The Relationship of Biomarkers and Radiographic Progression in Patients with Ankylosing

Ankylosing spondylitis (AS), the prototype of spondyloarthritides (SpA), is a frequently occurring chronic inflammatory disease with a prevalence of about 0.5%.¹ AS occurs mainly in young patients² and is clinically characterised by axial and peripheral symptoms (pain and swelling). Imaging plays an important role in the diagnosis and monitoring of the disease. Even in the early stages, inflammation of the sacroiliac joints and the spine can be assessed by magnetic resonance imaging (MRI).^3,4 In late stages, fatty degeneration seen on MRI is characteristic of the disease,³ while bony hyperproliferation can be assessed by both conventional radiographs and MRI.^5,6

Recently, guidelines for the treatment of AS were published by the Assessment of SpondyloArthritis International Society (ASAS) and the European League Against Rheumatism (EULAR),⁷ supporting the use of anti-tumour necrosis factor (anti-TNF) drugs in patients who fail treatment with non-steroidal anti-inflammatory drugs (NSAIDs) and physiotherapy. Therapy of active AS patients with anti-TNF agents such as the monoclonal antibody infliximab has shown clinical efficacy not only after some weeks8 but also in long-term follow-up.^9,10 In the same patients, improvement of inflammatory spinal lesions after therapy with infliximab has been demonstrated by MRI.11 However, anti-TNF treatment has not been able to show any influence on the development of structural abnormalities,¹² especially syndesmophytes.¹³ So far only the presence of syndesmophytes at the time of presentation was shown to be significantly predictive of higher rates of radiographic progression in follow-up examinations.¹³ An influence of inflammatory activity MRI or other objective (C-reactive protein [CRP]) or patient-orientated measurements for disease activity on radiographic progression has been found. However, the role of biomarkers associated with new bone formation in this scenario also remains to be clarified.¹⁴ In this study, we determined the level of different biomarkers, analysed their relevance in correlation to clinical, MRI and radiographic measurements and tried to define their role in the prediction of syndesmophyte formation in AS patients under anti-TNF treatment with infliximab.

Methods
Data of AS patients who participated in the Ankylosing Spondylitis Study for the Evaluation of Recombinant Infliximab Therapy (ASSERT) trial were retrospectively analysed. Complete data of the following biomarkers (measured by enzyme-linked immunosorbent assay [ELISA]) were available at baseline and after two years: vascular endothelial growth factor (VEGF) and transforming growth factor-β (TGF-β) for inflammation and osteocalcin (OC), interleukin-6 (IL–6), bone alkaline phosphatase (BAP), C-telopeptide 1 (CTX), N-telopeptide (NTX), osteoprotegerin (OPG) and cartilage oligomeric matrix protein (COMP) for bone turnover. Also, levels of disease activity, Bath Ankylosing Spondylitis Disease Activity Index (BASDAI);¹⁵ function, Bath Ankylosing Spondylitis Functional Index (BASFI);¹⁶ spinal mobility, Bath Ankylosing Spondylitis Metrology Index (BASMI);¹⁷ acute-phase reaction, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) damage, (radiographs) and MRI inflammation were assessed. For the assessment of radiographic progression, the modified Stokes AS score (mSASSS)18 was used, while MRIs were scored by using the AS spinal MRI score for activity (ASspiMRI-a).¹⁹ Radiographs and MR images were assessed independently by two groups of two readers who were not aware of the patient’s identity, and clinical or laboratory data as well as the mean scores of the readers were taken into account for calculations. Analyses were performed based on the outcome parameters severe radiographic progression ([SRP] increase of ≥3 mSASSS units/year) and/or the development of new syndesmophytes at two-year follow-up (yes versus no). Summary statistics were used for the baseline data, and linear and logistic regression to test for the association of serum markers with MRI activity, mSASSS scores, clinical indices and the development of new syndesmophytes. Receiver operating characteristic (ROC) analysis was used for optimal cut-point determination.