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Juvenile Spondyloarthritis
Miroslav Harjaček1, Lovro Lamot1,
Lana Tambić Bukovac1, Mandica Vidović1 and Rik Joos2
1Division of Rheumatology, Children’s Hospital Srebnjak, Zagreb
2Division of Rheumatology, University Hospital Gent, Gent
1. Introduction
Spondyloarthritis (SpA) is one of the most common chronic rheumatic diseases, with a
prevalence of 0.3% in Western Europe (Braun, Bollow et al. 1998; Andersson Gare 1999;
Saraux, Guedes et al. 1999; Fernandez-Sueiro, Alonso et al. 2004). Juvenile
spondyloarthritis (jSpA) is a term that refers to a group of inflammatory disorders
affecting children under the age of 16 years, with common clinical characteristics, all more
or less HLA B27 associated, producing a continuum of clinical symptoms through
adulthood. These diseases are characterized by enthesitis and arthritis affecting the joints
of the lower extremities and seronegativity for IgM rheumatoid factor and antinuclear
antibodies (Amor, Dougados et al. 1990; Dougados, van der Linden et al. 1991; Boyer,
Templin et al. 1993; Fink 1995; Cury, Vilar et al. 1997; Petty, Southwood et al. 1998;
Burgos-Vargas, Rudwaleit et al. 2002; Petty, Southwood et al. 2004; Heuft-Dorenbosch,
Landewe et al. 2007; Colbert 2010). The SpA often begins as ’undifferentiated’ disease, the
presentation of which differs in children and adults; most notably, spinal involvement is
uncommon, while hip arthritis is frequently seen in juvenile-onset disease. The SpA
family of diseases includes ankylosing spondylitis (AS), reactive arthritis (ReA), psoriatic
arthritis (PsA), arthritis associated with inflammatory bowel disease (IBD),
undifferentiated SpA and a juvenile form of SpA. The latter are under ILAR (The
International League of Associations for Rheumatology) classification of juvenile
idiopathic arthritis (JIA) classified as enthesitis-related arthritis (ERA) or psoriatic arthritis
(Petty, Southwood et al. 2004) Possible differences in the synovial immunopathologic
features of jSpA, when compared to adult patients with SpA will be discussed. In
addition, increasing evidence suggests that an anatomical zone referred to as the enthesis
is a primary target of the pathological process. Genetic and environmental factors play
important roles in the pathogenesis of the SpA, and will be discussed extensively. An
update on treatment, as well pharmacological and physical therapies, will be made.
2. Epidemiology
The prevalence of spondyloarthritis among whites is estimated at 0.7 to 1.2%, and the
female-to-male ratio is 1:2 (Rutkowska-Sak, Slowinska et al. 2010).
Challenges in Rheumatology
Estimates of the prevalence of juvenile SpA, and ERA specifically, are based on figures for
juvenile arthritis, which vary considerably depending on geographic location and case
definition (Colbert 2010). The worldwide prevalence of juvenile arthritis is reported between
7 and 400 per 100,000 children (0.007% to 0.4%), although the latter figure seems to be an
outlier overestimating the number of cases (Manners and Bower 2002). ERA and PsA each
comprise 2– 11% of those cases, which would give an estimated combined total of 0.28–88
cases per 100,000 children. Whether these figures include juvenile AS is not clear. The
frequency of childhood-onset among AS patients, is estimated between one and nine
percent, (Gomez, Raza et al. 1997; Hofer and Southwood 2002). In Croatian children,
frequency of jSpA among other rheumatic diseases was 8.2% (Prutki, Tambic Bukovac et al.
2008). These data are similar to the results of American, Canadian and British studies where
approximately 7.9 - 9.8 of all children referred to the pediatric rheumatology clinics were
children with jSpA (Bowyer and Roettcher 1996; Malleson, Fung et al. 1996; Symmons, Jones
et al. 1996). SpA is seen in approximately 20% of first-degree relatives of patients with jSpA
(Burgos-Vargas, 2002).
3. Immunopathogenesis
In this section the actual knowledge on immunopathogenesis in SpA is discussed and was
possible with referral to juvenile disease.
SpA is a multifactorial disease in which a disturbed interplay occurs between the immune
system and environmental factors on a predisposing genetic background. One of the
predisposing environmental factors could be bacterial infection. There is a well established
association with different enteric pathogens (Schiellerup, Krogfelt et al. 2008) but also with
Chlamydia (Gerard, Whittum-Hudson et al. 2010) and Clostridium (Birnbaum, Bartlett et al.
2008). In juvenile patients we found a relationship with Mycoplasma pneumoniae infection
(Harjacek, Ostojic et al. 2006),.
Whether a key role is reserved for the innate immunity or the adaptive immune system or
both is still not clear.
3.1 What is the possible role of the adaptive immune system?
Cellular infiltrates in SpA patients are localized at the sacroiliac joints, the synovium and the
entheseal structures. The inifltrates are characterized by the presence of both CD4+ and
CD8+ T lymphocytes, as well as B cells and macrophages (Saxena, Aggarwal et al. 2005;
Singh, Aggarwal et al. 2007; Melis and Elewaut 2009). These infiltrated T cells are activated
and require the active participation of costimulation pathways to play their role.
Dendritic cells (DCs) play a key role in discriminating between commensal microorganisms
and potentially harmful pathogens as well as in maintaining the balance between tolerance
and active immunity (Evans, Suddason et al. 2007). DCs as antigen-presenting cells, induce
primary T cell activation. Upon activation, expansion, and maturation effector T helper (Th)
cells derive from progenitor, naive CD4+ T cells. Committed CD4+ T cells may differentiate
into Th1, Th2, Th 17 phenotypes (the effector Th cell triad), with distinct cytokine products
and biological functions. They can also evolve into the inducible regulatory T (Treg) lineage,
with immunomodulatory functions.
Treg’s are important in the maintenance of immune homeostasis. Defects in Treg function or
reduced numbers have been documented in several human autoimmune diseases, including
RA and JIA (Nistala and Wedderburn 2009).
Juvenile Spondyloarthritis 91
In patients with undifferentiated spondyloarthritis (e.g. ERA) the number of peripheral
blood Th1, Th2, Th17, and Treg cells were found unchanged, but Th1 and Th17 cells were
increased, and Th2 cells were reduced in the synovial fluid (SF) compared to blood. It
appears that elevated levels of pro-inflammatory cytokines IL-1 and IL-6 in the SF may be
responsible for increased Th17 cells in those patients (Mahendra, Misra et al. 2009).
3.2 What is the possible role of the innate immune system?
Accumulating evidence suggests that the majority of the IL-17 released in SpA arthritis is
produced by innate immune cells rather than T cells, suggesting that the innate immune
pathway might be of greater relevance than the Th17 mediated adaptive immune response
in those patients (see below) (Appel, Maier et al. 2011).
In juvenile arthritis some differences in cytokine profile were noted compared to adults:
- SF levels of IL-1ss and IL-12p40 are increased in both Poly-JIA and ERA as compared to
- IL-6 levels were higher in ERA compared to RA;
- the increase in IFN-g in children with ERA with undetectable IL-4 suggests a Th1-
dominant immune response in this disease subset;
- additive or even synergistic effects with IL-1 and TNF-alpha in inducing cytokine
expression and joint damage have been shown in vitro and in vivo;
- ERA patients with an antigen-specific response to pathogenic enteric bacteria had a
higher ratio of SF/blood integrin, (CD103+) Treg’s compared to those with no antigen-
specific response. In those patients antigen-specific as well as mitogen-stimulated
cytokine production showed a clear Th1 bias (Saxena, Misra et al. 2006).
Microbes initiate immune responses through Toll-like receptors (TLRs). TLRs are
membrane-bound and frontline guardians in the human innate immune system. They
primarily function to recognize pathogen-associated molecular patterns (PAMPs) of
invading microorganisms, and on activation mount rapid, nonspecific innate responses and
trigger sequential delayed specific adaptive cellular responses, which are mediated by
complex signal transduction pathways involving adaptor molecules, costimulatory ligands
and receptors, kinases, transcription factors, and modulated gene expression (Drexler and
Foxwell 2010). Toll-like receptor 4 (TLR4) is a member of the Toll-like receptor family, and
activation of the TLR4 signalling pathway may induce the release of proinflammatory
cytokines such as tumour necrosis factor (TNF)-alpha and interleukin (IL)-12, which was
considered to play an important role in pathogenesis of SpA. Serum TLR4 protein and
mRNA levels, as well as TLR-4 gene expression were found to be significantly higher in AS
patients than in healthy controls (Yang, Liang et al. 2007; Assassi, Reveille et al. 2011). A
bacterial trigger possibly causes disease exacerbation in ERA patients. A recent study has
shown that increased TLR-2 and TLR-4 expression on PBMCs and SFMCs may recognize
microbial/endogenous ligands and up-regulate IL-6 and MMP-3 leading to disease
exacerbation (Myles and Aggarwal 2011).
3.3 Cartilage and bone destruction and bone remodeling
In chronic synovitis, cartilage and bone destruction occur as a consequence of synovial
inflammation. Bone remodeling is a lifelong continuous process conducted by osteoblasts,
synthesizing bone matrix, and its resorption by osteoclasts. Important regulators of
osteoclast recruitment and function are the three key molecules Osteoprotegerin (OPG),
Challenges in Rheumatology
Receptor Activator of Nuclear factor –κB (RANK) and its ligand (RANKL). RANKL
stimulates osteoclast production and survival via the membrane-bound receptor RANK,
while OPG inhibits osteoclast differentiation and activation due to its function as a non-
signaling decoy receptor for RANKL (Simonet, Lacey et al. 1997). The physiological
balance between RANKL and OPG is regulated by various calcitropic cytokines and
hormones, and alterations in their ratio are critical in the pathogenesis of bone diseases
(Hofbauer and Schoppet 2004). Osteoblasts and T cells are important producer cells of
RANKL. An inflammatory environment with T-cell activation may tilt the balance
between OPG and RANKL and increase osteoclast activation and bone resorption. In SF of
children ERA patients elevated soluble RANKL (sRANKL), reduced OPG levels, and
elevated sRANKL/OPG ratio was found, resulting in an environment associated with
bone loss (Schett 2009). Furthermore, ERA patients had a lower matrix metalloproteinase
(MMP) level as well as a lower MMP/TIMP (tissue metalloproteinase inhibitors) ratio
compared to poly JIA, which may partly explain the lesser degree of joint damage seen in
ERA, as compared to poly JIA (Agarwal, Misra et al. 2009). In AS, a chronic and most
severe form of SpA inflammation is associated with trabecular bone loss leading to
osteoporosis, but also with cortical new bone formation (e.g. formation of bone spurs,
such as syndesmophytes and enthesiophytes) leading to progressive ankylosis of the
spine and sacroiliac joints. Excessive bone formation in AS leads to ankylosis of joints and
poor physical function (Figure 1). This results in an apparent paradox of bone formation
and loss taking place at sites closely located to each other. Osteoporosis can be explained
by the impact of inflammation on the bone remodeling cycle. In contrast, new bone
formation has been linked to aberrant activation of bone morphogenic protein (BMP) and
Wingless-type like (WNT) signaling. (Figure 1 and Figure 2) (Lories, Derese et al. 2005;
Lories, Luyten et al. 2009; Carter and Lories 2011). By contrast, tumor necrosis factor
(TNF) does not appear to be the direct trigger for osteophyte formation in AS (Schett and
Rudwaleit 2010).
1. “ Squaring” of spine processes; 2. Syndesmophyite formation (anterior ankylosis); 3. Ankylosis of
apophyisial joints.
Fig. 1. The evolution of spine changes in jSpA patients with corresponding X-rays.
Juvenile Spondyloarthritis 93
(a) Physiological endochondral bone formation is stimulated by bone morphogenetic proteins (BMPs).
Wingless-type like (WNT) signaling plays a supportive role in relation to BMPs. However, some WNTs
have a negative effect on early chondrocyte differentiation. (b) In the presence of inflammation, tumor
necrosis factor (TNF) may stimulate BMP signaling but also the expression of DKK1, which acts a WNT
antagonist. The balance between TNF, BMP and WNT signaling may determine the onset and
progression of ankylosis. DKK, dickkopf. (Adapted from Arthritis Res Ther. 2009; 11(2): 221.Published
online 2009 April 27. doi: 10.1186/ar2642.)
Fig. 2. Roles of BMPs and WNTs in ankylosis
3.4 Subclinical gut inflammation
Subclinical gut inflammation has been demonstrated in patients with all forms of SpA
(Mielants, De Vos et al. 1996). In addition, several lines of evidence indicate that SpA may
originate from the relocation to the joints of the immune process primarily induced in the
gut (Fantini, Pallone et al. 2009). The transfer of the intestinal inflammatory process into the
joints implicates that immune cells activated in the gut-draining lymph nodes can localize,
at a certain point of the intestinal disease, either into the gut or into the joints. This is
indicated by the overlapping expression of adhesion molecules observed on the surface of
intestinal and synovial endothelial cells during inflammation. T cells activated in the Peyer’s
patches and mesenteric lymph nodes express the gut-addressing integrin α4/β7 and the
chemokine receptor CCR9 (Campbell and Butcher 2002). Once activated, these cells reach
the bloodstream through the efferent lymphatic’s and the thoracic duct. In the gut mucosa,
the interaction between α4/β7 integrin and its ligand, the mucosal addressin cell adhesion
molecule 1 (MadCAM-1) expressed on the venular endothelial sheet (Berlin, Berg et al. 1993;
Berlin, Bargatze et al. 1995) causes the initial rolling and subsequent arrest of activated T
cells. MadCAM-1 is normally expressed on the intestinal mucosa and its expression is
Challenges in Rheumatology
further enhanced during inflammation (Souza, Elia et al. 1999; Salmi and Jalkanen 2001).
Once arrested on the surface of the intestinal venules, activated T cells transmigrate through
the endothelial layer and move into the lamina propria following the gradient formed by the
CCR-9-specific ligand CCL-25 (Johansson-Lindbom, Svensson et al. 2003; Stenstad, Ericsson
et al. 2006). Therefore, the specific interaction between α4/β7 integrin with MadCAM-1, and
CCR9 with CCL-25 is pivotal for T cell homing into the gut. However it is worth noting that
other molecules mediate the cell-to-cell interaction in this process. For instance CD44, the
very late antigen-4 (VLA-4, α4β1) and the lymphocytes function associated antigen-1 (LFA-
1, αLβ2) expressed by activated T cells play a role in the recruitment of T cells into the gut
(Salmi and Jalkanen 1998).(Figure 3).
CCR9: Chemokine receptor-9; CCL-25: Chemokine ligand 25; MadCAM1: Mucosal addressin cell-
adhesion molecule-1; VCAM1: Vascular cell adhesion molecule-1; ICAM: intracellular adhesion
molecule; VLA-4: Very late antigen-4; LFA-1: Lymphocyte function associated antigen-1; VAP-1:
Vascular adhesion protein-1 (adapted modified from Fantini, Pallone et al. 2009, Kivi, Elima et al. 2009;
Aalto, Autio et al. 2011)
Fig. 3. The heterogeneous expression of adhesion molecules allows T cells activated in the
gut to home into joints.
Conti et al (Conti, Borrelli et al. 2005) investigated a group of 129 children for suspected
inflammatory bowel disease (IBD), 31 of whom had signs of axial and/or peripheral
arthropathy, and after ileo-colonoscopy with biopsy, 7 children had classic IBD, 12 had
indeterminate colitis, and 12 had lymphoid nodular hyperplasia of the distal ileum as the
main feature. All children were HLA-B27 negative. These patients may be a population at
Juvenile Spondyloarthritis 95
risk of developing a full IBD phenotype. A recent study has shown that active Treg cell
response, mainly dominated by IL-10 production, occurs in the gut of AS patients and is
probably responsible for the absence of a clear Th17 polarization in the ileum of AS patients.
Interestingly, a 5-fold increase in the proportion of Treg cells was observed in the gut of
patients with AS, as compared to healthy subjects, with 70-80% of these cells also producing
IL-10 (Ciccia, Accardo-Palumbo et al. 2010).
4. Histopathology
4.1 Enthesitis
Enthesitis is a distinctive pathological feature of spondyloarthritis and may involve synovial
joints, cartilaginous joints, syndesmoses and extra-articular entheses (Benjamin and
McGonagle 2007). This has traditionally been viewed as a focal abnormality, even though
the inflammatory reaction intrinsic to enthesitis may be quite extensive. Entheses together
with adjacent tissues may form mini organs, dubbed “enthesis organs or complex”.
According to this scenario the enthesis fibrocartilages that occupy a location adjacent to
synovium (in joint or bursae or tendons) are dependent on the synovium for lubrication,
oxygenation and removal of microdebris. The enthesis insertion being itself
fibrocartilagenous is avascular, and does not have a resident population of macrophages.
Therefore derangements in the enthesis would be expected to trigger an inflammatory
response in the adjacent vascular synovium (Braun, Khan et al. 2000) (Figure 4).
It consists of the enthesis itself (E), two complementary fibrocartilages (CF), an intervening bursa (BU)
and a pad of synovium-covered protruding fat (F). The complementary fibrocartilages line the deep
surface of the tendon (T) and cover the adjacent bone (BO) and protect these surfaces from compression
when the foot is dorsiflexed. The bursa allows free movement of tendon relative to bone and the fat pad
acts as a 'variable plunger' to prevent pressure changes from occurring in the bursa as the foot changes
position. (adapted from (McGonagle and Benjamin 2009).
Fig. 4. A diagrammatic representation of an enthesis organ, modeled on that of the Achilles
This means that pathology related to the enthesis could trigger synovitis. Indeed, normal
entheses are riddled with microdamage in aged subjects; this can be associated with
Challenges in Rheumatology
microscopic synovitis, including villus formation and microscopic inflammatory cell
infiltration in the immediately adjacent synovium, which is conceptualized in relationship to
a synovio-entheseal complex (Braun, Khan et al. 2000). In man, there is an anatomical,
biomechanical and temporal uncoupling between the inflammatory phase of disease and
new bone formation and it appears that the bone formation follows on from the
inflammation and may be a distinct phase.
4.2 Synovitis
Synovitis in juvenile SpA is characterized by marked lining layer hyperplasia, clear
hypervascularity, and pronounced inflammatory cell infiltration with lymphocytes and
macrophages, independent of disease duration or time of sampling. Despite some
similarities with adult SpA, the findings with regard to lining layer hyperplasia and CD163+
macrophage (defined by the expression of the group B scavenger receptor CD163)
infiltration are indicative of important differences in the synovial immunopathologic
features of juvenile-onset SpA. The partial overlap with other JIA subtypes, with the
exception of slightly lower vascularity in juvenile polyarthritis and higher inflammatory cell
infiltration in juvenile oligoarthritis, emphasizes the need for further biologic
characterization of JIA in order to define pathophysiologic, rather than phenotypic,
subgroups (Kruithof, Van den Bossche et al. 2006). It is of interest that resident tissue
macrophages, PMNs, and lining layer thickness, did correlate with global disease activity in
adult SpA, and that changes in expression of synovial macrophage subsets, PMNs, and
MMP-3 clearly reflected response to treatment (Kruithof, De Rycke et al. 2006).
5. Genetics
5.1 MHC genes
The central genetic factor recognized in SpA is the major histocompatibility complex (MHC)
(Figure 5). While the risk for specific HLA allele in SpA may vary from one population
group to another, the association of HLA-B27, and SpA has been well known for over 30
years. The HLA-B27 represents a family of 38 closely related cell surface proteins (encoded
by the alleles HLA-B*2701-39) called subtypes of HLA-B27, most of which have evolved
from the ubiquitous HLA-B*2705 (specifically the B*27052 allele) (Reveille and Maganti
2009). More recently, similar role for the HLA-B-7 has been proposed (Reynolds and Khan
1988; Cedoz, Wendling et al. 1995). Both antigens display significant levels of
polymorphism, and the region of amino acid positions 63-71 in HLA-B27 appears to
participate in the formation of at least three distinct epitopes shared by B27 and B7
identified as ME1, GSP5.3 and GS145.2, respectively (el-Zaatari, Sams et al. 1990; el-Zaatari
and Taurog 1992). The proportion of B27-positive patients in the different SpA forms
decreases from 95% in primary AS; to 70–80% in ReA; 50% in PsA and IBD with
sacroiliitis/spondylitis, and to 0–10% in undifferentiated SpA. Findings of human family
studies of twins and sibpairs support the notion that genetic factors other than B27
determine which B27-positive individuals develop arthritis. In Croatian patients with jSpA
we have shown that the odds ratio (OR) for HLA-B*07 was 2.61, while the highest OR for a
single HLA specificity was found for HLA-B*27 (OR=5.60). The HLA-B*07/B*27
combination found in 6/74 children showed higher risk (OR=14.82), but the combination of
specificities: HLA-B*07/HLA-B*27, and D6S273-134 microsatellite locus, located in the
HSP70-2 region, demonstrated the highest risk (OR=26.83) (Table 1.) (Harjacek, Margetic et
Juvenile Spondyloarthritis
Fig. 5. HLA region on chromosome 6.
B*07 2.61 1.40 - 4.87
B*27 5.69 2.93 – 11.06
D6S273-134 2.68 1.37 – 4.33
B*07; D6S273-134 2.72 1.34 – 5.53
B*27; D6S273-134 8.57 3.44 – 21.38
B*07/B*27 14.82 1.75 – 125.45
B*07/ B*27; D6S273-134 26.83 N/A*
OR – odds ratio: CI-confidence interval; * Not calculated due to the zero cell in table (Harjacek, Margetic
et al. 2008).
Table 1. The odds ratio (OR) of 74 Croatian jSpA patients conferred by selected alleles alone
or in combination.
al. 2008). During the genome-wide scan with polymorphic microsatellites, in addition to
HLA-B27, D6S273 microsatellite locus was found to be highly relevant (LOD 3.8, p< 0.00001)
in patients with AS (Brown, Pile et al. 1998).
Some recent progress has been made in understanding how B27 alleles confer such
susceptibility, but the mechanism(s) continues to remain largely unknown, and may require
new experimental approaches, and are beyond the scope of this review (Colbert, DeLay et
al. 2010) (van der Heijde and Maksymowych 2010). B27-transgenic animals develop
arthritis, and this directly involves B27 in the development of the disease (Khare, Bull et al.
1998). However, backcross studies in animal models of SpA suggest that multiple genes
contribute to disease susceptibility (Laval, Timms et al. 2001; Brown, Brophy et al. 2003;
Adarichev and Glant 2006). It is well known that the majority of SpA patients do not carry
any of the known susceptibility HLA alleles. Furthermore, findings of human family studies
in twins and sib pairs support the notion that genetic factors other than B27 determine
which B27-positive individuals develop arthritis (Tsuchiya, Shiota et al. 1998; Brophy,
Hickey et al. 2004).
5.2 Non MHC genes
There is little definitive knowledge about non- MHC in SpA. The ultimate goal in the
mapping of diseases to particular genes is to isolate and clone the disease-causing gene
itself. To clone such a gene successfully, it is necessary to map the disease gene to a very
small region, which can be difficult in the case of complex diseases. In fact, it may require
Challenges in Rheumatology
analyzing several hundreds or even several thousands of individuals (affected and
unaffected) to detect the genes that are involved in SpA. Global gene expression profiling is
a molecular technique that measures in parallel genome-wide expression of thousands of
genes in a sample of cells. Genome scanning using SNP’s (Single nucleotide
polymorphisms) has been carried out to identify regions of the genome that show evidence
of linkage to SpA outside the MHC (Sharma, Choi et al. 2009; Vegvari, Szabo et al. 2009;
Reveille, Sims et al. 2010) (Table 2). In adult SpA, many other regions and genes have been
implicated in candidate gene or linkage mapping studies, but will not be reviewed in depth
here. In one large study SNP’S were used in JIA patients (n = 1,054); subtype specific
association of the eraP1 gene (endoplasmic reticulum aminopeptidase 1) with ERA JIA, and
the IL23R gene with juvenile-onset psoriatic arthritis (jPsA), were found (Hinks, Martin et al.
2011). eraP1 encodes a multifunctional aminopeptidase, but its role in the pathogenesis in
any of the associated diseases has yet to be determined. It may play a role in trimming
peptides, in the endoplasmic reticulum, for binding to HLA class I molecules where they are
transported to the cell surface for presentation to T cells. Alternatively it may be important
through its function in cleaving pro-inflammatory cytokine receptors, such as tumor
necrosis factor receptor 1 (TNFR1) to generate soluble TNFR1. It is also thought to play a
role in the cleavage of interleukin 1 receptor 2 (IL1R2) and interleukin 6 receptor alpha
(IL6Rα), leading to increased soluble IL1R2 and IL6Rα (Haroon and Inman 2010).
GENE: Name of gene:
IL-1β locus Interleukin 1 beta
MMP Matrix metalloproteinases
CASP1 Caspase 1
IL18 Interleukin 18
IL10R Interleukin 10 receptor
TLR-4 Toll-like receptor 4
RGS1* Regulator of G-protein signaling
eraP1 Endoplasmic reticulum aminopeptidase 1
IL23R Interleukin 23 receptor
IL1R2 Interleukin 1 receptoc, type II
ANTXR2** Anthrax toxin receptor 2
Adapted from: (Gu, Wei et al. 2009; Sharma, Choi et al. 2009; Vegvari, Szabo et al. 2009; Haroon and
Inman 2010; Reveille, Sims et al. 2010; Hinks, Martin et al. 2011).
Table 2. The list of genes found by genome-wide expression profiling in SpA patients using
SNP’s (with exception of RGS1 that was found in undifferentiated SpA all other genes were
identified in AS patients).
Studies of gene expression with the use of DNA microarray technologies offers a novel
approach to determining pathogenesis of disease. In two pediatric studies, ability of
microarray-based methods (Affymetrix platform) to identify genes with disease-specific
expression patterns in peripheral blood mononuclear cells (PBMC) and synovial fluid
mononuclear cells (SFMC) of JIA patients (including ERA patients), and healthy controls
Juvenile Spondyloarthritis 99
was used. When compared to healthy controls, they found relevant gene expression in
JAK/STAT cascade and chemokine pathway, lower levels of angiostatic CXCL10
chemokine, higher leevels of ELR+ angiogenic chemokines and VEGF (vascular endothelial
growth factor) in ERA PBMC, and decreased adult hemoglobin gene expression (Barnes,
Aronow et al. 2004). They concluded that expression analysis identified differentially
expressed genes in PBMC’s obtained early in the disease from patients with different
subtypes of JIA and in healthy controls, providing evidence of immunobiologic differences
between these forms of childhood arthritis (Barnes, Grom et al. 2009). Our preliminary data
have shown that jSpA patients exhibit complex patterns of gene expression for functions
related to inflammatory and defense response, MAP kinase and cell cycle, chromatin
modulation and transcription, cell death, apoptosis, and interestingly, gene closely linked to
autoinflammatory diseases (NRLP3) (Harjacek M. 2010).
However, one should be cautious because microarray analysis produces vast amounts of
data that can be analyzed and interpreted in many different ways.
6. Classification
Classifying juvenile spondyloarthritis is a “work in progress” and clearly problematic
(Burgos-Vargas 2002; Colbert 2010). Since the recognition in 1982 by Rosenberg and Petty of
the seronegative enthesopathy and arthropathy (SEA) syndrome (Rosenberg and Petty 1982)
many attempts have been made to classify JSpA or SpA like diseases in children. The
International League of Associations for Rheumatology (ILAR) Taskforce on Classification
of Childhood Arthritis included the category of enthesitis-related arthritis (ERA) in the 1995
classification of juvenile idiopathic arthritis (JIA) (Fink 1995; Petty, Southwood et al. 1998)
among the seven subgroups of juvenile arthritides. However when psoriasis, or dactylitis
and nail pits along with arthritis are present, these children are excluded from ERA and may
be classified as psoriatic arthritis or even undifferentiated arthritis (Burgos-Vargas,
Rudwaleit et al. 2002; Colbert 2010). The classification criteria for ERA are excluding
psoriatic arthritis (PsA), while reactive arthritis is not even mentioned. Moreover IBD is only
maintained as a descriptor of the disease (Burgos-Vargas 2002). So, quite early in the
discussion this led to several propositions for revision (Fantini 2001; Manners, Lesslie et al.
Another set of criteria for spondyloarthritis was developed by the European
Spondyloarthropathy Study Group (ESSG) (Dougados, van der Linden et al. 1991). The
ESSG criteria have been validated in children, but the emphasis on inflammatory spinal pain
is problematic because such a symptom is uncommon in children in the first five years of
disease (Prutki, Tambic Bukovac et al. 2008). Also, their sensitivity, positive predictive value
and accuracy are lower than in adults (Prieur 1990). This classification includes PsA, ReA,
IBD arthropathies as part of the SpA group and ranks the two most important characteristics
of adult-onset SpA – inflammatory spinal pain and synovitis as major criteria. Since spinal
pain is a less common feature at the onset of the disease in younger children, these criteria
may be limited in children with jSpA.
Amor and coworkers (Amor, Dougados et al. 1990) also developed criteria for the
classification of spondyloarthritis in adults that could be applicable in children, but like
ESSG classification have lower sensitivity in childhood. According to Amor the features of
spondyloarthropathy are associated with points, and if six or more points are present the
diagnosis of SpA is confirmed.
Challenges in Rheumatology
A recent study showed that Garmisch-Partenkirchen criteria have the highest sensitivity and
proposed them for identifying spondyloarthritis in juvenile patients (Hafner 1987; Joos,
Dehoorne et al. 2009). According to these criteria probable spondyloarthritis is considered if
two major criteria or major criterion one or two plus two minor criteria are present.
SpA usually begins in children as an undifferentiated form of the disease: a peripheral
asymmetric oligoarthritis predominantly involving the lower limbs and/or with peripheral
enthesitis and/or with dactylitis, and progress to differentiated forms over time (Colbert
2010). Most of these children could be classified as undifferentiated SpA (uSpA) according
to the Amor (Amor, Dougados et al. 1990) and the ESSG criteria (Dougados, van der Linden
et al. 1991).
Children with the SEA syndrome or with ERA are at risk of developing the other
manifestations of the B27 associated disease process including axial involvement. In 1989,
Burgos-Vargas and Clark reported that 75% of their Mexican patients with the SEA
syndrome met the New York criteria for ankylosing spondylitis (AS) after 5 years of disease
(Burgos-Vargas and Clark 1989).
Experts from the Assessment of Spondyloarthritis International Society (ASAS), recently
developed definition criteria for inflammatory back pain (IBP), which is an important
clinical symptom in adult patients with SpA (Sieper, van der Heijde et al. 2009). In
addition, although revisions to the ILAR criteria have addressed some weaknesses
Burgos-Vargas, R., M. Rudwaleit, et al. (2002; (Duffy, Colbert et al. 2005) several problems
remain, some of which might have been exaggerated by the recent development of criteria
that identify pre-radiographic ‘axial SpA’ in adults. (Rudwaleit, Landewe et al. 2009;
Rudwaleit, van der Heijde et al. 2009). To best of our knowledge, these criteria are still not
validated in children.
Different classification criteria for SpA are shown in Table 3.
ESSG criteria (Dougados, van der Linden et al. 1991)
Inflammatory low back pain
OR Synovitis asymmetrical or predominantly of the lower limbs
AND at least one of the following criteria: familial history of spondyloarthropathy, uveitis or
inflammatory bowel disease; psoriasis, inflammatory bowel disease, enthesopathy, radiological sacroiliitis
AMOR criteria (Amor, Dougados et al. 1991)
A. Clinical signs or history of:
1. nocturnal pain lumbar or dorsal and/or morning stiffness (1 point);
2. asymmetrical oligoarthritis (2 point);
3. Indefinite buttock pain or alternating buttock pain (1 or 2 point);
4. Sausage finger or toe (2 point);
5. heel pain or any other enthesopathy (2 point)
6. iritis (2 point);
7. non gonoccocal urethritis or cervicitis within one month before the onset of the arthritis (1 point);
8. Diarrhea within one month before the onset of the arthritis (1 point);
9. Presence or history of psoriasis, and/or balanitis and/or chronic enterocolopathy (2 points).
B. Radiological signs:
10. Sacroiliitis (stage 2 if bilateral, or stage 3 if unilateral) (3 points)
C. Genetics:
11. Presence of HLA B27 and/or familial history of ankylosing spondylitis and/or Reiter’s syndrome and/or
psoriasis and/or uveitis and/or chronic enterocolopathy (2 points)
D. Reaction to treatment:
12. Improvement of pain within 48 hours by NSAIDs or relapse within 48 hours after stop of NSAIDs
(2 points)
Juvenile Spondyloarthritis 101
A spondyloarthropathy is declared in a patient having a score equal of greater than 6 as sum of the points
on the 12 criteria.
SEA syndrome (Rosenberg and Petty 1982)
SERONEGATIVITY = absence of RF and ANA
ENTHESOPATHY = tendonitis of the Achilles tendon, fascia plantaris or quadriceps tendon
ARTHROPATHY = inflammatory arthritis of the axial skeleton or oligoarthropathy
ERA (Durban criteria) (Petty, Southwood et al. 1998)
Arthritis OR Enthesitis
PLUS two or more of the following:
A. Sacroiliac joint tenderness AND/OR inflammatory spinal pain;
B. Presence of HLA-B27;
C. Family history involving one or more first or second degree relatives with an HLA-B27 related disease,
confirmed by a physician;
D. Anterior uveitis (typically with pain, redness and/or photophobia);
E. Onset of arthritis in a boy > 8 years of age
AND none of the following:
A. Presence of psoriasis in a first or second degree relative, confirmed by a dermatologist;
B. Presence of a systemic arthritis.
Atypical spondyloarthritis in children (Hussein, Abdul-Khaliq et al. 1989)
1. SA or oligoarthritis in family;
2. enthesopathy;
3. Arthritis of digital joints;
4. Sacroiliitis;
5. HLA B27 positive;
6. Recurrent arthritis or arthtalgia.
1. Begin after age od 10 years
2. Male sex;
3. Only lower extremities affected;
4. Acute iridocyclitis or conjunctivitis;
5. Arthritis of hips;
6. Begin following unproven enteritis.
Atypical spondyloarthritis was considered as probable when three major and two minor criteria were
Juvenile spondarthritis (Garmisch-Partenkirchen criteria) (Hafner 1987)
1. Asymmetrical oligoarthritis with involvement of hip, knee or ankle joint;
2. Enthesopathy;
3. Pain of the lumbar spine or sacroiliac region;
4. acute idirocyclitis.
1.Peripheral arthritis of 5 or more joints;
2. Male sex;
3, Disease inset after the age of 6 years;
4. HLA B27 positivity;
5. (Suspicion of) spondarthritis in family history
Probable spondarthritis was considered if two major criteria or major criterion one or two plus two minor
criteria were present.
ILAR = International League of Associations for Rheumatology; JIA = Juvenile Idiopathic Arthritis;
ERA = Enthesitis related arthritis; ESSG = European Spondyloarthropathy Study Group;
Table 3. Classification criteria for spondyloarthritis.
Challenges in Rheumatology
None of the criteria evaluated above are perfect for the classification of JSpA. However, the
Garmisch-Partenkirchen criteria are the major candidates for future research in identifying
spondyloarthritis in juvenile patients (Kasapcopur, Demirli et al. 2005; Joos, Dehoorne et al.
7. Clinical manifestations
In this section we will try to give an overview of the different characteristics of the diseases.
The authors consider several subforms of jSpA:
1. Reactive arthritis: resulting from an infection or inflammation on a distant location of
the arthritis. It is merely an acute phenomenon, possibly relapsing and in a part of the
patients evolving chronically.
2. Undifferentiated SpA: a chronic form of asymmetrical oligoarthritis, affecting the lower
limbs, often accompanied by entheisitis and a number of extra-articular manifestations.
3. Juvenile ankylosing spondylitis: affecting preferentially the axial skeleton and can be
considered as a clear precursor to the adult ankylosing spondylitis.
4. Juvenile psoriatic arthritis.
5. Inflammatory bowel disease-related arthritis
6. Juvenile ankylosing tarsitis
7. Clavicular cortical hyperostosis
These forms are discussed extensively below.
7.1 Reactive arthritis (ReA)
a. Reactive arthritis (ReA) comprises a number of diseases following infection or
inflammation on a distant location in the body. The term is usually restricted to HLA-
B27 associated disease triggered in about 80% of patient by arthritogenic bacteria such
as Salmonella, Yersinia, Shigella, and Campylobacter. Mycoplasma pneumonia and Chlamydia
pneumonia are less frequently responsible for the disease. Primary infection, regardless
of the triggering agent, may be completely asymptomatic or with mild symptoms, and
it usually precedes arthritis onset up to four weeks.
Reactive arthritis commonly involves joints (knees, ankles) and entheses of the lower
limbs. It can also affect temporomandibular joints and the cervical spine (Arabshahi,
Baskin et al. 2007). It is marked with severe pain and swelling, sometimes with
erythema over the affected joints, rarely with only mild symptoms. ReA following
Salmonella or Yersinia infection sometimes presents with polyarthritis that affects small
joints of the hands. Arthralgias may precede the onset of arthritis.
Extra-articular manifestations of ReA include conjunctivitis, anterior uveitis,
balanopostitis, urethritis, cervicitis (occurring more frequently in adolescent age with
sexually acquired ReA caused by Chlamydia), aphthous stomatitis, diarrhea (as part of
a generalized mucositis), erythema nodosum (particularly in Yersinia triggered ReA),
and keratoderma blenorrhagicum (which clinically and histologically resembles
b. If arthritis, conjunctivitis and urethritis are present as a triad, reactive arthritis might be
referred to as Reiter’s syndrome.
c. A number of children, particularly those with HLA-B27, develop a chronic course, and
may even develop AS (Leirisalo, Skylv et al. 1982; Hussein 1987; Artamonov, Akhmadi
et al. 1991; Cuttica, Scheines et al. 1992; Yli-Kerttula, Tertti et al. 1995; Leirisalo-Repo,
Juvenile Spondyloarthritis 103
Helenius et al. 1997; Leirisalo-Repo 1998). Children without HLA-B27 who have ReA,
particularly when the disease is triggered by Yersinia or Campylobacter, usually have a
rather short and benign course.
Diagnosis of ReA in children has usually been made in patients developing arthritis
after a specific episode of infection, or those having positive serological tests against
bacteria (Cassidy and Petty 2001). However, diagnostic tests (serology, PCR, etc.) may
identify the etiologic agent in about 50% of the cases depending on the clinical picture
and tests selected (Fendler, Laitko et al. 2001; Sieper, Rudwaleit et al. 2002). On the
other hand, bacterial DNA has been identified in synoviaI fluid cells of patients with
long-standing juvenile onset AS or undifferentiated SpA (Pacheco-Tena, Alvarado De
La Barrera et al. 2001). In this sense, ReA constitutes a link rather than exclusion to ERA
and SpA.
d. Poststreptococcal reactive arthritis (PSRA) has been proposed as a homogeneous
clinical entity, distinct from acute rheumatic fever (ARF) and from other forms of
reactive arthritis. However, available literature at present supports the idea that PSRA
is in reality a heterogeneous group of clinical entities, some of which share clinical
features with ARF and others with HLA B27-related spondyloarthritis. The assumed
causal role of streptococcal infection is far from proven. Joint involvement is typically
non-migratory and affects the large joints, particularly those of the lower limb. Mono,
oligo and polyarthritis are equally represented (Moorthy, Gaur et al. 2009). The
published data support the possibility, however, that there may be a subset of patients
with PSRA who are HLA-B27-positive and are more likely to develop sacroiliitis
(Mackie and Keat 2004). Elevated antistreptolysin titers may support but not definitely
diagnose a poststreptococcal complication. The more specific and expensive antibody
tests may be warranted, including antihyaluronidase, antideoxyribonuclease B, and
antistreptokinase antibodies. American Heart Association, and the Red Book of the
AAP suggest that antibiotic prophylaxis be given to all proven PSRA patients for 1 year,
and if no carditis is observed, then prophylaxis should be discontinued. Moreover,
physicians should be aware that antibiotic therapy might prevent the development of
an antibody response (Barash, Mashiach et al. 2008).
7.2 Undiffentiated spondyloarthritis (ERA)
The onset of ERA is usually insidious and characterized by intermittent musculoskeletal
pain and stiffness or inflammation of peripheral joints, mostly of the lower limbs, with
enthesitis at one or more sites around the knee or foot. Axial skeleton symptoms are not
common at the disease onset, but might become manifest in the later course (Burgos-Vargas
Arthritis and enthesitis are the hallmark of jSpA. Peripheral joint involvement at onset is
present in over 80% of these patients, while inflammatory spinal pain in only 20-25%. This is
one of the major differences between adult- and juvenile-onset spondyloarthritis. In most
patients arthritis is either unilateral or asymmetrical oligoarthritis at onset. Distal joints of
lower extremities (knee, ankle, tarsus) are affected more frequently than proximal joints.
Polyarthritis is not common at disease onset and its distribution is generally asymmetrical
(Burgos-Vargas 2002). At this stage of the disease it is difficult to differentiate jSpA from
other forms of juvenile arthritides.
The sites of attachment of ligament, tendon, fascia or joint capsule to bone are characteristic
sites of inflammation in the jSpA. In contrast to arthritis its specificity and diagnostic value
Challenges in Rheumatology
are much more significant in jSpA. Enthesitis is frequently associated with tenosynovitis and
bursitis, particularly of the foot, where arthritis also occurs. Foot enthesitis, including tarsal
and calcaneal entheses (Achilles’ tendon, plantar fascia), is the most common sign of jSpA
and one of the most disabling conditions in these children. Its clinical manifestation is pain
on standing and walking, and foot swelling, pressure tenderness at the insertion of tendons
and ligaments to bone. Soft tissue swelling is the result of inflammation of tendon sheets
and adjacent bursae. Enthesitis in the later course of the disease varies from rare episodes of
active inflammation of one or few entheses to frequent recurrence of inflammation involving
many sites, particularly the feet. Persistent enthesitis is associated with bone edema and
overgrowth, cartilaginous proliferation, bone bridging and ankylosis. Subcortical bone cysts
and erosions at tendon insertions are rare.
The severity, duration and consequences of arthritis and enthesitis may not parallel each
other throughout the clinical course of the disease.
The most common extraarticular manifestation of ERA is uveitis, while mucositis, skin
disease (excluding psoriasis), or cardiopulmonary and nervous system disease happens
Uveitis in ERA is characterized by redness and pain in the eye with photophobia. It is
usually unilateral, frequently recurrent and rarely leaves ocular residua. The occurrence of
uveitis in children with ERA is less than 20% (lower incidence than in adults), but longer
follow-ups reveal higher figures (Packham and Hall 2002; Petty, Smith et al. 2003).
Musculoskeletal examination should be focused on entheses, peripheral joints and axial
skeleton including joints of the pelvis, spine and chest.
Marked localized tenderness on the patella at 2-, 6-, and 10-o’clock positions (Figure 6A), at
the tibial tuberosity, at the attachment of the Achilles tendon (Figure 6B) or plantar fascia to
the calcaneus (Figure 6C), at the attachment of the plantar fascia to the base of the fifth
metatarsal (Figure 6C), and at the heads of the metatarsal bones (Figure 6C) suggests
enthesitis. Tenderness as the sign of enthesitis is rarely demonstrable at the great trochanter
of the femur, superior anterior iliac spine and iliac crest, pubic symphisis, ischial tuberosity,
costochondral junctions, and entheses of the upper extremities. Walking on the toes and
heels usually demonstrates altered weight bearing as the patient avoids pressure on
inflamed entheses.
Peripheral joints in ERA are commonly affected asymmetrically and predominantly involve
the lower limbs. Unilateral hip involvement is more likely to be a manifestation of ERA than
the presenting feature of other forms of JIA. Knee involvement is often present both in ERA
and oligoarticular JIA, but the child’s age and sex, as well as the presence of HLA-B27, could
be helpful in distinguishing the diagnosis. Small joint involvement of the foot and toes,
especially intertarsal joints (tarsitis) may be characteristic of ERA, while polyarthritis with
the involvement of small joints of the hands suggests another type of JIA (Berntson,
Damgard et al. 2008).
Axial skeleton involvement is rarely present in the younger age and in the early stage of the
disease. However, it is one of the major manifestations in the later course of ERA. Pain by
direct pressure over one or both sacroiliac joints, compression of the pelvis, or distraction of
the sacroiliac joints by Patrick test (Faber test) highly suggests sacroiliac inflammation.
Lower back pain is usually present and associated with morning stiffness. Abnormalities in
spine contour, such as reduction in the normal lumbar lordosis, exaggeration of the thoracic
kyphosis, or increased occiput-to-wall distance can be revealed by simple inspection of the
back. Restriction of hyperextension or inclination, loss of the normal curve in the lower part
Juvenile Spondyloarthritis 105
Fig. 6. A, Arrows indicate the most common sites of tenderness associated with enthesitis at
the insertion of the quadriceps muscles into the patella and the attachments of the patellar
ligament to the patella and tibial tuberosity. B, Arrow indicates the site of tenderness at the
insertion of the Achilles tendon into the calcaneus. C, Arrows indicate the most common
sites of tenderness associated with enthesitis at the insertion of the plantar fascia into
calcaneus, base of the fifth metatarsal, and heads of the first through fifth metatarsals.
Swelling in this area is best visualized by having the child lie prone on the examining table
with the feet over the edge.
of thoracolumbar spine in the full forward flexion position is the usual sign of axial
involvement. The rigid spine or cervical spine involvement are not common in children,
especially in the early stage. The modified Schober test is a good tool for documenting
thoracolumbar mobility. It is easily performed (Figure 7) and sequential measurements
provide a useful parameter in the disease follow-up. With the child standing with the feet
together, a line joining the iliac crests is used as a landmark for the lumbosacral junction. A
mark is made 5 cm below (point A) and 10 cm above (point B) the lumbosacral joint. With
the patient in maximal forward flexion with the knees straight, the increase in distance
between points A and B is used as an indicator of lumbosacral joint mobility. In general, a
distance less than 6 cm is regarded as abnormal. Measurement of the distance from the
fingertips to the floor on maximal forward flexion is also used for quantification of spinal
motion but it is poorly reproducible and does not correlate with Schober test. This
measurement reflects hip flexion disturbances as well as back flexion. Nevertheless, because
of lower height, measuring spine mobility with Schober test is potentially difficult in
younger children.
Sequential measurements of thoracic excursions may be useful in documenting progressive
loss of range. Since normal thoracic motion varies a lot depending on the age and sex of the
patient, a single measurement is not useful. However, any chest excursion of less than 5 cm
Challenges in Rheumatology
Fig. 7. Schober test. A, Measurement 10cm above and 5cm below the lumbosacral junction
(the dimples of Venus) in the upright position. B, Measurement of the distance between the
upper and the lower marks when the child is bending forward.
(maximum expiration and maximum inspiration measured at the fourth intercostal space) in
the adolescent should be considered as abnormal (Burgos-Vargas, Castelazo-Duarte et al.
1993). In the late development of the disease it may be restricted to 1 or 2 cm, even in the
absence of symptoms.
Pain and tenderness at costosternal and costovertebral joints, as well as sternoclavicular
joints are often present, rarely at sternomanubrial junction and may be elicited by firm
Arthritis characteristics in the later course of jSpA are variable. Enteric bacteria may have a
role in the exacerbation of disease in patients with ERA, implying that ERA could be a form
of chronic reactive arthritis (Saxena, Misra et al. 2006). HLA-B27 negative patients usually
have fewer episodes of arthritis and less symptoms of axial disease. HLA-B27 positive
disease is associated with more severe and more frequent episodes of active oligoarthritis or
polyarthritis, sacroillitis and axial involvement often. It also predicts evolvement to
ankylosing spondylitis (AS) (Leirisalo, Skylv et al. 1982; Leirisalo-Repo 1998).
The long-term follow-up of children with HLA-B27 who have JIA reveals that between
18,5% and 75% develop spondyloarthritis (Burgos-Vargas, Pacheco-Tena et al. 2002).
7.3 Juvenile-onset ankylosing spondylitis (jAS)
Juvenile-onset ankylosing spondylitis (jAS) is a definite form of jSpA characterized by
inflammation of the sacroiliac and vertebral joints leading to stiffening of the spine.
Back pain is common in young people with one year prevalence rates varying from 7% to
58% (Smith 2007). Low back pain (LBP) in childhood and adolescence is a significant risk
factor for LBP in adulthood (Jones and Macfarlane 2005; Hestbaek, Leboeuf-Yde et al. 2006).
Juvenile Spondyloarthritis 107
However, most cases of back pain are non-specific and self-limiting. A recent prospective
study of 73 children under age 18 years, with back pain of greater than 3 months duration
found only 21% of the patients with positive findings after diagnostic evaluation or a
minimum of 2 years follow-up. Spondylolysis with or without spondylolisthesis was the
most common diagnosis (Bhatia, Chow et al. 2008).
Children with jAS may present with back or buttock pain, but the typical history of morning
stiffness, gradual resolution of pain with activity and clinical exam findings of limited lumbar
mobility (Figure 7, Figure 8), sacroiliac joint tenderness and peripheral enthesitis or arthritis,
usually allow the practitioner to make the correct diagnosis (Cassidy and Petty 2006).
Fig. 8. Boy shown in the position of maximal forward flexion. Note the flattened back
Inflammation in the caudal region of the sacroiliac joint is one of the earliest features of spinal
disease in AS. Often this begins on the iliac side of the joint and then involves the sacral side as
inflammation progresses (Bollow, Hermann et al. 2005). Frank erosions become evident, but
may not appear for months to years after inflammation has begun. Sclerosis occurs and is often
progressive, eventually resulting in fusion of the joint (Colbert 2010).
There is a less common subgroup of adult-like juvenile onset AS that is called genuine jAS, in
which patients develop clinical and radiographic evidence of disease affecting the axial
skeleton earlier than children progressing from SEA syndrome to AS. Seronegative enthesitis
and arthritis (SEA) syndrome comprises the combination of enthesitis and arthritis, and
Challenges in Rheumatology
probably represents the early stage of jAS or ERA. Most patients with persistent arthritis and
enthesitis, who are HLA-B27 positive, develop ankylosing spondylitis five to ten years after
initial symptoms. (Burgos-Vargas, Vazquez-Mellado et al. 1996).
jAS differs from adult-onset AS in clinical features at onset, presenting with higher
prevalence of peripheral joint involvement and lower prevalence of axial disease. In contrast
to adults, spinal pain in children does not seem to improve with movement. The prevalence
of HLA-B27 is similar in both groups (Lin, Liang et al. 2009).
Although the pattern of peripheral arthritis and enthesitis is similar to that of other jSpA,
jAS is characterized by persistent axial involvement. Enthesitis is usually more severe and
episodes last for a longer period of time. During the initial period of six months most
patients have oligoarthritis possibly evolving into polyarthritis by the end of the first year.
Axial symptoms first appear in the lumbar and thoracic spine, and less frequently in the
cervical spine and sacroiliac joints.
Fever, weight loss, muscle weakness and atrophy, fatigue, lymphadenopathy, leukocytosis
and anemia may be present in up to 10% of patients with JAS. Cardiovascular and nervous
system manifestations are rare, although radiculopathy may be present in the late course of
the disease. Interestingly, up to 80% of patients with jAS might have nonspecific intestinal
bowel disease (Mielants, Veys et al. 1993).
7.4 Juvenile-onset psoriatic arthritis (jPsA)
According to the ILAR criteria, jPsA represents approximately 7% of patients with JIA. It is
defined as arthritis with onset before the 16th birthday that lasts for at least 6 weeks, and is
associated either with psoriasis or two of the following: dactylitis, nail pitting, onycholysis,
or psoriasis in a first-degree relative (Cassidy and Petty 2001). ILAR criteria exclude the
diagnosis of jPsA in patients with positive rheumatoid factor, HLA-B27 positive boys over
the age of 6 years, or patients with a first-degree family history of HLA-B27 associated
disease. In our opinion, the majority of jPsA patients fits under the jSpA umbrella and only a
minority of patients will belong to other subtypes of PsA as seen in children or adults
(Mease 2011; Stoll and Punaro 2011).
While the disease can have a variable presentation (especially in a younger child), in
general, 50% of patients will have arthritis at disease onset, 40% will have psoriasis, and 10%
of patients will have a coincidence of arthritis and skin changes. Dactylitis is common in
both groups (20% to 40% of patients with jPsA), and refers to swelling within a digit that
extends beyond the joints, giving the typical “sausage-like” appearance. Index finger and
second toe are most commonly affected. Axial disease in jPsA is milder than in jAS, the
cervical spine being involved more than other spinal segments, with a tendency for
asymmetric sacroiliac joint involvement and a failure to progress to spinal ankylosis. The
latter patients are frequently associated with HLA-B27 antigen. Enthesitis is prevalent in the
older onset subgroup of patients with jPsA, which is similar to the patients with adult PsA.
Severe skin and nail disease is rare in children with arthritis. Most children have mild
psoriatic skin lesions in the capilitium, retroauricular, umbilical and intergluteal regions,
extensor surfaces of the extremities, and slight nail pitting or onycholysis. Most patients
with skin disease have psoriasis vulgaris (80%), 30% have guttata, and a minority of 2%
have pustular psoriasis (Burgos-Vargas 2002). The severity of the skin lesions does not
usually parallel the severity of arthritis. Systemic manifestations are rare and reflect chronic
inflammation: fever, loss of appetite, anemia, growth retardation, and very rarely
pericarditis, inflammatory bowel disease, or amyloidosis.
Juvenile Spondyloarthritis 109
In contrast, patients with early-onset jPsA bear similarities to early-onset oligoarticular and
polyarticular JIA patients, including female preponderance and antinuclear antibody (ANA)
positivity. The majority of those patients will have oligoarthritis or polyarthritis of the upper
and lower extremities (Stoll, Zurakowski et al. 2006; Stoll and Punaro 2011). Psoriasis and
adult PsA are strongly associated with HLA-Cw*0602 HLA-B38, and non-MHC genes psors
1 and psors 2, but HLA associations in jPsA are inconsistent, probably due to great
variability within jPsA across the pediatric age spectrum (Stoll and Punaro 2011).
Other extra-articular manifestations include uveitis in about 15% of patients. The uveitis in
psoriatic patients is heterogeneous in its aspect. Sometimes it resembles the acute anterior
uveitis and is associated with the HLA B27 antigen, in other patients however it evolves as a
chronic posterior and even panuveitis and needs regular ophthalmologic work out as well
as preventive controls for relapse.
7.5 Inflammatory bowel disease-related arthritis (IBD)
Crohn’s disease (CD) and ulcerative colitis (UC) are two major IBD associated with
arthropathies. Peripheral or axial arthritis are the most common extraintestinal
manifestations of these diseases, and are present in 7% to 21% of children with IBD, more
frequently in UC than in CD (Burgos-Vargas 2002; Jose, Garnett et al. 2009). CD involves the
mucosa and regional lymphatics of the colon, distal ileum and other segments of the
intestinal tract, with characteristic noncaseating granulomas. UC is a diffuse inflammatory
bowel disease with characteristic crypt abscesses in the colonic mucosa. Approximately one
third of patients with CD and about 15% of those with UC have onset before the age of 20
years (Burbige, Huang et al. 1975; Hamilton, Bruce et al. 1979).
Initial gastrointestinal symptoms are cramping abdominal pain, often with localized
tenderness, diarrhea, loss of appetite to anorexia, sometimes fever. Bloody diarrhea is more
suggestive of UC, while perianal skin tags and fistulae are typical for CD. Gastrointestinal
symptoms usually precede joint disease by months or even years and rarely they coincide.
Arthritis mostly affects peripheral joints with predomination on lower extremities (knees and
ankles). Episodes of acute peripheral arthritis usually last not more than two weeks and rarely
cause joint damage or functional loss. Axial disease and sacroillitis are rare, and association
with HLA-B27 is common in the older age-onset patients with juvenile CD or juvenile UC.
Subclinical gut inflammation (“low-grade-IBD”) is very common in jSpA and occurs in up to
80% of patients, and destructive arthritis of small joints is more common in biopsy proven
“low-grade-IBD” children (Mielants, Veys et al. 1987). Peripheral arthritis (mono or oligo)
improves with colectomy (disease control), but axial disease shows little improvement.
Erythema nodosum is commonly associated with IBD. Reddish, painful, nodular lesions
usually occur in the pretibial region and persist for several weeks, recurring in crops
sometimes for several months. Articular involvement often accompanies exacerbations of
erythema nodosum.
Painful oral ulcerations could be a part of the initial clinical presentation, especially in CD,
and should not be misdiagnosed as Behcet disease.
Children with IBD may also have asymptomatic uveitis.
7.6 Ankylosing tarsitis (AT)
Ankylosing tarsitis represents a set of clinical and radiological manifestations originally
described in patients with HLA-B27 positive jSpA, and include inflammation from the ankle
Challenges in Rheumatology
to the metatarsophalangeal joints (synovitis, enthesitis, tenosynovitis, bursitis), followed by
proliferative changes that finally lead to the fusion of tarsal bones) (Burgos-Vargas, Pacheco-
Tena et al. 2002; Alvarez-Madrid, Merino et al. 2009)
Clinical features are usually midfoot swelling, swelling around the malleoli, Achilles tendon
and plantar region of the feet, with decreased mobility of tarsal, ankle and
metatarsophalangeal joints. The condition has a variety of radiologic features, which include
osteopenia of the tarsal bones at the beginning, with the progression to erosions, osseous
proliferation at enthesis, bone cysts, joint space narrowing and finally ankylosis.
Ankylosing tarsitis may occur in patients with undifferentiated jSpA, but it can also be a
part of the clinical manifestations in children with jAS. There are some differences between
children diagnosed with jSpA initially affected with tarsitis and those without it. It can be
often misdiagnosed as soft tissue infection at the beginning of disease (Alvarez-Madrid,
Merino et al. 2009).
7.7 Clavicular cortical hyperostosis (CCH)
Clavicular cortical hyperostosis (CCH) is characterized by unilateral sterno-clavicular
swelling (Figure 9). Some authors described it as a variant of chronic recurrent multifocal
osteomyelitis (CRMO) (Girschick, Krauspe et al. 1998), and some as a sternoclavicular
syndrome (Kalke, Perera et al. 2001). Histopathology is characterized by osteitis,
hyperostosis and bone edema, without signs of microorganisms, or evidence of CRMO
features. Some patients have jSpA features, and some are HLA-B27 positive. In adults, it is
associated with spondyloarthritis, but the possible association to jSpA is not well
established. Our preliminary data of the gene expression profiling study of patients with
CCH and jSpA showed significant concordance in expression of genes linked to
autoinflammatory (TLR-4, PTPN12) and autoimmune diseases (STAT3, CD36) (Harjacek,
Lamot et al. 2011).
a) b)
Fig. 9. Seventeen-year-old male patient with CCH. Note the unilateral sternoclavicular
swelling (A). Schematic representation of the sterno-clavicular joint (B).
Basic characteristics of juvenile spondyloarthritis are shown in Table 4.
Juvenile Spondyloarthritis 111
Table 4. The basic characteristics of jSpA
Challenges in Rheumatology
8. Laboratory yests
There are no pathognomonic blood tests for spondyloarthritis. Erythrocyte sedimentation
rate might be elevated though it is nonspecific. The negative ANA and rheumatoid factor
(“seronegativity”), in combination with positive HLA-B27 in a child with asymmetric
arthritis and enthesitis, would be helpful. However, less than 5 percent of people who are
HLA-B27 positive ever develop spondyloarthritis, so diagnosis should not rely solely on this
9. Imaging in jSpA
Imaging studies usually reveal osteopenia mostly in the foot and hip area in the early stage,
joint space narrowing and ankylosis in the later course of the disease. Erosions and
destruction are rare, but enthesophytosis and bone bridging, particularly in the feet, are
common. Subchondral sclerosis and irregularities of the articular surface in the lower third
of the sacroiliac joints on the iliac side are usually seen, and this may progress to erosions,
joint space narrowing, bone bridging and complete fusion of the sacroiliac bones. Long
lasting disease activity leads also to syndesmophytosis and ligamentous calcification of the
spine. Magnetic resonance (MR) and ultrasound (US) are useful methods for disease activity
monitoring. MR may even reveal sacroiliac joint inflammation in children with neither
symptoms nor radiographic changes (Braun and Baraliakos 2011).
9.1 Ultrasound
Musculoskeletal US assessment in general is safe, noninvasive, and comparably cheap,
showing itself as a complimentary tool to clinical evaluation in Spa. Nevertheless, it is
very user dependent (D'Agostino, Aegerter et al. 2011). US has an increasing and relevant
role in the evaluation of SpA mainly for its ability to assess joint and periarticular soft
tissue involvement and in particular for its capacity to detect enthesitis, the clinical
hallmark feature of SpA. A number of ultrasound studies have also shown that clinically
unrecognised enthesitis is common in the lower limbs including those insertions
amenable to sonographic assessment adjacent to the knee joint in patients with jSpA
(Riente, Delle Sedie et al. 2007; D'Agostino, Aegerter et al. 2011). Since most cases of
enthesitis are subclinical, addition of gray-scale US and Power-Doppler US (PDUS)
appears to be a valuable first-line diagnostic tool to confirm a diagnosis in a patient with
suspected SpA (D'Agostino, Aegerter et al. 2011). Changes include thickening and edema
of the insertions, increased vascularity, bone erosion, and new bone formation (Borman,
Koparal et al. 2006). Also, in cases of dactylitis, US can accurately delineate the underlying
pathology. US allow clinicians to guide needle positioning within inflamed joints, tendon
sheaths and entheses in order to inject steroids or other drugs. The clinical application of
US in SpA extends to the monitoring of therapy efficacy, particularly when coupled with
power Doppler imaging. Very slight changes in vascularity are easily detected in joints,
entheses or tendons, aiding the rheumatologist in the assessment of the effects of local or
systemic therapies. Subclinical Achilles enthesitis, detected with gray-scale US, is
described in a subset of AS patients and a significant improvement can be demonstrated
after 2 months of TNF-alpha antagonist therapy (Aydin, Karadag et al. 2010). In addition,
in children with JIA subclinical synovitis detected by US is common, and often missed
clinically (Magni-Manzoni, Epis et al. 2009).
Juvenile Spondyloarthritis 113
9.2 MRI
Diagnosing spondyloarthritis (SpA) early in young patients with inflammatory back pain
and normal findings on radiographs of the sacroiliac joints (SIJ) remains a challenge in
routine practice. Magnetic resonance imaging (MRI) is regarded as the most sensitive
imaging modality for detecting early SpA before the radiographic appearance of structural
lesions (Figure 10). Single MRI lesions suggestive of inflammation can be found in the SIJ
and the spine in up to one quarter of healthy controls and young patients with mechanical
back pain (Weber and Maksymowych 2011).
Fig. 10. MRI of the SI joints in a 12 year old boy with right-sided buttock pain. Coronal SE T1
WI shows erosive changes of articular facets of right sacroiliac joint with sclerotic
subchondral bone.
Challenges in Rheumatology
MRI is highly sensitive for active enthesitis and depicts not only the enthesis itself but also
associated findings such as soft-tissue involvement and bone marrow edema. Extensive and
diffuse patterns of bone marrow edema are more closely related to inflammatory enthesitis,
as shown in the hip. When soft-tissue involvement occurs in a synovial joint, synovitis may
mask some, if not all, MRI features of enthesitis. Still, differentiation between the different
causes of enthesitis (i.e., inflammatory, mechanical, metabolic) is only reliably possible in
the context of the available clinical information. Despite these limitations, MRI represents a
significant advance for the early diagnosis of ERA and for monitoring therapy that targets
entheseal inflammation (Eshed, Bollow et al. 2007).
9.3 Conventional radiography
Imaging studies usually reveal osteopenia mostly in the foot and hip area in the early stage,
joint space narrowing and ankylosis in the later course of the disease. Erosions and
destruction are rare, but enthesophytosis and bone bridging, particularly in the feet, are
common. Subchondral sclerosis and irregularities of the articular surface in the lower third
of the sacroiliac joints on the iliac side are usually seen, and this may progress to erosions,
joint space narrowing, bone bridging and complete fusion of the sacroiliac bones. Long
lasting disease activity leads also to desmophytosis and ligamentous calcification of the
spine. Plain radiography is insensitive to most of the early inflammatory changes in the
sacroiliac joints in AS, yet to fulfill the modified New York criteria (van der Linden,
Valkenburg et al. 1984), sacroillitis must be present as either grade 2 (erosion and sclerosis)
or greater bilaterally, or grade 3–4 (erosion, sclerosis, and/or ankylosis) unilaterally (Figure
11). In one study, it took 5 years in 36%, and 10 years in 59% of patients with IBP and
radiographically normal (or suspicious) sacroiliac joints to develop radiographic sacroillitis
(Mau, Zeidler et al. 1988). Although conventional radiography is indicated in the initial
evaluation of sacroiliac joints diseases, it is often insensitive for demonstrating the early
changes of sacroillitis, so other imaging techniques typically are often necessary to clarify
the pathology and for establishing the early diagnosis of seronegative SpA (Guglielmi,
Scalzo et al. 2009).
We have to take into account that these New York criteria were designed for pathology in
adult patients. In children the development of the skeleton does not allow us to interpret
plain radiographs of the sacroiliac joints in a proper way until the Risser index reaches stage
five. If that is not a case, sacroillitis may be misdiagnosed because of pseudowidening of the
articular space and irregular margins.
10. Treatment of jSpA
In cases of juvenile-onset SpA, treatment decisions are based on clinical experience rather
than on evidence from clinical trials (Burgos-Vargas, 2009). Medications and physical
therapy are the mainstays of therapy. NSAIDs might be helpful to a degree, especially if
there is inflammatory back pain or peripheral arthritis. Sulfasalazine can work well for
peripheral arthritis, but it is not as effective for axial disease (Burgos-Vargas, Vazquez-
Mellado et al. 2002). Methotrexate as second line agent is a good option in other forms of
JIA, however its use in jSpA is limited. Steroids are used sparingly, mostly as intra-articular
injections with triamcionolone hexacetonide. The combination of these conventional
medications is often inadequate in controlling spondyloarthropathy.
Juvenile Spondyloarthritis 115
The therapeutic value of low-energy lasers (LLLT) for enthesitis is controversial, and has not
been systematically studied in children with spondyloarthritis. LLLT (Ga-Al-As laser) is a
light source that generates extremely pure light, of a single wavelength. The effect is not
thermal, but rather related to photochemical reactions in the cells (Brosseau, Robinson et al.
2005; Hawkins, Houreld et al. 2005). Laser therapy is used in many biomedical sciences to
promote tissue regeneration (Mester, Mester et al. 1985; Karu 1999). Many studies involving
the low-level laser therapy have shown that the healing process is enhanced by such therapy
(Enwemeka 1988; Rochkind, Rousso et al. 1989; Nemeth 1993; Grossman, Schneid et al. 1998;
O'Brien, Li et al. 1998; Lilge, Tierney et al. 2000; Maegawa, Itoh et al. 2000; Schlager,
Kronberger et al. 2000; Sommer, Pinheiro et al. 2001; Wong-Riley, Bai et al. 2001; do
Nascimento, Pinheiro et al. 2004; Eells, Wong-Riley et al. 2004; Pinheiro, Meireles et al. 2004;
Hawkins, Houreld et al. 2005). In Table 5 we show the results of LLLT therapy in the pilot
study of 38 children with jSpA diagnosed based on both ESSG and ILAR criteria, which we
treated, in addition to standard NSAID therapy, with LLLT (Harjacek and Lamot 2008).
No. of patients 38
Cumulative dose 2.5 – 3 J/m3
Treatment duration (days) 15,6 (10-40)
Infrapatelar 13
Achilles 20
AC 10
Inguinal 5
VAS before 5
VAS after 1,2
Table 5. LLLT (Ga-Al-As laser) treatment response.
In this pilot study we have shown that LLLT (Ga-Al-As laser) seems to be very effective in
reducing pain in children with jSpA and enthesitis (76% VAS pain reduction). Visual
analogue scales have become an acceptable measurement tool, and the use of a VAS to
measure pain has been shown to have a high interclass correlation of 0.95. (Chow, Heller et
al. 2006). This is in concordance with other studies that have found the lowering of VAS for
the 2 points on a 10- point scale to be significant (Farrar, Portenoy et al. 2000; Farrar, Young
et al. 2001; Chow, Heller et al. 2006; Van Breukelen 2006).
Currently, the best treatment for severe cases of juvenile-onset SpA is probably anti-TNF
therapy. Anti-TNF alpha agents are also approved for use in Crohn’s disease and psoriatic
arthritis in children. Etanercept (Enbrel), infliximab (Remicade) and adalimumab (Humira)
are in this group and work in the majority of patients. They have improved short-term
outcomes in ankylosing spondylitis and psoriatic arthritis dramatically, and it seems they
change the long-term disease course and outcome (Henrickson and Reiff 2004; Tse, Burgos-
Vargas et al. 2005; Sulpice, Deslandre et al. 2009; Lamot, Bukovac et al. 2011). jSpA patients
treated with TNF-blockers, such as infliximab and etanercept, have shown significant
Improvements in the number of active joints and tender entheses, ESR, CRP levels, and
CHAQ scores (Henrickson and Reiff 2004; Tse, Burgos-Vargas et al. 2005; Sulpice, Deslandre
Challenges in Rheumatology
et al. 2009; Lamot, Bukovac et al. 2011). In addition, the results of a 3-month, randomized,
double-blind, placebo-controlled trial to assess the efficacy of infliximab showed that this
treatment significantly improved most measures of disease activity compared to placebo,
including the number of active joints and tender entheses, pain intensity, patient and/or
parent assessment of well-being and physician assessments of disease activity, health status,
CHAQ score and CRP level (Burgos-Vargas 2007). There was no difference between groups
in the frequency of adverse events.Regular exercises for stretching the spine and physical
therapy are important to keep spinal and joint mobility in patients with jSpA.
Basic principles in the treatment of jSpA are shown in Figure 12.
Fig. 12. Treatment of jSpA.
11. Prognosis
It is difficult to accurately estimate prognosis because the spectrum of jSpA is so broad. In
comparison with other forms of juvenile arthritis, juvenile SpA tends to have a poorer
outcome. While prognosis for ReA is clearly favorable, the majority of children who start out
with undifferented jSpA (ERA), if not treated properly and early-enough, will eventually
develop ankylosing spondylitis (Andersson Gare 1999; Burgos-Vargas 2002; Minden,
Niewerth et al. 2002). In addition, patients might have long periods of remission, although
“outgrowing” jSpA is not an expectation. In the pre-anti-TNF therapy reported remission
rates of ERA following treatment and prior to adulthood range from 17% to 37%, and the
risk of developing sacroillitis within the first 5 years after diagnosis ranges from 6% to
approximately 50% across studies (Flato, Smerdel et al. 2002; Pagnini, Savelli et al. 2010;
•NSAIDS (Indomethacine)
•IA triamcinolone hexacetonide
•Pulse laser therapy/Magnetotherapy
•Leflunomide, MTX?, Bisphosphonates
•Infliximab/Adalimumab/Etanercept/Abatacept (?)
Juvenile Spondyloarthritis 117
Stoll, Bhore et al. 2010). Long term outcome is rather impaired as illustrated by a
retrospective study by Flato et al. (Flato, Hoffmann-Vold et al. 2006) and by Minden et al.
(Minden, Niewerth et al. 2002). Functional scores (measured by HAQ) are elevated and
quality of life (measured by SF-36) is diminished. Remission rates varied from 18 % after 11
years (Minden, Niewerth et al. 2002) to 44 % after 15 years of disease (Flato, Hoffmann-Vold
et al. 2006). In 35 % sacroillitis was found during the course of disease (Flato, Hoffmann-
Vold et al. 2006) and in 39 % definite As developed (Minden, Niewerth et al. 2002). In older
boys with JIA the positive HLA-B27 predicts increasingly extended disease within the first 3
years. It is also associated with involvement of small joints in the lower extremities
(primarily subtalar and tarsal joints) in boys but not in girls, and with inflammatory back
pain in both sexes (Berntson, Damgard et al. 2008). The new epidemiologic and outcome
data in a “post-TNF-” era are clearly warranted.
12. Conclusions
The juvenile spondyloarthritis is a group of seronegative, immune-mediated inflammatory
pediatric disorders characterized by enthesitis and arthritis, and a variety of extra-articular
symptoms. They must be distinguished from JIA, however the distinction may not always
be obvious. While the reactive arthritis is by far the most common form, in many children,
the specific chronic disorder remains “undifferentiated”; most of these children fulfill
criteria for ERA . Other children might develop more differentiated forms: jAS, jPsA, as well
as, IBD-related arthritis. Although these are distinctive diseases, they have a number of
clinical, radiologic, and genetic characteristics in common, which permit them to be
classified under the unifying term “spondyloarthritis. There is not a specific test to be used
since HLA-B27 is neither necessary nor sufficient, but clearly involved in the pathogenesis of
disease. Since plain radiograph is often difficult to interpret in a growing child, the US is
becoming the primary and most important imaging modality for the assessment of these
diseases. Children with jSpA are at risk for sacroillitis, which may be present in the absence
of suggestive symptoms or physical examination findings. Therefore, a routine screening by
MRI has been recently proposed. Axial involvement is usually a late finding. The treatment
decisions are based on clinical experience rather than on evidence from clinical trials;
NSAID’s and physiotherapy (including LLLT) are frequently used to manage symptoms.
Sulphasalazine seems to be more effective on peripheral arthritis then on axial disease. New
biologic therapies appear to improve outcomes, but education, exercise, physical and
occupational therapy for stretching and maintaining range of motion are still the key
components of management. Despite significant advances in the treatment of jSpA over the
past few years, a better understanding of pathogenesis is likely to improve outcome by
identifying ways to provide greater and more sustained clinical responses.
13. Key points
1. Juvenile spondyloarthritis (jSpA) is a term that refers to group inflammatory disorders
affecting children under the age of 16 years, characterized by enthesitis and arthritis
affecting predominantly the joints of the lower extremities.
2. The jSpA often begins as ’undifferentiated’ disease (ERA), the presentation of which
differs in children and adults; most notably, spinal involvement is uncommon, while
hip arthritis is frequently seen in juvenile-onset disease.
Challenges in Rheumatology
3. jSpA are multifactorial diseases in which a disturbed interplay occurs between the
immune system and environmental factors on a predisposing genetic background.
The jSpA are polygenic in nature, both MHC genes (e.g. HLA-B27, etc.), and non-MHC
genes (e.g. TLR-4, etc.) play a significant role in the disease pathogenesis.
4. Subclinical gut inflammation has been demonstrated in patients with all forms of
juvenile spondyloarthritis.
5. While classification of juvenile spondyloarthritis is a “work in progress” and clearly
problematic, the Garmisch-Partenkirchen criteria are the major candidates for future
research in identifying spondyloarthritis in juvenile patients.
6. There are no pathognomonic blood tests for spondyloarthritis.
7. Magnetic resonance (MR) and ultrasound (US) are useful methods for disease activity
monitoring, even in the asymptomatic patient.
8. In cases of juvenile-onset SpA, treatment decisions are based on clinical experience
rather than on evidence from clinical trials; in addition to NSAID’s and sulfasalazine,
anti-TNF therapy has become the best treatment for severe cases of jSpA.
9. Education, exercise, physical and occupational therapy for stretching and maintaining
range of motion are still the key components of management
10. Prognosis in the post “anti-TNF-” era is largely unknown but clearly more favorable
than before. Better understanding of pathogenesis is likely to improve outcome by
identifying ways to provide greater and more sustained clinical responses.
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... Spondyloarthritis (SpA) is a term that comprises a group of seronegative, immune-mediated inflammatory disorders with similar clinical and genetic manifestations [1]. These diseases are characterized by enthesitis and arthritis affecting the joints of the lower extremities and seronegativity for IgM rheumatoid factor and antinuclear antibodies. ...
Full-text available
Microarray gene expression analysis is high-throughput method in which many different sized DNA molecules are attached to solid surface in designated spots. These molecules are used for the discovery of specific RNA molecules isolated from various biological samples of interest. Core principle of this method is hybridization of complementary nucleotides (A-T and G-C), which leads to creation of double stranded nucleic acids. Gene expression differences in two groups of samples are discovered and quantificated by comparison of signal intensity values in microarray spots. Systemic analysis of data gathered in microarray gene expression measurement is performed by various bioinformatic methods such as group analysis, annotation analysis as well as network and pathway analysis. Expression comparison of all genes in different cells of the same individual or same cells of different individuals provides an insight into the mechanism responsible for development of a certain condition or disease.
... Spondyloarthritis (SpA) is a term that comprises a group of seronegative, immune-mediated inflammatory disorders with similar clinical and genetic manifestations [1]. These diseases are characterized by enthesitis and arthritis affecting the joints of the lower extremities and seronegativity for IgM rheumatoid factor and antinuclear antibodies. ...
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Association of juvenile spondyloarthritis (jSpA) with the HLA-B27 genotype is well established, but there is little knowledge of other genetic factors with a role in the development of the disease. To date, only a few studies have tried to find those associated genes by obtaining expression profiles, but with inconsistent results due to various patient selection criteria and methodology. The aim of the present study was to identify and confirm gene signatures and novel biomarkers in highly homogeneous cohorts of untreated and treated patients diagnosed with jSpA and other forms of juvenile idiopathic arthritis (JIA) according to ILAR criteria. For the purposes of the research, total RNA was isolated from whole blood of 45 children with jSpA and known HLA genotype, 11 children with oligo- and polyarticular forms of JIA, as well as 12 age and sex matched control participants without diagnosis of inflammatory disease. DNA microarray gene expression was performed in 11 patients with jSpA and in four healthy controls, along with bioinformatical analysis of retrieved data. Carefully selected differentially expressed genes where analyzed by qRT-PCR in all participants of the study. Microarray results and bioinformatical analysis revealed 745 differentially expressed genes involved in various inflammatory processes, while qRT-PCR analysis of selected genes confirmed data universality and specificity of expression profiles in jSpA patients. The present study indicates that jSpA could be a polygenic disease with a possible malfunction in antigen recognition and activation of immunological response, migration of inflammatory cells and regulation of the immune system. Among genes involved in these processes TLR4, NLRP3, CXCR4 and PTPN12 showed almost consistent expression in study patients diagnosed with jSpA. Those genes and their products could therefore potentially be used as novel biomarkers, possibly predictive of disease prognosis and response to therapy, or even as a target for new therapeutic approaches.
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Juvenile spondyloarthritis (jSpA) is a complex disease with both genetic and environmental factors contributing to etiology. Multiple studies have shown that epigenetic mechanisms could link the environment and gene expression and thus provide a potential explanation for external contribution in the pathogenesis of numerous diseases, including rheumatic. Previously obtained gene signatures in jSpA patients revealed distinctive expression of important immune-related genes, though the mecha-nism(s) responsible for those alterations remained unknown. The purpose of this study was to evaluate the methylation levels of the TLR4, CXCR4, NLRP3, and PTPN12 gene promoter, along with the expression of several non-coding microRNAs (miR-150, miR-146a, miR-181a, and miR-223) in jSpA patients. Peripheral blood samples were obtained from 19 patients newly diagnosed with jSpA according to ILAR classification criteria for enthesitis-related arthritis (ErA) and seven gender-and age-matched subjects without any symptoms or signs of inflammatory disease. The expression of specific microRNAs was analyzed using qRT-PCR with predeveloped microRNA assays. DNA promoter region methylation status of selected genes was assessed by methylated DNA immunoprecipitation (MeDIP) analysis. Fold enrichment of immunoprecipitated DNA differed significantly for NLRP3 promoter site, while the expression analysis of selected microRNAs showed no significant difference in fold change between jSpA patients and healthy controls. The results indicated that epigenetic modifications in the initial phase of the disease could be responsible for some of the expression alterations in jSpA patients. Since NLRP3 has a crucial role in inflammasome assembly and inflammasomes have been shown to shape microbiota, it is tempting to assume that dysbiosis in jSpA patients can at least partially be explained by reduced NLRP3 expression due to hypermethylation, stressing for the first time the epigenetic contribution to jSpA pathophysiology.
Objective. Cytokines are the major mediators of joint damage in chronic arthritis. Data on synovial fluid (SF) cytokine concentrations in patients with juvenile idiopathic arthritis (JIA), especially enthesitis related arthritis (ERA), are limited. We measured levels of different monocyte derived cytokines, T cell derived cytokines, and a proinflammatory chemokine in SF specimens from children with ERA or polyarticular (Poly) rheumatoid factor (RF)-negative JIA. Methods. Macrophage products [tumor necrosis factor-alpha (TNF-alpha), interleukin 1 beta (IL-1 beta), IL-6, IL-12p40)], T lymphocyte products [IL-2, IL-4, interferon-gamma (IFN-gamma)], and a proinflammatory chemokine (IL-8) were assayed using ELISA in SF specimens from 53 patients with JIA [ERA 34, polyarticular RF-negative 19] and 40 patients with rheumatoid arthritis (RA). Results. In the ERA group, median SF cytokine levels were higher compared to RA (all values are pg/ml): IL-1 beta [< 15.6 (< 15.6-213) vs < 15.6 (< 15.6-41); p < 0.01], IL-12p4O [236 (< 15.6-1714) vs 21 (< 15.6-520); p < 0.0001], and IL-6 [1139 (< 4.6-2187) vs 835 (< 4.6-875); p < 0.0001]. TNF-alpha and IFN-gamma levels were similar to RA. IL-8 levels were significantly less than RA (p < 0.0001). The median levels of IL-1 beta [39.4 (< 15.6-558) vs < 15.6 (< 15.6-41); p < 0.0001] and IL-12p40 [209 (< 15.6-849) vs 21 (< 15.6-520); p < 0.0001] were higher in patients with Poly-JIA compared to RA. TNF-alpha, IL-6, and IL-8 levels in Poly-JIA were comparable to RA. IL-2 and IL-4 were not detectable in any patient with JIA. Cytokine profile comparison between the 2 subsets revealed that the median IL-6 [1139 (< 4.6-2187) vs 790 (17.4-2119); p < 0.01] and IFN-gamma levels [235 (< 4.6-600) vs < 4.6 (< 4.6-412); p < 0.0001] were higher in ERA than in Poly-JIA. In contrast, median IL-8 levels were higher in Poly-JIA [200 (3.8-200)] compared to ERA [74.6 (4-200); p < 0.001]. However, there was no difference in levels of TNF-alpha, IL-1 beta, and IL-12p40 between patients with these 2 subtypes of JIA. Conclusion. SF levels of IL-1 beta and IL-12p40 are increased in both Poly-JIA and ERA as compared to RA. IL-6 levels were higher in ERA compared to RA. Levels of TNF-alpha were comparable to RA in both Poly-JIA and ERA. This suggests that joint inflammation in JIA is mediated predominantly by monocytes. In ERA the levels of IL-6 and IFN-gamma are higher than in Poly-JIA. The increase in IFN-gamma in children with ERA with undetectable IL-4 suggests a Th1-dominant immune response in this disease subset.
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Objective To assess the frequency of sacroiliitis and the radiographic and clinical outcome in juvenile idiopathic arthritis (JIA) and determine patient characteristics, early disease variables, and genetic markers that predict development of sacroiliitis.Methods We performed a retrospective cohort study of 314 (79%) of the 400 JIA patients first admitted to the hospital between 1980 and 1985. The participants were examined after a median disease duration of 14.9 years (range 11.7–25.1). Radiographs of the sacroiliac joints, hips, ankles, and tarsi were obtained and studied in a blinded manner by 2 radiologists. The presence of HLA–DRB1 and DPB1 alleles was determined by genotyping and that of HLA–B27 by serologic testing. Variables relating to the onset and course of the disease were obtained by chart reviews.ResultsTwenty (6%) of the JIA patients developed radiographic sacroiliitis according to the New York criteria. In 9 patients (45%), sacroiliitis had not been demonstrated before the followup examination. At followup, spinal flexion (lateral and anterior) was reduced in 70–75% of patients with sacroiliitis and in 30–35% of those without sacroiliitis. Compared with the JIA patients without sacroiliitis, those with sacroiliitis more frequently had inflammatory back pain, enthesitis, radiographic changes in the hips and calcanei, erosions of any peripheral joint, and uveitis.Predictors of sacroiliitis were HLA–B27, absence of DPB1*02, hip joint involvement within the first 6 months, and disease onset after age 8 years. The following factors were more common among patients in whom sacroiliitis developed than in other JIA patients: DRB1*04, male sex, family history of ankylosing spondylitis, psoriasis, inflammatory back pain, and enthesitis within the first 6 months.Conclusion In the current study, radiographically evident sacroiliitis had developed in 6% of JIA patients after a median disease duration of 14.9 years. HLA–B27, absence of DPB1*02, late onset of disease, and early hip involvement were predictors of sacroiliitis.