Biologic agents in juvenile spondyloarthropathies

Abstract

The juvenile spondyloarthropathies (JSpA) are a group of related rheumatic diseases characterized by involvement of peripheral large joints, axial joints, and entheses (enthesitis) that begin in the early years of life (prior to 16th birthday).
The nomenclature and concept of spondyloarthropathies has changed during the last few decades. Although there is not any specific classification of JSpA, diseases under the spondyloarthropathy nomenclature umbrella in the younger patients include: the seronegative enthesitis and arthropathy (SEA) syndrome, juvenile ankylosing spondylitis, reactive arthritis, and inflammatory bowel disease-associated arthritis. Moreover, the ILAR criteria for Juvenile Idiopathic Arthritis includes two categories closely related to spondyloarthritis: Enthesitis-related arthritis and psoriatic arthritis.
We review the pathophysiology and the use of biological agents in JSpA. JSpA are idiopathic inflammatory diseases driven by an altered balance in the proinflammatory cytokines. There is ample evidence on the role of tumor necrosis factor (TNF) and interleukin-17 in the physiopathology of these entities. Several non-biologic and biologic agents have been used with conflicting results in the treatment of these complex diseases. The efficacy and safety of anti-TNF agents, such as etanercept, infliximab and adalimumab, have been analysed in controlled and uncontrolled trials, usually showing satisfactory outcomes. Other biologic agents, such as abatacept, tocilizumab and rituximab, have been insufficiently studied and their role in the therapy of SpA is uncertain. Interleukin-17-blocking agents are promising alternatives for the treatment of JSpA patients in the near future. Recommendations for the treatment of patients with JSpA have recently been proposed and are discussed in the present review.

Full text

R E V I E W Open Access
Biologic agents in juvenile
spondyloarthropathies
María Martha Katsicas
*
and Ricardo Russo
Abstract
The juvenile spondyloarthropathies (JSpA) are a group of related rheumatic diseases characterized by involvement
of peripheral large joints, axial joints, and entheses (enthesitis) that begin in the early years of life (prior to 16
th
birthday).
The nomenclature and concept of spondyloarthropathies has changed during the last few decades. Although there is
not any specific classification of JSpA, diseases under the spondyloarthropathy nomenclature umbrella in the younger
patients include: the seronegative enthesitis and arthropathy (SEA) syndrome, juvenile ankylosing spondylitis, reactive
arthritis, and inflammatory bowel disease-associated arthritis. Moreover, the ILAR criteria for Juvenile Idiopathic Arthritis
includes two categories closely related to spondyloarthritis: Enthesitis-related arthritis and psoriatic arthritis.
We review the pathophysiology and the use of biological agents in JSpA. JSpA are idiopathic inflammatory diseases
driven by an altered balance in the proinflammatory cytokines. There is ample evidence on the role of tumor necrosis
factor (TNF) and interleukin-17 in the physiopathology of these entities. Several non-biologic and biologic agents have
been used with conflicting results in the treatment of these complex diseases. The efficacy and safety of anti-TNF agents,
such as etanercept, infliximab and adalimumab, have been analysed in controlled and uncontrolled trials, usually
showing satisfactory outcomes. Other biologic agents, such as abatacept, tocilizumab and rituximab, have been
insufficiently studied and their role in the therapy of SpA is uncertain. Interleukin-17-blocking agents are promising
alternatives for the treatment of JSpA patients in the near future. Recommendations for the treatment of patients with
JSpA have recently been proposed and are discussed in the present review.
Keywords: Biologic agents, Juvenile, Spondyloarthropaties
Background
The juvenile spondyloarthropathies (JSpA) are a group
of related rheumatic diseases characterized by involve-
ment of peripheral large joints, sacroiliitis / spondylitis
and enthesitis that begin in the early years of life (prior
to 16
th
birthday) [1]. Spondyloarthropathies are strongly
associated with the human leukocyte antigen (HLA)
B27. The nomenclature and concept of spondyloar-
thropathies has changed during the last several
decades. The classification criteria defined by the
European Spondylarthropathy Study Group (ESSG)
marked an important milestone in the common nomen-
clature for these diseases [2]. Diseases under the spondy-
loarthropathy nomenclature umbrella in the younger
patients include: the seronegative enthesitis and arthropa-
thy (SEA) syndrome, juvenile ankylosing spondylitis (JAS),
reactive arthritis, and inflammatory bowel disease-
associated arthritis. Enthesitis-related arthritis (ERA) and
psoriatic arthritis (PsA) are categories of juvenile idio-
pathic arthritis (JIA) according to the ILAR classification.
The definition of ERA includes children with arthritis and
enthesitis, or arthritis plus other features associated with
spondyloarthropathy [3–7]. ESSG criteria were developed
for adult population and subsequently validated in chil-
dren. ERA and psoriatic arthritis patients –according to
ILAR- might fulfill ESSG criteria [3–8]. ERA represents
nearly 15–20 % of patients with JIA in cohort studies, but
it does differ in different parts of the world [8, 9]. Figure 1
Probably differences in prevalence could be related with:
ethnicity, environment and different microbiological epi-
demiologies. JSpA are pathogenetically different from
other types of JIA [10].
JSpA can be divided into classified and unclassified.
Classified diseases includes those that fulfill criteria, but
* Correspondence: mmkatsi@yahoo.com.ar
Service of Immunology & Rheumatology, Hospital de Pediatría Juan P.
Garrahan, Combate de los Pozos 1881, 1245 Buenos Aires, Argentina
© 2016 Katsicas and Russo. 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.
Katsicas and Russo Pediatric Rheumatology (2016) 14:17
DOI 10.1186/s12969-016-0076-6
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others with peripheral arthritis and presence of HLA-
B27 are often considered as unclassified JSpA. Usually
those patients with positive HLA-B27 will develop axial
involvement later.
JSpA is a group of several conditions, the course of
which depends partially upon the presence or absence of
the HLA-B27 allele, which predisposes the patient to-
wards a chronic, progressive axial involvement (includ-
ing sacroiliitis) and final fulfillment of the ankylosing
spondylitis (AS) (modified New York) criteria [11].
Other risk factors for development of sacroiliitis include
number of active joints (multiple joints involvement)
and entheses, hip arthritis, and elevated erythrocyte sedi-
mentation rate (ESR) at disease onset [12, 13]. The de-
velopment and severity of AS would be linked to certain
variables such as: poor efficacy of NSAIDs, elevated
erythrocyte sedimentation rate, limitation in range of
motion of the lumbar spine, oligoarthritis (defined as
four or fewer affected joints), isolated hip arthritis, dac-
tylitis, and onset before the 16
th
birthday [14–16].
The beginning of treatment for JSpA includes NSAIDs
and physiotherapy, but this therapy may not be effective
in a large proportion of patients who will require
disease-modifying anti-rheumatic drugs (DMARDs). The
purpose of this paper is to review the pathogenesis and
role of biologic therapy in JSpA.
Pathophysiology of spondyloarthropathies
Different pathogenetic mechanisms have been proposed
for the SpA.
The strong association between SpA and HLA-B27
suggests that a genetically determined mechanism is in-
volved in its pathophysiology. The role of HLA-B27 in
the pathogenesis of spondyloarthropathies has been
extensively studied. The tendency of HLA-B27 heavy
chains to misfold in the endoplasmic reticulum would
lead to an unfolded protein response and inappropri-
ate cytokine secretion. This hypothesis and the
demonstration of the association between some innate
immunity-related genes or cluster of genes (such as
interleukin IL-1 or ARTS-1 gene [also known as
Endoplasmic Reticulum Aminopeptidase or ERAP-1])
with AS support the concept of SpA being a disease
with both autoimmune and autoinflammatory mecha-
nisms [17, 18] (Fig. 2). The spondyloarthropathies are
a polygenic disease in which polymorphisms in genes
related to the innate immune system are involved:
CARD9,TNF receptor family member 1A,TNF recep-
tor superfamily 15 (TNFSF15), IL-1 (IL1A,ILR2), IL-
23/IL-17 (IL-23R), signal transducer and activator of
transcription 3 (STAT3) [19].
Molecular mimicry between arthritogenic bacteria and
certain domains of the HLA-B27 molecule has been pro-
posed as another probable pathogenic mechanism [20].
An alternative hypothesis focuses on the presentation of
certain arthritogenic peptides in the HLA-B27 pocket to
the lymphocyte bound CD4 molecule. In this model,
CD4+ T cells recognize these bacterial peptides and pro-
duce high levels of interferon (INF) γand other cytokines
which act on macrophages. The relationship between
HLA- B27 and CD8 + T cells would elicit cross-reactivity
between HLA and certain microbial epitopes [21].
Certain cytokines appear to have a prominent role in
the pathophysiology of SpA. TNF-α, a potent pro-
inflammatory cytokine that shows a pivotal role in
inflammatory arthritis [20, 22], has been linked to the in-
flammation of sacroiliac joints in early AS [23]. Higher
serum TNF-receptor (TNFR) 1 and TNFR2 levels have
Fig. 1 Historical Juvenile Spondyloarthropathy Concept. References: JAS: Juvenile Ankylosing spondylitis; PsA: Psoriatic arthritis; ReA: Recative
arthritis; IBD:inflammatory bowel disease. SEAS:Seronegative enthesitis and arthritis syndrome; ERA (ILAR Criteria) Enthesitis_related arthritis:
arthritis and enthesitis or arthritis or enthesitis with at least two of the following: sacroiliac joint tenderness and/or inflammatory spinal pain;
presence of HLA-B27, family history in at least one first-degree relative with medically confirmed HLA-B27 associated disease, anterior uveitis that
is usually associated with pain, redness, or photophobia, onset of arthritis in a boy after 6 years of age. Exclusions: psoriasis confirmed by a derma-
tologist in at least one first- degree relative, presence of systemic arthritis
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been reported in patients with AS and RA. Serum
TNFR1 has been proposed as an inflammatory marker
in AS since its serum levels drop in patients on anti-
TNF treatment [24].
Recent evidence has implicated the Th23-17 axis in
the pathogenesis of SpA [25]. Misfolded HLA-B27 re-
sults in the production of IL-23 which induces Th17
cells to release the pro-inflammatory cytokine IL-17
[26]. This cytokine can stimulate different cell types, in-
cluding synovial fibroblasts, macrophages, and synovial
lining cells to produce pro-inflammatory cytokines (such
as TNFαand IL-6, Receptor Activator for Nuclear Factor
κB Ligand (RANKL), and granulocyte-macrophage
colony-stimulating factor (GMCSF), which can increase
osteoclast numbers and enhance their activity. Several
studies have explored the relationship between IL-17
and IL-23 in SpA [27–30]. Elevated levels of IL-17 in
synovial fluid have been also described in 43 patients
with ERA by Agarwal et al. [31]. Biologic fluid IL-17
levels were similar in children with ERA and adults with
SpA and its concentration was higher in the synovial
fluid than in the serum. This study also analyzed the
production of IL−6, IL−8, Matrix Metalloproteinase
(MMP)-1, MMP-3 and tissue inhibitor of metallopro-
teinases (TIMP) in supernatants from cultures of fibro-
blasts derived from synovial cells that were stimulated
with IL-17 and TNFα. The results suggest that levels
of synovial IL-17 in ERA correlate with disease activ-
ity, possibly due to locally induced MMP production
by fibroblasts. Synovial fluid IL-17 correlated with
number of swollen joints (r= 0,35; p= 0,05) and num-
ber of tender joints (r= 0.46; p= 0.01); no correlation
was found with erythrocyte sedimentation rate [31].
Finally, experimental studies have shown that serum
IL-6 levels are elevated in adult patients with AS and
PsA [32]. Although these conditions are not pediatric,
these studies are the unique evidence of the relation-
ship between IL-6 levels and disease activity in SpA.
In addition, IL-6 was expressed in biopsies of sacro-
iliac joints from patients with AS, especially in those
with recent-onset disease [33].
Biologic agents in JSpA
Over the last decade, biologic agents have demonstrated
an impressive beneficial effect on the inflammatory
features of several rheumatic inflammatory diseases,
including the SpA. Most strikingly, TNF inhibitors have
demonstrated a dramatic impact on the symptoms and
disease course of adult patients with SpA [34]. However,
TNF inhibitors may not be effective for the suppression
of new bone and syndesmophyte formation [35, 36]. As
Fig. 2 Interactions between genes products and cytokines. References: ERAP1: endoplasmic reticulum aminopeptidasa. UPR : unfolded protein.
The misfolding HLA-B27 mechanism in the endoplasmic reticulum, up regulate the UPR. Higher levels of UPR generates an inappropriate genes
activation that perpetuate the inflammatory state
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pathogenic clues are being elucidated, new therapeutic
targets will appear on the horizon.
Experience in pediatric cohorts
Anti-TNF agents
Uncontrolled and controlled studies have demonstrated
TNF inhibition is effective for children with JSpA, either
classified as ERA according to the ILAR criteria, JAS ac-
cording to the New York criteria, or JSpA according to
EESG criteria.
Henrickson et al. reported sustained efficacy of etaner-
cept in a cohort of pediatric patients with ERA over
2 years [37]. This study showed reduction in (mean):
morning stiffness (baseline: 175 m; last visit: 0 min); ac-
tive joint count (8; 0.3) and ESR (64 mm/h; 33 mm/h).
Additionally, Tse et al. reported improvement in 10
children with JSpA on etanercept or infliximab followed
for 1 year [38]. In another retrospective study, 20
patients with JSpA showed good response to TNF inhib-
ition (either etanercept (ETN), infliximab or adalimu-
mab) when they had been refractory to NSAIDs [39]. In
this study remission was achieved in 70 % of patients at
6 months after onset of anti-TNF therapy. During this
study, other efficacy variables were evaluated such as
spinal pain, hip pain and nocturnal awakening. All of
them showed improvement. Otten et al. also assessed
the effectiveness and safety of TNF-blocking agents in
children with ERA. All patients with ERA in whom a
biologic agent was initiated between 1999 and 2010 were
selected from the Dutch Arthritis and Biologicals in
Children registry. Twenty-two patients with ERA were
included. Anti-TNF treatment was effective and safe.
However, a sustained disease–free state could not be
achieved, and no patient could successfully discontinue
the TNF-inhibiting therapy [40].
Horneff et al. demonstrated a significant superiority of
adalimumab compared with placebo in the treatment of
JAS in a double-blind controlled study [41]. An open-
label study provided evidence that ETN at 0.8 mg/kg
once weekly was effective and well tolerated in pediatric
patients with ERA over 12 weeks of treatment. Primary
endpoint was the percentage of subjects achieving ACR
30 response criteria [42]. Effectiveness of ETN was also
evaluated with the following variables: tender entheseal
score, back pain, and nocturnal back pain. ETN was well
tolerated in this pediatric population for up to 12 weeks.
ACR 30 was achieved by 88,6 % of subjects. Limitations
in this trial included its open label design and the retrieval
of a placebo-control group from a historical database.
Burgos Vargas et al. have also showed that adalimumab
(ADA) reduced the signs and symptoms at week 12 in pa-
tients with ERA, while safety and efficacy were sustained
up to 52 weeks [43]. Likewise, Hugle et al., in an observa-
tional study showed early clinical remission in 13/16
(83 %) patients. Children on anti-TNF treatment (ETN or
infliximab) had sustained response except for those who
had hip disease [44].
Recently, Horneff et al. have published the first phase
III randomized, double-blind study to assess the efficacy
and safety of ETN therapy in children with ERA. In this
study the proportion of patients who achieved ACR
pediatric 30, 50, 70, 90, and 100 response rates at week
24 were 93, 93, 80, 56 and 54 % respectively during the
initial open-label phase. At week 48, there was a 35 %
reduction in the relapse risk in the treated patients dur-
ing the double-blind phase [45].
Although anti-TNF therapy is considered safe, increased
risk of tuberculosis has been widely accepted. A prelimin-
ary screening to detect latent or tuberculosis infection
should be considered previous to start of treatment [46].
The musculoskeletal involvement of histoplasmosis and
other fungal infections should also kept in mind.
Table 1 shows different studies on the use of anti-
TNFαagents in patients with JSpA.
Other biologic agents (non TNFαblockers)
Several agents that have been effective in patients with
JIA have not been specifically studied in patients with
JSpA. Different studies about non TNFαblockers have
been developed in adult patients with SpA and are dis-
cussed below.
Abatacept did not prove useful in AS in a 24 week,
prospective, open–label, pilot study involving 30 patients
with active AS divided into two groups: TNF-inhibitor
naive and TNF-inhibitor refractory. Response was evalu-
ated with Assessment of SpondyloArthritis International
Society (ASAS) criteria. ASAS40 was reached by 13 %
and 0 % of patients respectively [47]
Tocilizumab (TCZ) showed no benefit in clinical out-
comes in 99 AS patients compared with placebo in a 12-
week randomized trial. Response was evaluated with
ASAS20 [48]. Response rates were 37.3 % and 27.5 % in
TCZ and placebo arms respectively (p= 0.28) [49]. Only
a decrease in C-reactive protein levels was observed as a
beneficial indicator. Despite the association between in-
creased serum IL-6 levels and disease activity in patients
with AS reported in previous studies, IL-6 blockade did
not correlate with clinical effectiveness in clinical prac-
tice. However, TCZ was beneficial in AS patients in
small case studies [50, 51].
Song et al. demostrated that rituximab (RTX) did not
seem to be effective in patients with AS that had not
responded to anti-TNFαagents, but it had significant ef-
ficacy in anti-TNF-naïve patients in an open-label, phase
II clinical trial [52].
The efficacy and safety of Secukinumab (an anti-IL17A
monoclonal antibody with proven efficacy in psoriasis), was
tested in a double -blindtrial in adult patients with AS.
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Primary outcome was ASAS20 at 16 weeks. Sixty percent
of patients achieved improvement which was sustained up
to 52 weeks [53].
Recommendations for the treatment of JSpA
There are currently no specific recommendations for the
treatment of JSpA. Available recommendations address
the JIA group as a whole despite ERA being a distinct
category. On the other hand, recommendations for adult
patients with SpA have been developed and might be ap-
plicable to patients with JSpA.
The ASAS recommends the use of TNF blockers for pa-
tients with high disease activity despite conventional treat-
ment, which includes non-steroid anti-inflammatories and
glucocorticoids, and DMARDs such as methotrex-
ate (MTX) and/or sulfazalazine for adult patients with
SpA [54]. AS patients have demonstrated poor response
to conventional DMARDs, and it is recommended that
TNFαinhibitors be used as first line therapy for patients
with axial disease [54]. There are no data showing that
traditional DMARDs are effective in the axial disease of
SpA [55]. Roychowdhury et al. did not show any signifi-
cant improvement in disease activity as measured by the
Bath Ankylosing Spondylitis Disease Activity Index (BAS-
DAI) and CRP in AS patients receiving methotrexate as
compared to patients in the placebo group [56]. Other
studies have showed sulfasalazine is ineffective in axial dis-
ease. A multicenter, double-blind, placebo-controlled trial
showed that sulfasalazine is only effective in peripheral
arthritis [57]. Recently, the American College of Rheuma-
tology (ACR) has elaborated recommendation for the
treatment of Ankylosing Spondylitis that could be used
for patients below 18 years of age [58].
Important differences exist in how spondyloarthritis
begins and progresses in children and adults, supporting
the need for pediatric-specific recommendations. As pre-
viously shown, there is evidence that TNFαinhibitors
are beneficial in JSpA, consistent with results from
Table 1 Anti-TNFαin JSpA
Source Drug JSpA patients (n) Study duration Outcome
a
Study design
Henrickson [37] ETNERCEPT 8 24 months improvement
b
Open-label
Uncontrolled
Tse [38] ETANERCEPT 2
INFLIXIMAB 8 12 months improvement Open-label
Uncontrolled
Sulpice [39] 20 (23 treatments)
ETANERCEPT 19 12 months improvement Retrospective
Cohort
INFLIXIMAB 3
ADALIMUMAB 1
Otten [40] 22 (24 treatments)
ETANERCEPT 20
INFLIXIMAB 2 24 months improvement Multicenter
Observational
Register
ADALIMUMAB 2
Horneff [41] ADALIMUMAB 17 6 months improvement Double-Blind
Placebo-controlled
Horneff [42] ETANERCEPT 122 3 months improvement Open-label
Uncontrolled
Burgos Vargas [43] ADALIMUMAB 46 12 months improvement Double-Blind
Placebo-controlled
Hugle B [44] INFLIXIMAB 10 84 months Open-label
ETANERCEPT 6 improvement Observational
Horneff G [45] ETANERCEPT 41 12 months improvement Double-Blind
Placebo- controlled
References:
a
Outcome measures observed were different: morning stiffness, active joints count, tender enthesal count, ESR, ACRped 30/50/70/90, inactive disease, ASAS 20/40,
CHAQ, BASFI
b
Improvement was defined according to each author's criteria as decrease in morning stiffness, active joints, tender enthesal count and ESR, improvement in
functional capacity (CHAQ and/or BASFI). Also tools used in improvement assessment were ACR ped, BASDAI, JADAS 10, ASAS. inactive disease and remission
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multiple adult SpA trials. Moreover, both peripheral
arthritis and enthesitis, two important therapeutic tar-
gets in JSpA, appear to be responsive to TNFαinhibition
[59].
The ACR recommendations for the treatment of JIA
do not address JSpA as a distinct category, but provide a
dedicated strategy for children with sacroiliitis. It is rec-
ommended to use a TNFαinhibitor early for patients
with axial involvement who exhibit radiographic damage
(defined as erosions or joint space narrowing), and mod-
erate or high disease activity (meeting one or two of the
following: erythrocyte sedimentation rate (ESR) or C-
reactive protein greater than twice upper limit of nor-
mal, physician global assessment of overall disease activ-
ity ≥7 of 10 or patient/parent global assessment of
overall well-being ≥4 of 10) [60]. The treatment of
enthesitis was omitted from the 2011 recommendations
due to the lack of sufficient supporting evidence. Ac-
cording to these recommendations, in the presence of
low disease activity and lack of radiographic damage,
TNFαinhibitors should be used only after MTX or
Sulfasalazine have proven ineffective for at least
3 months. In patients with active peripheral arthritis but
no active sacroiliitis, treatment with anti-TNF therapy is
recommended only after a 3 to 6 months-long MTX
treatment has proven to be ineffective [60].
Several drawbacks actually limit the acquisition and
use of sound evidence for the development of specific
recommendations for the treatment of JSpA. Specific
disease outcome measures have not been usually used in
therapeutic trials performed in a pediatric population.
Moreover, assessment of enthesitis has seldom been in-
cluded. The Juvenile Spondyloarthtris Disease Activity
Index still needs to be prospectively validated in a large
international cohorts [61]. Also, the design of prospect-
ive trials should include more homogeneous cohorts,
larger sample size, longer observation periods, controlled
use of concomitant medications, and probably inclusion
of patients with early disease. Also, clear definitions of
active/inactive disease, flare, and remission in JSpA are
needed.
Conclusions
The spondyloarthropathies are a diverse group of arthriti-
des, classically involving large joints of the lower extrem-
ities, axial joints and entheses. There is evidence for a
pathogenetic role of pro-inflammatory cytokines, espe-
cially TNF-α, in the pathogenesis of JSpA. IL-1, IL-6, and
IL-17 may also play a meaningful pahogenetic role.
Anti-TNF agents have proven to be effective and safe
for the treatment of JSpA in uncontrolled and controlled
trials. Other biologic agents have not been formally
tested in JSpA, but could be useful in particular cases.
There are currently no treatment recommendations
for JSpA. Evidence does favor the early use of anti-TNF
agents in patients with JSpA with active axial involve-
ment or MTX-refractivity. In the coming years, a deeper
understanding of the pathogenic mechanisms involved
in JSpA may provide scientific evidence for other effect-
ive therapies, such as IL-17 inhibitors.
Competing interests
The authors declare that they have no competing interests.
Authors’contributions
Both authors have contributed in: conception, design, and revising it
critically before publication. Both authors read and approved the final
manuscript.
Received: 28 September 2015 Accepted: 7 March 2016
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