, she has participated in
contract research with Astellas Pharma US and Novartis Pharmaceuticals
Corporation for which all research funds were paid to heremployer.
Consent to publish
Not applicable.
Ethics and consent to participate
Not applicable.
Author details
1
Saint Louis University, Cardinal Glennon Children’s Hospital, 1465 South
Grand Avenue, St Louis, MO 63104, USA.
2
Prescott Medical Communications
Group, 205 North Michigan Avenue, Suite 3400, Chicago, IL 60601, USA.
3
University of Texas-Houston Medical School, 6655 Travis, Suite 980, Houston,
TX 77030, USA.
Received: 6 August 2015 Accepted: 13 May 2016
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