Autoimmunity Reviews 20 (2021) 102760

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Autoimmunity Reviews
journal homepage: www.elsevier.com/locate/autrev

Review

Exploring IL-17 in spondyloarthritis for development of novel treatments

and biomarkers
Solveig Skovlund Groen a, b, *, Dovile Sinkeviciute a, c, Anne-Christine Bay-Jensen a,
Christian S. Thudium a, Morten A. Karsdal a, Simon Francis Thomsen b, e, Georg Schett f,
Signe Holm Nielsen a, d
a
Immunoscience, Nordic Bioscience, Herlev, Denmark
b
Biomecial Sciences, University of Copenhagen, Copenhagen, Denmark
c
Department of Clinical Sciences Lund, University of Lund, Lund, Sweden
d
Biotechnology and Biomedicine, Technical University of Denmark, Kgs. Lyngby, Denmark
e
Department of Dermatology, Bispebjerg Hospital, Copenhagen, Denmark
f
Department of Internal Medicine 3, Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen,
Erlangen, Germany

A R T I C L E I N F O A B S T R A C T

Keywords: Spondyloarthritis (SpA) is an umbrella term describing a family of chronic inflammatory rheumatic diseases.
Biomarker These diseases are characterised by inflammation of the axial skeleton, peripheral joints, and entheseal insertion
Spondyloarthritis sites throughout the body which can lead to structural joint damage including formation of axial syndesmophytes
IL-17
and peripheral osteophytes. Genetic evidence, preclinical and clinical studies indicate a clear role of interleukin
pathogenesis
treatment
(IL)- 23 and IL-17 as mediators in SpA pathogenesis. Targeting the IL-23/− 17 pathways seems an efficient
strategy for treatment of SpA patients, and despite the remaining challenges the pathway holds great promise for
further advances and improved therapeutic opportunities. Much research is focusing on serological markers and
imaging strategies to correctly diagnose patients in the early stages of SpA. Biomarkers may facilitate person­
alised medicine tailored to each patient’s specific disease to optimise treatment efficacy and to monitor thera­
peutic response. This narrative review focuses on the IL-17 pathway in SpA-related diseases with emphasis on its
role in pathogenesis, current approved IL-17 inhibitors, and the need for biomarkers reflecting core disease
pathways for early diagnosis and measurement of disease activity, prognosis, and response to therapy.

1. Introduction ankylosis including syndesmophytes formation in the spine. The in­

Spondyloarthritis (SpA) represents a group of related but pheno­
typically distinct inflammatory autoimmune diseases. SpA includes axial
SpA (axSpA, summarizing radiographic (ankylosing spondylitis, AS);
=”” axialSpA) and non-radiographic disease, peripheral SpA (pSpA) and
psoriatic arthritis (PsA) [1,2]. These subforms of SpA have overlapping
clinical features that reflect shared genetic risk factors and pathophys­
iology. Genetics plays a role in the aetiology of SpA sharing a close as­
sociation with the major histocompatibility complex (MHC) class I
surface antigen HLA-B27 (human leukocyte antigen B27), which is
believed to be the major genetic susceptibility factor [3].
AxSpA involves inflammation, bone and cartilage loss which is fol­
lowed by new local bone formation that can lead to progressive
flammatory processes and new bone formation take place in the
entheses, axial skeleton, and peripheral joints through mechanisms that
are poorly understood [2]. Extra-articular manifestations can appear
with anterior uveitis, as well as co-occurrence of psoriasis (PsO) and
inflammatory bowel disease (IBD) [4]. As mentioned, axSpA consists of
two diagnostic entities, non-radiographic axSpA (nr-axSpA) and AS [5].
The latter is the prototype of axSpA and is characterised by definite
radiographic damage in the sacroiliac joints and/or in the spine as
defined by the Assessment of SpondyloArthritis international Society
(ASAS) classification criteria [5,6]. On x-ray, patients with nr-axSpA are
visualised without characteristic damage and may represent an early
form of AS. However, some patients may never develop structural
damage on radiographs However, some patients may never develop

* Corresponding author at: Nordic Bioscience, Herlev Hovedgade 205–207, 2730 Herlev, Denmark.
E-mail address: ssg@nordicbio.com (S.S. Groen).

https://doi.org/10.1016/j.autrev.2021.102760
Received 6 November 2020; Accepted 14 November 2020
Available online 22 January 2021
1568-9972/© 2021 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
S.S. Groen et al. Autoimmunity Reviews 20 (2021) 102760

Fig. 1. Venn diagram illustrating the categorisation and overlapping relationships between the Spondyloarthritis subsets. AS, Ankylosing Spondylitis; PsA, Psoriatic
Arthritis; ReA, Reactive Arthritis; IBD-SpA, inflammatory bowel disease (IBD) associated spondyloarthritis (IBD-SpA). Figure modified from [6].

Fig. 2. Healthy spine compared to spine with ankylosing spondylitis. Severe inflammation can lead to fusion of vertebrae bodies which can result in a less flexible
spine with loss of normal curvature seen in a healthy S-curved spine. Additionally, ankylosing spondylitis is characterised by inflammation in the sacroiliac joints.
Figure has been modified from [23].

structural damage on radiographs [7]. The pSpA category covers
inflammation predominantly in peripheral joints rather than axial,
commonly affecting the lower extremities asymmetrically. pSpA also
includes enthesitis, anterior uveitis and/or dactylitis. Patients diagnosed
with reactive arthritis and IBD-associated arthritis often fit into the pSpA
category [6] (Fig. 1). In addition, while PsA is usually considered a
separate disease entity, PsA often fulfils the criteria for pSpA.
AxSpA affects 0.5–1.5% of the western population [8], and it has
been suggested that the entire spectrum of SpA may be more prevalent
than rheumatoid arthritis (RA) in the United States [9]. Although TNF
inhibitor therapy improves symptoms, functional mobility and reduces
disease activity [10–14], almost 40% of axSpA patients do not suffi­
ciently respond to anti-TNF treatment [15,16]. Therapies directed
against TNF may be successful in suppressing the inflammation, how­
ever, axSpA involves both inflammation, bone loss and new bone
formation.
Bone erosion seen in AS is a frequent complication but is often of
limited severity. Eventually, the principal cause of structural damage is
the aberrant new bone formation which can lead to fusion of the
sacroiliac joints and zygapophyseal joints, including outgrowth of syn­
desmophytes in the spine bridging the vertebral bodies resulting in
ankylosis [17] (Fig. 2). Until now, no treatment has shown improvement
in long-term outcomes in axSpA, particularly loss of movement caused
by bone ankylosis [18]. Hence, treatment that only suppresses inflam­
mation may not resolve bone loss and aberrant bone formation.
In the past decade, strong evidence from genetic, animal, trans­
lational and clinical studies has confirmed the role of the IL-23/− 17 axis
in the pathogenesis of SpA. Clinical evidence suggests that TNF blockade
in AS patients does not influence the IL-23/− 17 axis [19]. Instead,
therapeutics have been directed towards the IL-23 and IL-17 which are
considered as key disease-modifying targets in the treatment of SpA.
This has recently contributed to development of a range of novel ther­
apeutics targeting IL-17 and IL-23 pathway in SpA, PsA and PsO [20]. IL-
17 inhibitors have shown beneficial effects on symptoms by significantly
improving psoriatic skin lesions, reducing pain and inflammatory joint
lesions [21]. Furthermore, recent results have showed that IL-17

2
S.S. Groen et al.
inhibition arrests the progression of catabolic and anabolic bone
changes in the joints of PsA patients and may potentially slow disease
progression [22]. Yet, comprehensive evidence is still needed to deter­
mine whether these therapeutics control the SpA disease and succeed as
effective disease-modifying anti-rheumatic drugs (DMARDs).
In recent years, studies have focused on clinically applicable bio­
logical markers to overcome the challenges in the management of SpA
related to unclear pathogenesis, lack of early diagnosis and accurate
monitoring of disease activity and inability to predict joint damage or
response to treatment. Applying biomarkers to address the many chal­
lenging aspects of SpA may enhance the development of novel treat­
ments which may offer more specialised and effective treatment of
patients [24].
This narrative review will explore the role of IL-17 in homeostasis
and its heterogeneous effects in inflammation and structural damage to
justify for the potential advantageous effect of IL-17 inhibition in AS and
PsA. Furthermore, the review will assess the current challenges in the
management of SpA and summarise promising biomarkers of inflam­
mation and tissue remodelling including parameters of angiogenesis and
autoantibodies that may improve the diagnosis, prognosis and treatment
outcomes in SpA.
2. IL-17 signalling and production
The IL-17 superfamily consists of six structurally related proin­
flammatory cytokines IL-17A, IL-17B, IL-17C, IL-17D, IL-17E and IL-
17F, which are involved in the immune-mediated antimicrobial
response. Excessive production of IL-17 during chronic inflammation
has been associated with development of inflammatory diseases [20]. IL-
17A is the best characterised member of the IL-17 family and generally
referred to as IL-17. Of the six cytokine family members, IL-17F is the
closet related member to IL-17A with 55% sequence identity [25] and
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Autoimmunity Reviews 20 (2021) 102760
Fig. 3. IL-17 signalling pathway. IL-17 binds the
heterodimeric IL-17RA and IL-17RC receptor complex
mediating downstream signalling. The recruitment
and binding of Act1 to the cytoplasmic tail of IL-17R
together with the binding of TRANF6 mediates the
canonical pathway where C/EBP, AP-1 and NFKB
pathways can be activated resulting in transcription
of inflammatory genes. Additionally, Act1 interacts
with the TRAF2/TRAF5 complex modulating the
noncanonical pathway where the mRNA stability is
controlled through multiple RNA-binding proteins,
including HuR and Arid5a. TRAF3 can bind directly
to the IL-17R to block the formation of the IL-17R-
Act1-TRAF6 complex. Furthermore, TRAF4 can
compete with TRAF6 for the TRAF binding site on
Act1 and inhibit TRAF6 signalling. IL-17R, IL-17 re­
ceptor; TRAF, TNF receptor associated factor; SEFIR,
similar expression of fibroblast growth factor and IL-
17Rs; SEFEX, SEFIR-extension; HuR, Human antigen
R; Arid5a, AT-rich interactive domain-containing
protein; TAK1, transforming growth factor β-acti­
vated kinase 1; NFKB, nuclear factor kappa light
chain enhancer of activated B cells; MAPK/AP1,
mitogen-activated protein kinase activator protein-1.
Figure modified from [27,28,39].
often co-produced with IL-17A by Th17 cells [26]. Both IL-17A and IL-
17F exist as disulphide-linked homodimers or as IL-17A/-17F hetero­
dimers. All forms of IL-17A and IL-17F cytokines signal through a het­
erodimeric IL-17RA and IL-17RC receptor complex. The cytoplasmic tail
of IL-17RA possesses discrete signalling motifs, a conserved SEFIR
domain (similar expression of fibroblast growth factor and IL-17Rs) with
an additional ‘SEFIR-extension’ domain (SEFEX) which are both
required for functional downstream IL-17 signalling [27]. Upon IL-17A
binding to the IL-17R complex, the IL-17R undergoes a conformational
change enabling interactions between the signalling adaptor protein
Act1 and SEFIR domains mediating downstream events [28]. The
recruitment of Act1 represents a hallmark of IL-17 signalling and is an
essential signalling component of the IL-17R signalling event, not seen in
any other known class of receptors [29]. Act1 contains a TNF receptor
associated factor (TRAF)-binding site which enables association with
different TRAF family proteins. Hereof, Act1 operates as a docking sta­
tion for the different TRAF proteins being able to activate several in­
dependent signalling pathways. The engagement with TRAF6 drives the
activation of the canonical pathway (de novo gene transcription) which
includes the nuclear factor kappa light chain enhancer of activated B
cells (NFKB) pathways activated by the transforming growth factor
β-activated kinase 1 (TAK1), mitogen-activated protein kinase activator
protein-1 (MAPK/AP1) pathways and C/EBP pathways [30].
Collectively, these IL-17A/-17F-activated pathways initiate tran­
scriptional induction of target genes resulting in release of proin­
flammatory cytokines (IL-1β, IL-6, GM-CSF, G-CSF and TNF-α),
chemokines (CXCL1, CXCL2, CXCL8, CCL20 and many others), antimi­
crobial peptides (AMPs; mucins, defensins), tissue remodelling matrix
metalloproteinases (MMPs; MMP -1, − 2, − 3, − 8, − 9, and − 13), and
additional inflammatory effectors (acute-phase proteins and comple­
ment) [31,32]. Furthermore, the IL-17A/-17F-mediated production of
IL-1β, IL-6, and TNF-α contributes to a positive feedback loop leading to
S.S. Groen et al.
enhanced IL-17 signalling [31,33]. Besides activating the transcription
of inflammatory genes, the binding of TRAF2 and TRAF5 to Act1 acti­
vates the noncanonical pathway, which mediates post-transcriptional
mRNA stabilisation, particularly CXCL1 mRNA encoding chemokines
[34]. The post-transcriptional stabilisation is controlled through multi­
ple RNA-binding proteins, including the human antigen R (HuR) and AT-
rich interactive domain-containing protein 5a (Arid5a) [35,36]. The
stabilised transcripts are deposited in cytoplasmic granules, where they
can be translated or degraded instantly [27]. The IL-17-mediated sig­
nalling not only activates proinflammatory cascades but also promotes
numerous regulatory pathways. Upon IL-17A stimulation, TRAF4 which
acts as a negative modulator of IL-17-mediated signalling, can be
recruited and compete with TRAF6 for Act-1 binding [36,37]. Addi­
tionally, TRAF3 also acts as a negative regulator by similar competing
action on the IL-17 signalling [36,38] (Fig. 3). The IL-17 signal trans­
duction overall consists of many non-redundant mechanisms to fine-
tune IL-17-induced inflammation, however, these mechanisms are not
fully understood [27].
2.1. Effects of IL-17 on inflammation
In close cooperation with the other IL-17 cytokine family members,
IL-17A plays a prominent role in host defence to clear off pathogens at
epithelial and mucosal barriers in the skin, intestinal tract and airways
[40–42]. The inflammation is predominantly induced through the
ability of IL-17 to induce the secretion of chemotactic factors which
leads to recruitment of neutrophils to the site of infection [43,44]. IL-17
also stimulates the release of chemokine CCL20 which promotes the
migration of immature dendritic cells and Th17 cells [45]. Moreover, IL-
17 stimulates various cell types, including keratinocytes [46–49],
chondrocytes [50–52], fibroblasts [53,54], osteoclasts [55], osteoblasts
[56], endothelial cells [57–59], macrophages [60–63] and epithelial
cells [64]. Interaction between migrating Th17 cells and local mesen­
chymal cells contributes to an immense production of IL-17 [65]. On its
own, IL-17 is a weak inducer of inflammation compared to other
proinflammatory molecules, such as TNF-α. Nonetheless, IL-17 can act
synergistically with TNF-α and other proinflammatory cytokines and
inflammatory effectors, generating a powerful and rapid inflammatory
response [27,66–68].
The cellular production of IL-17 is complex and heterogeneous. Both
innate cell populations and different adaptive T cell subsets can produce
IL-17. Notably, naïve CD4+ T cells differentiated into Th17 cells are the
main producing cells of IL-17. However, during inflammation most IL-17
is secreted by innate immune cells including innate-acting lymphocytes
such as γδ T cells, invariant natural killer T (iNKT) cells [69], lymphoid
tissue inducer (LTi) cells [70], type 3 innate lymphoid cells (ILC3s) [71],
macrophages [72], neutrophils [73] and Paneth cells [74]. Additionally,
IL-17 can be secreted by Tc17 cells subsets of CD8+ T cells [75,76] and
resident memory T cells [77]. Several animal and human studies have
demonstrated that these cells produce IL-17 in response to inflamma­
tion, but their respective contributions to the SpA pathogenesis remain
unexplored [30].
Although the pathogenic mechanisms underlying SpA are not fully
elucidated, multiple areas of investigation have recently converged to
provide strong evidence implicating the IL-23/− 17 axis in rheumatic
diseases including AS and PsA. The following section will describe
several lines of evidence from genetics, preclinical and clinical studies
emphasising a pivotal role of the IL-23/− 17 axis in SpA.
3. Role of the IL-23/¡17 axis in SpA
3.1. Genetic evidence
IL-23 is responsible for promoting the expansion and survival of
Th17 subsets including the production of IL-17 from Th17 cells [78]. IL-
23R gene polymorphisms with functional relevance in T cell immune
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Autoimmunity Reviews 20 (2021) 102760
response have been strongly associated with the development of AS
[79], PsO [80], and IBD [81]. Additionally, a genome-wide association
study (GWAS) in AS has identified several variants in genes including
CARD9, IL-12B, PTGER4, IL-6R, IL-27, TYK2 and STAT3, which are
implicated directly or indirectly in the IL-23/− 17 axis [82,83].
3.2. Evidence from preclinical studies
The importance of IL-17 in the pathogenesis of SpA has further been
defined in several animal studies. In 2012, Sherlock et al. systemically
overexpressed IL-23 in transgenic mice and identified a unique popu­
lation of CD3+/CD4-/CD8- T cells in the enthesis which expressed the
Th17 transcription factor RAR-related orphan receptor-γt (ROR-γt), and
the IL-23 receptor. Upon activation with IL-23, these T cells produced IL-
17A, IL-17F, IL-6, and IL-22 resulting in enhanced axial and peripheral
enthesis and sacroiliitis followed by IL-22 dependent osteoproliferation
in the absence of synovial inflammation. In addition, blockade of IL-17
and IL-22 with neutralising antibodies significantly diminished the
disease severity, especially when the two antibodies were administered
together [84]. The existence of this unique T cell population may explain
the generation of the SpA phenotype in the early phases of the disease,
without activating CD8+ T cell mediated autoreactivity or other IL-17
secreting cells [18]. IL-17-deficient mice have shown to exhibit less
inflammation in a type II collagen-induced arthritis (CIA) model [85]
and the IL-17R-deficient mice also demonstrated reduced secretion of
proinflammatory cytokines into the synovium preventing cartilage
degradation [86].
3.3. Evidence from clinical studies
IL-17 and IL-23 levels have been measured in serum of AS patients
and healthy controls by enzyme linked immunosorbent assay (ELISA).
Results demonstrated significantly elevated IL-17 and IL-23 levels in AS
patients compared to controls [87–89]. Furthermore, flow cytometry
measurements showed increased numbers of circulating Th17 cells
found in the peripheral blood (PB) of PsA and AS compared to RA pa­
tients, which showed no increase of circulating Th17 cells in PB [90,91].
In addition, Th17 levels in synovial fluid samples from PsA patients were
analysed by flow cytometry. In PsA patients, levels of Th17 cells were
significantly elevated compared to RA patients and correlated with
disease activity measures and progression of radiographic joint erosion
[91]. Increased mRNA expressions of IL-17 and IL-22 were found in skin
lesions from PsO patients including elevated levels of Th17 cells in PB
measured by fluorescence-activated cell sorting (FACS) [92]. In mast
cells, IL-17 levels measured by ELISA were upregulated in the synovium
of peripheral joints in patients with SpA [93]. By immunohistochemical
analysis, enhanced expression levels of IL-17 were found in CD15+
neutrophils located in the subchondral bone marrow of inflamed spine
from SpA patients with low abundance of Th17 cells indicating that IL-
17 producing cells other than the Th17 cells are relevant in local
inflammation in SpA [94]. IL-23, but not IL-17, has been found over­
expressed in inflamed ileum in AS patients analysed by RT-PCR [95]. IL-
23 positive cells within the subchondral bone marrow and fibrous tissue
in facet joints of AS patients were significantly elevated compared to
osteoarthritis (OA) patients measured by immunohistochemistry [96].
Altogether, these results are strong evidence of both the innate and
adaptive mechanisms including the IL-23/− 17 axis may drive the
pathogenesis of SpA.
In 2011, Bowness et al. found elevated numbers of CD4+ Th17 cells
expressing the receptor KIR3DL2 in PB and synovial fluid from AS and
SpA patients. KIR3DL2 responds to the HLA-B27 homodimer molecule
by promoting survival of Th17 cells and upregulation of IL-17 secretion
in AS patients [97]. Nevertheless, levels of CD4+ Th17 cells were not
found elevated in other studies [94,98] including the expression of
KIR3DL2 [99], whereas IL-23R+ γδ T cells were observed instead [100].
γδ T cells have shown to be involved in large productions of IL-17 in a
S.S. Groen et al.
murine model accumulating enthesitis with enhanced bone regeneration
[101,102]. Analysis of the PB and synovial fluid in SpA has been
considered inadequate to uncover whether pathologic processes were
present or not in the sacroiliac joints, vertebral bodies, zygapophyseal
joints including bone marrow next to the axial inflammatory lesions. For
instance, TNF-α serum levels were not consistently elevated in SpA pa­
tients and even found to be lower than in healthy controls [18]. Thus,
this viability of the T cell subtypes seems to be an important factor
compared to TNF-α levels and may be an essential therapeutic target.
The important role of IL-23/− 17 in SpA has not only been evidenced
as mentioned above, but the significant clinical efficacy of IL-17 in­
hibitors in treating AS, PsA and PsO has also been acknowledged and
will be discussed in the next section.
4. Targeting the IL-23/¡17 axis in SpA
As evidence from genetic, animal and human studies support the
importance of IL-23 and IL-17 in the pathogenesis of SpA, therapeutics
inhibiting IL-23 would be expected to show similar clinical efficacy as
drugs inhibiting IL-17 in SpA. Interestingly, clinical studies with IL-12/
IL-23 inhibitor, ustekinumab, showed lack of efficacy in axSpA, while
effective in PsA and PsO [103]. Furthermore, the efficacy of risankizu­
mab, an IL-23 p19 subunit inhibitor, was evaluated in patients with
active AS in a phase II study. Risankizumab did not reduce the signs and
symptoms of AS patients compared to placebo, questioning whether IL-
23 is a relevant driver of AS pathogenesis and symptoms [104].
Conversely, IL-17A inhibition has demonstrated efficacy in AS, PsA, and
PsO in clinical trials. A fully human anti-IL-17A monoclonal antibody,
secukinumab, has been approved for treatment of AS, PsA and PsO based
on several large randomized controlled trials [105–110]. Another IL-
17A inhibitor, ixekizumab, a humanized anti-IL-17A antibody has
been approved for treatment of PsA and PsO and has shown significant
efficacy in AS in two large phase III trials [111–115]. These results
suggest that IL-17A is a key cytokine facilitating disease pathogenesis in
AS, PsA and PsO. In AS, IL-17 seems to be produced in a largely IL-23-
independent way. Furthermore, in human interspinous entheseal tis­
sue IL-23 receptor positive and negative subpopulations of γδ T cells
were found signifying the role of IL-23-independent IL-17 production
[116]. A broader understanding of the divergent roles of IL-23 and IL-17
in the pathophysiology of axSpA is still needed. Evidence towards
anatomical and immunological differences between axial and peripheral
disease may be one of the reasons for the IL-23/− 17 axis pathway
divergence. For instance, more peripheral enthesis is observed in PsA
with inflammation in the entheseal soft tissue [117] while in AS,
inflammation is observed in the peri-entheseal bone in the spine and
more severe axial bone edema has been observed with much higher
frequency in HLA-B27 positive patients [118].
5. Implication of IL-17 in bone damage
Currently, the focus has primarily been on the mechanisms that
trigger chronic inflammation in joints and entheses. However, as a result
of chronic inflammation, structural damage evolves which is a critical
contributor to morbidity in patients suffering from AS and PsA [119].
5.1. Bone homeostasis and abnormal turnover
The bone remodelling cycle is a tightly regulated balance between
osteoclasts, which are responsible for bone resorption involving removal
of mineralised bone matrix, and osteoblasts, which form and replace the
resorbed bone [120]. To maintain bone homeostasis, the resorption and
formation processes are tightly coupled ensuring that the amount of
bone removed equals the amount of bone formed. Within the bone
matrix, bone growth factors, such as transforming growth factor-β (TGF-
β) and bone morphogenetic proteins (BMPs) are stored. These growth
factors are released during the resorptive phase promoting bone
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Autoimmunity Reviews 20 (2021) 102760
formation to maintain bone homeostasis [121].
Abnormal bone turnover is a feature shared by several rheumatic
diseases including AS and PsA, and these bone alterations are displayed
in different forms [17,120]. Bone turnover in AS and PsA is distin­
guished from RA by occurrence of prominent focal areas of new bone
formation involving endochondral ossification. This process is normally
active during the period of skeleton growth and development and in­
volves the replacement of the cartilaginous matrix with mature miner­
alised bone. However, during bone healing after e.g. fracture or
pathological bone growth associated with the ankylosing process,
endochondral bone formation can be reactivated through a series of cell
differentiation steps ultimately leading to new postnatal bone forma­
tion. Although the mechanism behind the reactivation of endochondral
bone formation is incompletely understood, it is believed that the
mesenchymal progenitor cells commit to chondrogenic differentiation
ending up differentiating into hypertrophic chondrocytes which begin to
calcify the cartilage tissue matrix. Consequently, through direct bone
formation osteoblast precursor cells invade and progressively degrade
the matrix and replace it with bone [122]. In addition, hypertrophic
chondrocytes have been shown to transdifferentiate into osteoblasts in
endochondral bone during development [123]. This indicates that
endochondral and direct bone formation are both involved in the pro­
gressive ankylosis with the outlay of a cartilage template as a key
element in the development of syndesmophytes [122]. This aberrant
new bone arises at specific localised anatomical sites and may be the
effect of prolonged entheseal inflammation [124]. Both IL-23 and IL-17
are involved in the pathway that expands entheseal inflammation and
are closely linked to the new bone formation by promoting catabolic and
anabolic bone alterations [124].
5.2. The effects of IL-17 on bone
Bone loss seen in PsA, and in some AS patients, is believed to be
related to activation of the IL-23/− 17 axis by stimulating differentiation
of osteoclasts. Kotake et al. have demonstrated that IL-17 influences
bone homeostasis by showing that IL-17 promoted osteoclastogenesis in
an osteoblast-osteoclast co-culture model [125]. IL-17 can induce the
expression of receptor activator of NFKB ligand (RANKL) on osteoblasts
which stimulates RANK signalling on osteoclastic precursors vital for the
production of mature osteoclasts [126–128]. Several studies have
demonstrated pro- osteoclastogenic effect of IL-17 [129,130] including
Th17 cells being the main T cell subset to stimulate osteoclast iffer­
entiation by releasing IL-17 and increasing expression of RANKL on
osteoblasts [131]. During chronic inflammation, IL-17 has been shown
to activate MMPs and promote matrix turnover leading to cartilage loss
in joint tissue [132]. Chabaud et al. have demonstrated that adding IL-
17 to human bone samples increased the production of bone-
destructive cytokines and bone resorption in vitro [133]. In contrast,
the inhibition of IL-17 showed an anti-inflammatory effect and reduced
bone destruction and an even more efficient anti-inflammatory effect
was obtained when IL-17 was inhibited in combination with TNF-α and
IL-6 [67]. These studies suggest that IL-17 activity affects the bone ho­
meostasis by inducing osteoclastogenesis which partially explains the
development of destructive bone lesions and loss seen in PsA and AS.
In addition to the effects of IL-17 on bone loss, IL-17 also critically
orchestrates the activation and differentiation of osteoblasts. Studies
have shown that IL-17 enhances osteogenic differentiation of mesen­
chymal stem cells (MSCs) [134–136]. Furthermore, Osta et al. have
demonstrated that IL-17 combined with TNF-α can stimulate osteogenic
differentiation of human MScs [137]. Although these findings suggest
that IL-17 is involved in the osteogenesis, the role of IL-17 on osteogenic
MSCs is still not clear.
Besides the effects of IL-17 on bone remodelling, the development of
enthesitis and entheseal new bone formation have been shown to
depend on IL-22 [138]. Entheseal resident T cells producing IL-22 have
been shown to activate osteoblast-mediated bone remodelling [84].
S.S. Groen et al. Autoimmunity Reviews 20 (2021) 102760

Fig. 4. Overview of the bone erosion and new bone formation in AS and PsA activated by the IL-23/− 17 axis. IL-23 stimulates Th17 to secrete IL-17 and IL-22.
Subsequently, IL-17 induces the expression of RANKL on osteoblasts which initiates osteoclast differentiation via upregulating of RANK, the receptor for RANKL.
In combination with other proinflammatory cytokines such as TNF-α, IL-1, and IL-6, IL-17 can also directly promote osteoclastogenesis leading to bone erosion.
Moreover, the pathological bone growth includes both direct bone formation and reactivation of the endochondral bone formation. IL-17 and IL-22 promote dif­
ferentiation of bone marrow-derived mesenchymal stem cells (MSCs) which further differentiate either into hypertrophic chondrocytes that form calcified cartilage
tissue matrix, or osteoblasts promoting osteoproliferation. Eventually, the calcified cartilage will be progressively degraded and replaced with bone matrix by os­
teoblasts. This exaggerated new bone formation can result in ankylosis. RANK, receptor activator of NFKB; RANKL, receptor activator of NFKB ligand. Adapted
from [18,122,124].

Furthermore, in vitro IL-22 has been shown to enhance MSC osteo­
genesis and increase proliferation and migration of human MSCs in in­
flammatory environments [139]. Hereof, IL-22 may play an important
role of the IL-23/− 17 axis in bone remodelling providing a novel
pathway for studying the pathological and inflammatory osteogenesis in
SpA [30].
5.3. Aberrant bone formation in AS
AS is mainly characterised by ankylosis of the sacroiliac joints and
vertebral bodies which involves excessive bone formation encompassing
both endochondral and direct bone formation [17]. Inflamed sacroiliac
joint tissue from patients with AS has been examined by Braun et al. who
observed localised nodules of endochondral ossification within the
inflamed tissue [140]. TGF-β and BMPs have been proposed as potential
key players of the enhanced bone formation in AS. The endochondral
bone formation during development and postnatal fracture repair are
induced by TGF-β and BMPs and have been implicated in this process
[141,142]. TGF-β and BMPs signal through the wingless (Wnt) pathway
which is a main regulator of skeletal patterning and post-natal bone
remodelling [143]. The activation of the Wnt/ β-catenin pathway results
in transcriptional activation of the osteoprotegerin (OPG) gene, which is
a potent inhibitor of RANK ligand, the principal regulator of osteoclast
differentiation and activation [144].
Lories et al. have elaborated on the concept of a potential relation
between biomechanical factors and the ankylosing process [122]. The
skeleton consists of mechanosensitive tissue which can adapt biome­
chanical loading controlled by the bone remodelling cycle. In axSpA
patients, osteitis in vertebral bodies and sacroiliac joints influences the
normal bone homeostasis by cytokine-mediated osteoclast activation
increasing net bone loss. Lories et al. suggested that increased bone net
loss leads to instability of the axial skeleton and that the loss of stability
triggers tissue remodelling which includes syndesmophyte formation
[122]. Studies have suggested that the bone may not be able to
compensate for the bone loss in a normal physiological way due to
osteoblast activation being suppressed by proinflammatory cytokines or
bone formation inhibited by the Wnt signalling antagonist Dickkopf-1
(Dkk1) driven by TNF-α [145].
In summary, bone remodelling seen in AS seems much more complex
compared to primary erosive forms of arthritis such as rheumatoid
arthritis (RA). Although synovial inflammation in the peripheral joints
of patients with AS exhibits histopathologic characteristics similar to
those seen in the RA joints, differences have been observed in the excess
bone formation and repair pattern [120]. IL-17 has showed to promote
excessive osteogenesis at sites of entheses under conditions of mechan­
ical stress, resulting in formation of new bone and syndesmophytes, the
key difference between RA and AS [146]. Determining the heteroge­
neous effects of IL-17 in new bone formation remains a central avenue of
future research.
5.4. Bone erosion and formation in PsA
Whereas AS is mainly characterised by extensive aberrant bone
formation primarily in the axial joints, PsA manifests in the peripheral
joints with both increased bone destruction and increased bone forma­
tion [147] and differs from RA by its characteristic calcification of
entheses [148]. Despite main involvement of peripheral joints, certain
PsA patients may have axial involvement with inflammatory back pain
and sacroiliitis. In PsA, the bone remodelling homeostasis is disrupted by
several cytokines and growth factors altering the differentiation and
function of osteoclasts and osteoblasts [149]. These cytokines include
both IL-17, IL-6, TNF-α, RANKL, and the growth factors BMPs and TGF-
β, similar to AS [150].
Prolonged effect of inflammatory cytokines such as IL-17 has been
linked to increased fracture risk in PsA patients [151]. As previously
mentioned, IL-17 induces osteoclast differentiation and facilitates bone
erosion [126–128,131,152] and these observations provide basis for
focusing on IL-17 inhibition in PsA to protect from bone erosion.
Consistent with these results, clinical studies have showed that PsA
patients treated with IL-17A inhibitors, exhibit significantly reduced
inflammation and structural damage versus placebo in the short- and
long-term [106,153,154]. Recently, the PSARTROS study demonstrated
no progression of catabolic or anabolic alterations in the joints of PsA
patients treated with secukinumab for 24 weeks [22].
Comparing RA and PsA, similar cytokine expressions have been
observed suggesting related mechanisms involved in joint inflammation
and destruction [155,156]. However, significant differences between
RA and PsA are seen in the bone resorptive phenotype. In RA, the

6
S.S. Groen et al.
Fig. 5. IL-17 therapy options for management of SpA and upcoming treatment. Overview of approved IL-17 inhibiting therapies and novel drugs investigated in the
development phases for the treatment of patients with psoriasis (PsO), ankylosing spondylitis (AS), and psoriatic arthritis (PsA). mAb, monoclonal antibody; IL-17R,
IL-17 receptor. Data adapted from [177].
phalangeal joints are most frequently involved in a symmetric manner
with U-shaped lesions involving bone destruction and insufficient repair
leading to local and systemic bone loss [157,158]. In contrast, PsA ex­
hibits a tubular or omega-like asymmetric bone erosion pattern less
severe in size and depth [159]. This suggests that the bone repair
mechanism and pathogenesis may be different between PsA and RA.
New bone formation has been observed in PsA patients with enthe­
seophytes and ankylosis mainly manifested in the peripheral joints.
However, bone formation in the axial skeleton has also been observed in
PsA thus, axial disease can occur both in AS and PsA patients. Likewise,
PsO can occur in AS patients which has initiated a debate on whether
axial PsA is essentially AS with PsO, or if these conditions are two
separate diseases with overlapping features [160]. Like in AS, the
mechanisms behind the new bone formation are currently unknown.
Hereof, the aberrant bone formation seems to be like AS, but they differ
somewhat in their pathology [161].
According to radiographic differences between AS and PsA, the
syndesmophytes are symmetrically distributed with a primary marginal
shape in AS, while the distribution in PsA is rather asymmetric along the
spine with equal amounts of marginal and paramarginal syndesmo­
phytes. From radiographs, the axial severity appears to be worse in AS
than in PsA by the number of syndesmophytes and the Bath AS Radi­
ology Index (BASRI) [162]. Like in AS, anabolic growth factors are
considered to play one of the key roles in the bone formation in PsA by
mediating the formation of hypertrophic chondrocytes and osteoblasts.
7
Autoimmunity Reviews 20 (2021) 102760
Yet, the connection between inflammation and new bone formation is
not clearly understood. In mouse models of PsA, BMP signalling in DBA/
1 mice showed to trigger spontaneously PsA-like arthritis indicating that
BMP signalling may be related to the abnormal development of bone in
PsA [141,163].
Unlike RA, decreased levels of Dkk1 have been reported in PsA serum
compared to healthy subjects which agrees with the increased bone
formation and indicates that Wnt/β-catenin signalling plays an impor­
tant role in directing osteoblast differentiation and function in PsA
[164]. Interestingly, in serum samples from AS patients high levels of
Dkk1 showed to protect from developing syndesmophytes [165]. Other
studies have reported additional high levels of Dkk1 in PsA patients
highlighting the complexity of PsA as a disease involving the combina­
tion of extensive bone destruction and aberrant bone formation
[166,167] (Fig. 4).
6. IL-17 therapy options for management of SpA
In early 2015, secukinumab was approved in the US and the EU as
the first IL-17A inhibiting drug developed for treatment of patients with
plaque PsO [168] and in 2016 secukinumab was approved as treatment
of AS and PsA patients [169]. Subsequently, another IL-17 inhibitor,
ixekizumab, was approved for the treatment of plaque PsO and PsA and
is yet under investigation for treatment of AS [170]. In 2017, the latest
IL-17 receptor inhibitor class medication, brodalumab, was approved for
S.S. Groen et al.
treatment of patients with plaque PsO. Brodalumab, however, has been
associated with increased risk of suicidal behaviour [171].
Several novel drug candidates of anti-IL-17 are currently investi­
gated in the development phase. Netakimab, tackling IL-17A is under
investigation for treatment of plaque PsO and is now in phase III clinical
trials [172]. Bimekizumab, tackling both IL-17 A and IL-17F has shown
promising results in phase II trial in AS, PsA and PsO and is currently
undergoing phase III trials [173]. Another bispecific agent, afaseviku­
mab, which neutralises IL-17A and IL-17F, is in early phases of clinical
trials [174]. One more novel approach is the development of the
nanoantibody, ALX-0761, which is undergoing phase II clinical trials for
treatment of PsO [175] (Fig. 5). For future treatment of SpA, bispecific
biologic therapies which inhibit both TNF-α and IL-17 are of great in­
terest. Dual inhibition of these cytokines in a type II collagen-induced
arthritis model has been shown to improve protection against joint
damage compared to TNF-α inhibition alone [68,176]. Thus, the com­
bination of blocking TNF-α and IL-17 may provide additional thera­
peutic value for treatment of SpA. Dual IL-17/TNF-α inhibitors, such as
remtolumab and COVA322, are in phase II clinical trials [173].
7. Biomarkers in drug discovery and development
Over the past decade it has become clear that biomarkers constitute a
high priority for the drug discovery process and understanding of the
pathogenesis of SpA. Although the ASAS classification and response
criteria are useful clinical tools, they are built on patient-reported out­
comes including questions about pain and stiffness which is purely
subjective and can have high levels of individual variability and bias.
Hereof, the usage of more objective measures should be considered in
combination with the ASAS criteria [170].
The rheumatoid factor (RF), anti-citrullinated protein antibodies
(ACPA), erythrocyte sedimentation rate (ESR) and C-reactive protein
(CRP) levels are well-established serological biomarkers to evaluate
disease activity in RA patients [178]. However, SpA patient are sero­
negative by the lack of induced levels of serum autoantibodies including
RF and ACPA, and ESR and CRP only are used as serum biomarkers,
directly reflecting inflammation. CRP is a relative insensitive marker in
SpA diseases and correlates poorly with disease activity and is not pre­
sent in all AS patients thus, may not be useful [179,180]. The onset of
disease in SpA patients typically manifests between the ages of 20–30
years with slow progression and is associated with vague symptoms
[181]. Altogether, with the lack of confirmatory blood tests and an
average delay in diagnosis of AS of 5–10 years, there is a growing in­
terest in the discovery of new biomarkers [181]. Earlier diagnosis and
initiation of appropriate therapy would improve the success rates of
clinical remission and may prevent the development of structural lesions
including ankylosis.
In recent years, several new and expensive therapeutic options such
as TNF and IL-17 inhibitors have been approved for treatment of PsA and
AS. These agents have shown to improve symptoms, quality of life, and
slow down radiographic progression. However, new data on the genetic
profiles of the different types of arthritis have appeared with clear evi­
dence of little or no genetic overlap between the different types of
arthritis, suggesting that therapies may not be efficient on all these forms
[182]. For example, despite the positive effect of IL-17A inhibition in AS
and PsA, clinically secukinumab showed to be ineffective in SpA patients
with IBD and even exacerbated the symptoms in some patients [183].
Due to the improved understanding of AS and PsA together with the new
therapeutic options, more accurate analysis tools are needed to predict
early diagnosis, disease activity, disease progression and response to
therapy significantly increasing the need for new biological markers.
Several biomarkers have been proposed for SpA but they are still in the
research phase and not yet widely utilised in clinical practice. This
section reviews well-known and new promising biological markers.
8
Autoimmunity Reviews 20 (2021) 102760
7.1. CRP
CRP is an acute-phase protein which reflects systemic inflammation.
Although CRP is not elevated in a substantial proportion of patients with
active SpA, it is commonly used as a reliable acute inflammatory marker
of disease activity. Levels of CRP are frequently higher in patients with
full-blown radiographic forms of AS compared to nr-axSpA. CRP cor­
relates with Ankylosing Spondylitis Disease Activity Score (ASDAS) and
moderately correlates with MRI inflammation which is the preferred
method to assess disease activity in SpA, though very costly [184]. In a
study by Poddubnyy et al. elevated levels of CRP were observed as a
solid predictor of radiographic sacroiliitis progression in AS and nr-
axSpA patients [185]. Subsequently, in 2016 Poddubnyy et al. investi­
gated the link between several disease activity parameters (CRP, ASDAS
and BASDAI) and radiographic spinal progression in early AS patients.
Here, five time points of the mentioned parameters were available
during 2 years of follow up. The study confirmed an association between
high disease activity and development of structural damage in the spine
in patients with early AS [186]. In several studies, SpA patients have
been treated with TNF inhibitors which has been shown to decrease the
elevated CRP levels, and thus, CRP has been demonstrated as a reliable
biomarker for therapeutic response [187–189]. In a study by Pedersen
et al. the development of new syndesmophytes resulted in a more sig­
nificant decrease in CRP levels while chronic systemic inflammation was
associated with absence of radiographic progression throughout a brief
period [188]. These findings support the hypothesis that resolved
inflammation results in an increased rate of ossification of the repaired
tissue whereas persistent inflammation prevents the formation of syn­
desmophytes [184].
7.2. Anti-CD74
CD74, also known as human lymphocyte antigen (HLA) class II
gamma chain or invariant chain, is involved in the assembly and
transport of human histocompatibility complex class II (MHC II) mole­
cules [190]. It is believed to mediate B cell proliferation and bind the
macrophage migration inhibitory factor (MIF) leading to NFKB activa­
tion and thus, expression of pro-inflammatory mediators [191]. ELISA
studies performed by Baerlecken et al. 2013 observed antibody reac­
tivity against full-length human CD74 in 56% of 41 patients sera with AS
and 5% of 100 healthy subjects. Furthermore, antibody reactivity
against CLIP domain of the CD74 protein was observed in 67% of the
216 SpA patients with axial (n = 156) and peripheral (n = 60) SpA.
Antibody reactivity was also observed in 45% of 40 PsA patients, 11% of
the 80 RA patients, 15% of the 40 patients with systemic lupus, and 0.8%
of 125 healthy blood donors. In the 67% of SpA patients, 97% experi­
enced inflammatory back pain of <1 year and hereafter, the reactivity
declined by 65% after >20 years after onset and no association with
disease activity was observed indicating a potential biomarker for early
diagnosis of SpA [192]. In an additional European study, similar results
were observed with reactivity in 85.1% of 94 axSpA patients and in 7.8%
of 51 controls [193]. However in another study, anti-CD74 IgG and IgA
autoantibodies have no diagnostic value in early axSpA demonstrating
reactivity with IgG antibodies in 46.4% of 274 axSpA patients and
47.9% of 319 non-SpA chronic back pain controls [194]. This points
towards two opposite conclusions in the role of anti-CD74 autoantibody
in the diagnosis of SpA. Furthermore, anti-CD74 was measured by ELISA
in sera from 71 Chinese SpA patients and 70 controls. The results
demonstrated reactivity of 14.1% in SpA patients and 2.9% in healthy
controls. Although these results showed higher reactivity in SpA
compared to controls, the prevalence of anti-CD74 was lower than in the
European studies. This suggests that CD74 may not be a useful diag­
nostic biomarkers in an Asian population [195]. Based on these results,
further investigation is needed to test the efficiency of CD74 as a good
target biomarker molecule for axSpA diagnostics.
S.S. Groen et al.
7.3. PPM1A
Protein phosphatase magnesium-dependent 1A (PPM1A) is a serine/
threonine protein phosphatase contributing to the formation of bone
including syndesmophytes which is a key feature of AS. PPM1A partic­
ipates in the bone formation by regulating the BMP and Wnt signalling
pathways, including suppressing TGF-β signalling [196,197]. By using
high-density protein microarrays, antibody reactivity to PPM1A was
tested in sera from patients with PsA (n = 34), PsO (n = 6), and AS (n =
16), RA (n = 21), juvenile idiopathic arthritis (n = 15), and pulmonary
artery hypertension (n = 23). Here, higher levels of antibodies against
PPM1A were detected in AS patients compared to the other autoimmune
diseases. Moreover, in AS patients with grade 3 and 4 radiographic
sacroiliitis, higher levels of anti-PPM1A autoantibody were observed
compared to those with grade 2 radiographic sacroiliitis. Furthermore,
the AS patients were treated with TNF inhibitor which resulted in a
significant decrease in the serum levels of anti-PPM1A, which also
showed to correlate positively with degree of sacroiliitis in AS by the
Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score.
PPM1A was also found to be highly expressed in synovial tissue taken
from AS patients and driving osteoblast differentiation, which suggests
that PPM1A may participate in the pathogenesis of AS. In Korean pa­
tients, significantly higher levels of anti-PPM1A were also observed in
AS patients (n = 45) compared to RA patients (n = 20), and healthy
controls (n = 30). In rats, transgenic for HLA-B27 and human β2-
microglobulin, anti-PPM1A levels were also increased in sera [198].
Despite these remarkable observations and the potential association
with SpA pathogenesis, more research is needed to examine PPM1A as a
diagnostic biomarker.
7.4. miRNA
Diagnostic biomarker candidates have been considered from gene
expression of transcriptomic markers. A meta-analysis performed on
gene expression arrays discovered 905 cases of differentially expressed
genes in axSpA patients compared to healthy subjects. Here, the most
significantly expressed genes represented pathways linked to antigen
processing and presentation [199]. In another report, RNA sequence
analysis revealed upregulated expression of microRNA (miR)-146a-5p,
miR-125a-5p, miR-151a-3p and miR-22-3p, and downregulated
expression of miR-150-5p and miR-451a in AS (n = 53) compared to
healthy subjects (n = 57). Furthermore, syndesmophyte development in
patients with AS was associated with the expression of miR-125a-5p,
miR-151a-3p, miR-150-5p and miR-451a [200]. Another miRNA, miR-
10b-5p, has shown to be a Th17 regulator present in Th17 cells from
AS patients. Thus, miR-10b-5p decreases the IL-17A production by
inhibiting the mitogen-activated protein kinase 7 (MAP3K7) in CD4+ T
lymphocytes [201]. Other miRNAs found in diseased tissue of hip liga­
ments from AS patients showed differential expression of 22 miRNAs
from AS patients compared to health controls [202]. Altogether, these
miRNAs could be attractive promising biomarker candidates for AS
diagnosis which may help to clarify the disease pathogenesis, however,
further validation is required.
7.5. CRPM
The MMP-cleaved protein fragment of CRP (CRPM) has been asso­
ciated with local inflammation [203] and appears to be a more specific
inflammation biomarker for AS compared to measuring the full-length
CRP [204]. CRPM was measured in serum from axSpA patients (nr-
axSpA = 121, AS = 72) and CRPM levels were higher compared to
asymptomatic controls (n = 100). In addition, CRPM levels were
increased in AS patients compared to nr-axSpA, indicating that CRPM
reflects axSpA associated inflammation. CRPM correlated with ASDAS-
CRP in AS patients and with CRP in nr-axSpA patients. In summary,
this study indicated that the CRPM biomarker seems to have potential as
9
Autoimmunity Reviews 20 (2021) 102760
prospective laboratory tool to assess disease activity in axSpA patients.
However, this study had several limitations such as the lack of whole-
body MRI in AS and nr-axSpA to examine the correlations between
CRPM and local inflammation [205].
7.6. Connective tissue remodelling markers
In inflammatory joints disease, the tissue remodelling homeostasis is
disrupted leading to altered extracellular matrix (ECM) remodelling.
The ECM consists of several collagens including type I, II, III and IV
collagens and when degraded by proteases, it generates new collagen
metabolites fragments called neoepitopes, which have been suggested as
useful future serological biomarkers of SpA [206].
The neoepitope biomarker of type I collagen (C1M) is associated with
destruction of soft tissue and high levels have been observed in patients
with AS [207]. The neoepitope biomarker of type II collagen (C2M)
reflects the degradation of cartilage [208], and metabolite of type III
collagen is linked to degradation of soft tissue (C3M). Elevated levels of
C2M and C3M have been observed in patients with AS compared to
healthy subjects [207]. In addition, C3M has been found in inflamed
tissue of liver fibrosis [209]. The neoepitope biomarker of type IV
collagen (C4M) has also been found elevated in soft tissue destruction
[210]. Recently, C1M, C2M, and C3M have been related with the
response to biologic therapy in AS [206] and have shown correlation
with CRP, ESR, and radiographic severity [211]. Thus, it has been pro­
posed that the pathological process in AS involves a higher ECM turn­
over with elevated levels of MMP-cleaved collagen products. In a study
by Hušáková et al. C1M, C2M, C3M and C4M were quantified by ELISA
in serum from AS (n = 72) and nr-axSpA (n = 121) and controls (n =
100). All collagen metabolite biomarkers showed elevated levels in
axSpA patients compared to the controls. Furthermore, the serum levels
of C1M, C3M and C4M were significant higher in AS compared to nr-
axSpA. The best biomarker to distinguish between AS and nr-axSpA
was C3M, but more investigation of C3M is needed before validation
as a diagnostic tool within axSpA. Both C1M, C3M, and C4M were
correlated with ASDAS-CRP in AS and nr-axSpA reflecting association
with disease activity. Altogether, the current study showed that sero­
logical MMP-mediated metabolites from collagen may have potential as
novel disease activity biomarkers in axSpA however, more compre­
hensive studies are needed to confirm these results [212]. In another
study, Gudmann et al. measured the same serological neoepitope bio­
markers, C1M and C3M, in serum from patients with axSpA (n = 110),
PsA (n = 101), and healthy controls (n = 120). The C1M and C3M levels
were both significantly elevated in axSpA and PsA patients compared to
controls. Furthermore, C1M and C3M correlated with ASDAS and Dis­
ease Activity Score 28 (DAS28). In summary, this study demonstrated
that C1M and C3M could be used to distinguish between diseased and
healthy subjects and the increase in biomarker levels was associated
with disease activity in axSpA and PsA [213]. In addition, Siebuhr et al.
measured C1M, C2M and C3M including CRP, ESR, CRPM in serum from
AS patients during their first year of treatment with etanercept, a TNF
inhibitor. Study showed that ESR, CRP, BASDAI and C1M were signifi­
cantly decreased with treatment. Furthermore, C1M and CRP showed to
predict treatment efficacy. Overall, this study demonstrated that quan­
tification of acute inflammation and connective tissue remodelling can
determine which AS patients will most likely benefit from the etanercept
treatment [206].
Besides measuring tissue biomarkers from collagen degradation,
PRO-C2, a marker of mature cartilage collagen type IIB formation, and
C-Col10, a marker of type X collagen turnover exclusively expressed by
hypertrophic chondrocytes, were measured in 2016 by Gudmann et al.
The study aimed to investigate the cartilage metabolism in axSpA (n =
110) and PsA (n = 101) patients by measuring and evaluating the
diagnostic utility of PRO-C2 and C-Col10. The PRO-C2 levels showed to
be significantly increased in serum samples of both axSpA and PsA
compared to healthy subjects. Likewise, C-Col10 was significantly
S.S. Groen et al.
BIOMARKER DESCRIPTION OF BIOMARKER
DIAGNOSTIC BIOMARKERS
ANTI-CD74 Human lymphocyte angen
(HLA) class II gamma chain
(CD74), involved in the
assembly and transport of
human histocompability
complex class II (MHC II)
molecules.
ANTI-PPM1A Protein phosphatase P=16, C=99
magnesium-dependent 1A
(PPM1A), parcipate in the
formaon of bone including
syndesmophytes by regulang
the BMP and Wnt signalling
pathways, including suppressing
TGF-beta signalling.
MICRO-RNAS microRNAs (miRNAs), a group of P=53, C=57
single-stranded noncoding
RNAs. miRNA has been
appreciated to be important in
pathologies systemic rheumac
diseases and inflammaon by
regulang the post-
transcriponal control of gene
expression.
P=4, C=4
DISEASE ACTIVITY
CRP C-reacve protein (CRP), acute
phase reactant. Widely used in
the clinic. Elevated levels of
CRP are a direct indicator of
inflammaon and is used as a
predictor of clinical response to
an-TNF treatment.
Fig. 6. Summary of potential biomarkers for diagnosis, monitoring disease activity, treatment response, and prognostics in patients with spondyloarthritis. P, Pa­
tients; C, Controls.
increased in PsA patients compared to healthy subjects, and a similar
trend was seen in axSpA patients. Interestingly, a small group of axSpA
patients (n = 34) naïve to anti-TNF therapy were significantly lower in
C-Col10 levels compared to the axSpA patients undergoing TNF inhib­
iting treatment. This supports the previously mentioned theory that
resolved inflammation as a result of TNF inhibiting treatment leads to an
Autoimmunity Reviews 20 (2021) 102760
PARTICIPANTS PRIMARY STUDY OUTCOMES REFS
192
P=216, C=325 Anbody reacvity against CD74 in 56 %
of axSpA paents.
Anbody reacvity against CLIP domain
of the CD74 protein in 67 % of SpA
paents.
193
P=94, C=51 Anbody reacvity against CD74 in 85.1
% of 94 axSpA paents.
198
Anbody reacvity against PPM1A in AS
paents was higher compared to other
autoimmune diseases. Higher levels of
an-PPM1A autoanbody were
observed in AS paents with severe
radiographic sacroiliis compared to
those with mild radiographic sacroiliis.
200
Upregulated expression of (miR)-146a-
5p, miR-125a-5p, miR-151a-3p and miR-
22-3p, and lower expression of miR-
150-5p, and miR-451a were observed in
AS. miR-125a-5p, miR-151a-3p, miR-
150-5p and miR-451a were associated
with development of syndesmophytes
in paents with AS.
201
miR-10b-5p showed to be a Th17
regulator present in Th17 cells from AS
paents.
185
P=210 Elevated levels of CRP were a strong
predictor of radiographic sacroiliis
progression in AS and nr-axSpA
paents.
186
P=178 An associaon was observed between
disease acvity parameters (ASDAS,
BASDAI and CRP) and radiographic
spinal progression in paents with early
AS.
187
P=201, C=78 AS paents treated with infliximab
resulted in significant reducon in CRP
levels compared to placebo.
increased rate of ossification which is seen by the increase in C-Col10
levels reflecting hypertrophic chondrocytes. In conclusion, these find­
ings suggest that PRO-C2 and C-Col10 may be promising markers for
investigating the cartilage collagen metabolism in SpA patients [214].
10
S.S. Groen et al.
CRPM MMP-mediated metabolite of
CRP associated with local
inflammaon.
COLLAGEN MMP-degraded type I, II, III, IV
METABOLITE collagen markers, C1M, C2M,
S C3M, and C4M.
The extracellular matrix
remodelling is altered in joint
degenerave diseases.
Type II collagen formaon
markers, PRO-C2 and PRO-C10.
DISEASE PROGRESSION
SCLEROSTIN Wnt signalling inhibitor,
suppresses bone formaon.
Fig. 6. (continued).
7.7. Markers of bone remodelling
As previously mentioned, the Wnt/β-catenin signalling pathway
including its inhibitors, Dkk proteins and sclerostin, are believed to be
involved in the pathogenesis of SpA. Dkk1 and sclerostin have been
suggested as markers, however, conflicting data exists with regards to
bone formation, Dkk1 and sclerostin correlation to disease progression.
Sclerostin has shown to be significantly lower in serum and in local
Autoimmunity Reviews 20 (2021) 102760
188
P=60 Treatment with either infliximab,
etanercept or adalimumab, gave a
decrease in MRI inflammaon scores
and CRP levels in SpA paents.
Formaon of syndesmophytes was
associated with larger decrease in CRP.
189
P=155 Elevated baseline CRP levels was
observed in AS paents treated with
either etanercept or infliximab.
205
P=193, C=100 CRPM levels were higher in axSpA and
increased in AS compared to nr-axSpA,
indicang that CRPM reflects axSpA
associated inflammaon. CRPM
correlated with ASDAS-CRP in AS
paents and with CRP in nr-axSpA
paents.
212
P=193, C=100 Increased concentraons of C1M, C2M,
C3M and C4M were measured in axSpA.
Both C1M, C3M, and C4M correlated
with ASDAS-CRP.
213
P=211, C=120 Increased concentraons of C1M and
C3M in PsA and axSpA paents. C1M
and C3M correlated with ASDAS and
DAS28.
206
P=22 AS paents treated with etanercept
showed significant decreased levels of
C1M in response to treatment.
214
P=211, C=118 The PRO-C2 was significantly increased
in axSpA and PsA compared to healthy
subjects. Likewise, C-Col10 was
significantly increased in PsA compared
to healthy subjects, and similar trend
was seen in axSpA paents. axSpA
paents naïve to an-TNF therapy were
significantly lower in C-Col10 levels
compared to axSpA paents undergoing
TNF inhibiting treatment.
215
P=204, C=80 Lower sclerosn levels were found in AS
serum and correlated with high CRP
levels.
216
P=46, C=50 Low sclerosn serum levels have been
found in paents with AS and
expression in patients with AS compared to healthy controls [215,216].
Low serum levels of sclerostin have been related to the development of
syndesmophytes in AS patients [216]. AS patients treated with anti-TNF
therapy showed gradually increased levels of sclerostin over 12 months,
while the sclerostin levels stayed substantially lower in AS patients
compared to controls [217]. Higher baseline CRP levels were observed
in AS patients with lower serum sclerostin. Hereof, AS patients with low
serum sclerostin had increased risk of having high CRP levels after 12
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S.S. Groen et al. Autoimmunity Reviews 20 (2021) 102760

associated with the formaon of new

DKK1 Dickkopf-1 (Dkk1). Wnt
signalling inhibitor, affecng
bone formaon where
dysregulaon of Dkk1 leads to
bone pathologies seen in AS.
PROGNOSTIC BIOMARKERS
VISFATIN Adipokine involved in bone
metabolism, shown to promote
angiogenesis.
LEPTIN Adipokine involved in bone
metabolism.
MIF Macrophage migraon
inhibitory factor (MIF),
proinflammatory cytokine.
Proposed to promote
mineralisaon of osteoblasts.
syndesmophytes.
217
P=30, C=30 Low baseline levels of sclerosn in
serum are associated with high CRP
levels in AS paents receiving an-TNF
therapy.
215
P=204, C=80 Low Dkk1 levels are correlated with
high CRP levels in AS paents.
165
P=65 Higher levels of Dkk1 in paents with no
formaon of syndesmophyte compared
to those with clear syndesmophytes
progression.
221
P=86, C=25 Visfan levels were higher in AS
paents than in healthy subjects.
222
P=120 Serum levels of lepn are inversely
related to radiographic spinal growth in
paents with AS.
223
P=42, C=42 Higher serum lepn levels in men with
AS. Lepn levels correlated with serum
IL-6 levels and BASDAI.
225
P=147, C=61 Serum levels of MIF were elevated in AS
paents, parcularly in paents with
disease progression and with appearing
syndesmophytes. Increased levels of
MIF were found in synovial fluid
collected from inflamed peripheral
joints of paents with AS.

Fig. 6. (continued).

months of treatment compared to patients with higher baseline levels of
sclerostin [215,217]. These results may indicate that baseline levels of
sclerostin could serve treatment predictive potential of anti-TNF therapy
and most likely other types of treatment. Serum levels of Dkk1 have
shown to be lower in AS patients compared to healthy controls
[145,218]. In AS patients with no syndesmophyte growth, the Dkk1
levels were significantly higher compared to patients with formation of
syndesmophytes over 2 years. These results suggest that high serum
levels of Dkk1 are protective by reducing Wnt signalling and inhibiting
new bone growth, subsequently syndesmophyte growth and spinal
ankylosis [165]. Thus, low serum levels of sclerostin and Dkk1 may
explain the syndesmophyte growth and ankyloses. However, conflicting
data exists of the Dkk1 and sclerostin levels. In contrast to the low levels
of Dkk1 observed in AS patients, in another study high levels of serum
Dkk1 were found in AS patients compared to healthy subjects including
other types of arthritis. Furthermore, in a study employing meta-analysis
the serum levels of sclerostin in AS patients were not significantly
different to controls [219]. More studies are needed before knowing
whether sclerostin and Dkk1 levels can be used as potential biomarkers
for structural progression in patients with AS.
7.8. Adipokines
The adipokine, visfatin, is released by various cells and can affect
bone metabolism by directly activating osteoblasts and promoting
angiogenesis [220]. In a study by Syrbe et al., increased baseline levels
of visfatin have shown to predict radiographic spinal damage progres­
sion in AS over 2 years [221]. Leptin, another adipokine, together with
high molecular weight form of adiponectin (HMW-APN) showed to
significantly predict protection from spinal radiographic progression in
AS patients. In general, females with AS displayed higher levels of leptin
and HMW-APN compared to males, which may explain the decreased
structural damage in the spine compared to male patients with AS [222].
In addition, serum leptin levels were higher in men with AS compared to
healthy male controls and significantly correlated with serum IL-6 levels
and BASDAI [223]. From these results, leptin might have a protective
effect by inhibition of the extensive aberrant bone formation and a
possible role in the inflammatory reactions of AS.
7.9. MIF
Macrophage migration inhibitory factor (MIF) is a pro-inflammatory
cytokine which has previously been shown to be elevated in serum from
AS patients [224]. In a study by Ranganathan et al. serum levels of MIF
were significantly elevated in AS patients compared to healthy controls,
particularly in patients with disease progression and with appearing
syndesmophytes. In addition, increased levels of MIF were found in
synovial fluid collected from inflamed peripheral joints of patients with
AS. Furthermore, MIF have showed to increase the TNF-α secretion by
monocytes and mediated stabilisation of β-catenin and promoted min­
eralisation of osteoblasts. Thus, MIF has been proposed to have a direct
role on the mineralisation of osteoblasts [225]. More studies are needed

12
S.S. Groen et al.
to investigate the prognostic biomarker potential of MIF.
Although these biomarkers may have potential value in axSpA, most
of these studies have not yet been reproduced or evaluated in prospec­
tive studies for the validation as gold standard biomarkers (Fig. 6).
8. Conclusion
TNF inhibition has long been the only targeted approach to treat
SpA, showing good efficacy in a fraction of SpA patients yielding mixed
results in preventing ossification of damaged bone or cartilage [226].
This situation has created an emerging need to discover new treatment
targets for development of novel therapies for axSpA patients. Conse­
quently, the role of IL-17 in inflammatory process and structural damage
in axSpA has opened new opportunities to treat SpA. Secukinumab, the
first IL-17 inhibiting agent approved for treatment of axSpA patients, has
showed high clinical efficacy. Subsequently, several other IL-17 block­
ing agents such as ixekizumab, brodalumab, bimekizumab, netakimab,
remtolumab, and COVA322 are licensed or under development and
expected to be available for treatment in the next couple of years due to
positive results observed of phase II/III trials. The introduction of anti-
IL-17 therapy has expanded the number of options for targeting cyto­
kine pathways in SpA beyond TNF and marked a step forward in the
management of SpA. However, despite the positive results of IL-17 in­
hibitors on the symptoms which are mostly related to pain of SpA, only
limited data exist on their effect on such drugs on the inflammatory
disease process in itself and the related structural damage, especially in
axial disease. To approach these challenges, a search for objective bio­
markers reflecting disease activity including dynamic structural pro­
gression are of key interest. Moreover, combinations of biomarkers
together with imaging data may provide a future analysis platform for
novel drug discovery, improvement of clinical trial design, and patient
inclusion when testing new treatments, which can aid in the improve­
ment of individualised care.
Declaration of Competing Interest
Solveig Skovlund Groen, Dovile Sinkeviciute, Simon Francis Thom­
sen, Georg Schett have no competing interest. Morten A. Karsdal, Anne-
Christine Bay-Jensen, Christian S. Thudium and Signe Holm Nielsen are
employees of Nordic Bioscience. Morten A. Karsdal and Anne-Christine
Bay-Jensen hold stock in Nordic Bioscience.
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