Axial Spondyloarthritis: Comparison
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Axial spondyloarthritis (axSpA) is a chronic inflammatory disease that can lead to ankylosis by secondary ossification of inflammatory lesions, with progressive disability and a significant impact on quality of life. It is also a risk factor for the occurrence of comorbidities, especially cardiovascular diseases (CVDs), mood disorders, osteoporosis, and malignancies. Early diagnosis and treatment are needed to prevent or decrease functional decline and to improve the patient’s prognosis. In respect of axSpA, there is an unmet need for biomarkers that can help to diagnose the disease, define disease activity and prognosis, and establish personalized treatment approaches. The aim of this review was to summarize the available information regarding the most promising biomarkers for axSpA. It can be classified and identified six core categories of biomarkers: (i) systemic markers of inflammation; (ii) molecules involved in bone homeostasis; (iii) HLA-B27 and newer genetic biomarkers; (iv) antibody-based biomarkers; (v) microbiome biomarkers; and (vi) miscellaneous biomarkers. Unfortunately, despite efforts to validate new biomarkers, few of them are used in clinical practice; however, we believe that these studies provide useful data that could aid in better disease management.

  • axial spondyloarthritis
  • diagnosis
  • disease activity
  • prognosis

1. Axial Spondyloarthritis: Past, Present, and Future

Spondyloarthritis (SpA) comprises a group of chronic immune-mediated inflammatory conditions with overlapping clinical and genetic features but with substantial heterogeneity, as inflammation can affect peripheral and axial joints and also result in extraarticular manifestations (enthesitis, dactylitis, uveitis, inflammatory bowel disease, psoriasis) [1][2][3].
SpA comprises a spectrum of diseases with significant overlaps between SpA phenotypes, which can be classified according to the Assessment of Spondyloarthritis International Society (ASAS) 2009 classification criteria. These depend on where patients primarily experience symptoms in axial SpA (axSpA) with predominantly axial manifestations, including non-radiographic (nr-axSpA) and radiographic axSpA (r-axSpA) or ankylosing spondylitis (AS) and peripheral SpA (pSpA) with predominant peripheral involvement (psoriatic arthritis, reactive arthritis, enteropathic arthritis, juvenile-onset SpA, and undifferentiated SpA) [4]. While the spectrum of axSpA extends from early or mild disease through severe or late disease with erosive damage in the sacroiliac joints, this arbitrary division of nr-axSpA and r-axSpA is becoming less clinically relevant.
The symptoms of axSpA create a significant burden for both patients and society. The major disease feature is the progression to ankylosis by secondary ossification of inflammatory lesions, with progressive disability and a significant impact on quality of life.
AxSpA is also a risk factor for the occurrence of comorbidities, especially cardiovascular diseases (CVDs), mood disorders, osteoporosis, and malignancies, which shows that axSpA has a systemic character and influences patient health in a complex manner [2]. All these characteristics affect quality of life and, because all comorbidity types correlate with axSpA, early diagnosis and treatment are needed to prevent or decrease functional decline and improve the patient’s prognosis.

2. AxSpA and Biomarkers

According to the World Health Organization, a biomarker is a chemical, physical, or biological indicator of disease presence, activity, or severity, which can provide vital information. In respect of axSpA, there is an unmet need for biomarkers that can help to diagnose the disease, define disease activity and prognosis, and establish personalized treatment approaches [5].
Despite the progress made in the concept of axSpA, its identification remains challenging, frequently resulting in a diagnostic delay for patients. Ideally, the diagnosis should be made before the development of radiographic sacroiliitis, but currently the most sensitive imaging diagnosis method is magnetic resonance imaging (MRI), which is costly and not widely available [2].
AxSpA disease activity is monitored using the following scores: Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI), and Ankylosing Spondylitis Disease Activity Score (ASDAS), which may be subjective. Disease activity is also monitored by measuring of one of the most common inflammatory biomarkers, C-reactive protein (CRP), which is insensitive for this disease [6].
Although the range of effective modern drugs for axSpA has expanded in recent decades, therapeutic decisions and the response to specific therapies remain challenges in current practice, and further research is therefore required. Adequate evaluation of disease activity, radiographic progression, response to treatment and identification of negative prognostic factors can improve the therapeutic decision. In addition, data regarding the axSpA prognosis obtained in the early disease stages will improve therapeutic management [2].
The aim of was to summarize available information regarding the most promising biomarkers for axSpA. The researchers further refer to six core categories of biomarkers: (i) systemic markers of inflammation; (ii) molecules involved in bone homeostasis; (iii) HLA-B27 and newer genetic biomarkers; (iv) antibody-based biomarkers; (v) microbiome biomarkers; and (vi) miscellaneous biomarkers (Table 1, Figure 1). Furthermore, the association between biomarkers and diagnosis, disease activity, structural damage, and treatment response are described below.
Figure 1. Biomarkers significance in axial spondiloarthtitis.
Table 1. Biomarkers significance in axial spondyloarthritis.
Biomarker Predictability Study type Reference
Anti-CD74 antibodies Positive association with

diagnosis and disease activity.

Positive association with

radiographic progression.

Positive association with

diagnosis.

Negative association with

diagnosis.

Positive association with

diagnosis.		 Cross-sectional study



Prospective study



Prospective study



Prospective study



Prospective study		 2021, Marwa Mahmoud Abdelaziz [7]



2021, Lan Do [8]



2019, Nelly R. Ziade [9]



2018, Janneke J. de Winter [10]



2020, Chao-Jun Hu [11]
Bone morphogenetic protein 7 (BMP-7), sclerostin, dicckopf-1 (DKK-1) Positive association with

disease association		 Prospective multicenter study 2021, Elise Descamps [12]
C-reactive protein (CRP) Positive association with

cardiovascular risk

Positive association with

treatment response

Positive association with

treatment response

Positive association with

treatment response		 Retrospective analysis



Prospective study



Case-control study



Cross-sectional study		 2022, Luca Navarini [13]



2019, Xenofon Baraliakos [14]



2020, Xu Yuansheng [15]



2018, Björn Sundström [16]
C-C motif chemokine ligand 11 (CCL11) Positive association with

radiographic progression		 Cross-sectional study 2018, Dong Hyun Sohn [17]
CD163, CD206 Positive association with disease activity, treatment response Prospective study 2018, Line Dam Heftdal [18]
CD27-CD38lowCD21low B cells Positive association with

disease activity		 Cross-sectional study 2021, Rick Wilbrink [19]
circRNA hsa_circ_0079787 Positive association with

diagnosis, disease activity		 Cross-sectional study 2020, Qing Luo [20]
Circulating microRNAs Positive association with

disease activity

Positive association with

diagnosis and disease activity		 Prospective study



Cross-sectional study		 2020, Qing Luo [20]



2018, Carlos Perez-Sanchez [21]
Complement component C3 Positive association with

disease activity

and cardiovascular risk		 Cross-sectional study 2020, Ivan Arias de la Rosa [22]
CRP to albumin ratio (CAR) Positive association with

disease activity

Positive association with

disease activity		 Retrospective study



Cross-sectional study		 2021, Zheng Zhong [23]



2021, Melih Pamukcu [24]
Dickkopf homologue-1 (Dkk-1) Positive association with

radiographic progression		 Prospective study 2019, Zhonghai Zhao [25]
Bone morphogenetic proteins (BMPs) and Dkk-1 Positive association with

disease activity		 Prospective study 2018, Hsien-Tzung Liao [26]
Drug-neutralizing Antibodies against TNF-α Positive association with treatment response Cross-sectional study 2020, Krasimir Kraev [27]
ERAP1 (rs2287987, rs30187, rs27044), ERAP2 (rs2248374) Positive association with

diagnosis		 Case-control study 2019, Andrzej Wiśniewski [28]
Erythrocyte sedimentation rate (ESR)

ESR + Interleukin (IL)-6		 Positive association with

radiographic progression

Positive association with

treatment response		 Retrospective study



Prospective study		 2018, Kwi Young Kang [29]



2019, Yidian Dong [30]
Eukaryotic translation elongation factor 1 epsilon 1 (EEF1E1) Positive association with

diagnosis		 Prospective study 2019, Xutao Fan [31]
Fecal calprotectina and anti-Saccharaomyces cerevisiae antibodies (ASCA) Positive association with

disease activity		 Cross-sectional study 2019, Tor Olofsson [32]
Fibrinogen-to-albumin ratio (FAR) Positive association with

disease activity		 Retrospective study 2020, Meng Liu [33]
Galectin-3 Positive association with

disease activity		 Prospective study 2019, Ming-Yu Cao [34]
Galectin-3, soluble suppression-of-tumorogenity-2 (sST2) (cardiac fibrosis), hsCRP Positive association with

cardiovascular risk		 Prospective study 2018, Demet Ozkaramanli Gur [35]
H-ficolin, L-ficolin Positive association with

diagnosis		 Cross-sectional cohort 2020, Anne Troldborg [36]
Hepatocyte growth factor

(s-HGF)		 Positive association with

radiographic progression

Positive association with

radiographic progression		 Prospective cohort study



Prospective study		 2021, Anna Deminger [37]



2019, Liset Torres [38]
HLA B-27 antigen Positive association with

diagnosis

Positive association with

diagnosis

Positive association with

diagnosis		 Prospective study



Prospective study



Prospective study		 2019, Nelly Ziade [39]



2018, Chong Seng Edwin Lim [40]



2021, Henriëtte M Y de Jong [41]
Interleukin (IL)-31 Positive association with

radiographic progression		 Longitudinal prospective cohort study 2018, Nicolas Rosine [42]
IL-33 Positive association with disease activity and treatment response Prospective study 2021, Milena Iwaszko [43]
IL-12B and IL-6R Positive association with diagnosis and prognosis Prospective cohort study 2018, Wen-Feng Ruan [44]
IL-22 Positive association with

diagnosis		 Retrospective study 2022, Michal Sagiv [45]
IL-17

IL-23 and IL-17		 Positive association with

diagnosis

Positive association with

diagnosis		 Cross-sectional study



Case-control study		 2020, Dalia S. Saif [46]



2018, Jacob Sode [47]
Leptin Positive association with

radiographic progression

Positive association with

radiographic progression		 Longitudinal prospective study

Prospective study		 2017, Ji-Heg Park [48]



2019, Judith Rademacher [49]
Leptin + high molecular weight adiponectin + VEGF Positive association with

radiographic progression		 Cross-sectional study 2019, Judith Rademacher [49]
LINC00311 Positive association with

diagnosis and disease activity		 Prospective study 2019, Hongfa Zhong [50]
Lipocalin 2 (LCN 2), Oncostatin M (OSM) Positive association with disease activity and treatment response Longitudinal observational study 2021, Florence W.L Tsui [51]
Metalloproteinase (MMP)-degraded collagen type I (C1M), type II (C2M), type III (C3M), and type IV (C4M2) Positive association with

disease activity		 Prospective cohort study 2019, Markéta Husšáková [52]
Neutrophil extracellular trap (NET) Positive association with disease activity and treatment response Cross-sectional study, case report 2020, Patricia Ruiz-Limon [53]
Omentin-1 Positive association with

cardiovascular risk		 Prospective study 2020, Fernanda Genre [54]
Osteoprotegerin (OPG) and sclerostin (SCL) Positive association with

cardiovascular risk		 Prospective study 2018, Fernanda Genre [55]
Pentraxin 3 Positive association with

disease activity		 Cross-sectional study 2018, Renato Nisihara [56]
Procollagen I N-terminal peptide Positive association with

disease activity		 Cross-sectional study 2022, Xuegang Li [57]
Sclerostin and antisclerostin antibody Positive association with

gastrointestinal risk

Positive association with

diagnosis

Positive association with

radiographic progression		 Prospective study



Case-control study



Prospective study		 2018, Michele Maria Luchetti [58]



2018, Perrota Fabio Massimo [59]



2019, Judith Rademacher [49]
Semaphorin 3A (Sema 3A) Positive association with

disease activity

Positive association with

treatment response		 Prospective study



Prospective study		 2019, Hsien-Tzung Liao [60]



2017, Fabio Massimo Perrotta [61]
Serum amyloid A1 (SAA1) Positive association with

diagnosis		 Prospective study 2020, Shijia Liu [62]
Serum calprotectin Positive association with

disease activity

Positive association with

treatment response

Positive association with

cardiovascular risk

Positive association with

radiographic progression		 Prospective study



Prospective study



Prospective study



Prospective study		 2020, Matthias Jarlborg [63]



2019, Hua Hu [64]



2018, Fernanda Genre [65]



2022, Judith Rademacher [66]
Serum miR-214 Positive association with

disease activity		 Prospective study 2019, Hyun Yi Kook [67]
Tenascin-C (TNC) Positive association with

disease activity

Positive association with

disease activity		 Prospective study



Prospective study		 2020, Kristyna Bubova [68]



2018, Latika Gupta [69]
Vaspin Positive association with

cardiovascular risk		 Prospective study 2021, Javier Rueda-Gotor [70]
Vimentin Positive association with

radiographic progression		 Prospective study 2019, Anne Sofie Siebuhr [71]
Visfatin Positive association with

cardiovascular risk

Positive association with

disease activity		 Prospective study



Prospective study		 2021, Rabia Aydogan Baykara [72]



2022, Judith Rademacher [66]

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