What do biomarkers tell us about the pathogenesis of ankylosing spondylitis?

Biomarkers may provide information that promotes understanding of prognosis, disease activity, and pathogenesis in ankylosing spondylitis. Biomarkers reflecting disease activity (metallo-proteinase-3) and inflammatory lesions on magnetic resonance imaging predict new bone formation and are ameliorated by anti-tumor necrosis factor therapy, yet this treatment may not prevent new bone formation. Moreover, elevated levels of biomarkers reflecting tissue repair (bone-specific alkaline phosphatase) post-treatment together with magnetic resonance imaging indicates such treatment may even promote repair through new bone formation. Tumor necrosis factor regulation of Dickkopf-1 may constitute a molecular brake that controls osteoblastogenesis through wingless and bone morphogenetic proteins in an established inflammatory lesion in ankylosing spondylitis

Progress in spondylarthritis. Spondyloarthritis: lessons from imaging

The advent of magnetic resonance imaging (MRI) and advanced sonographic techniques has led to a resurgence of interest in the role of imaging in the evaluation and management of spondyloarthritis. Radiography remains the cornerstone of diagnosis although MRI is more sensitive in early stages of the disease. Inflammatory changes in the sacroiliac joints and spine can now be reliably quantified and can also predict the subsequent development of radiographic changes in the corresponding locations. MRI-based scoring systems for inflammation are highly responsive, facilitating proof-of-concept studies of new therapies for spondyloarthritis. Assessment of chronic changes is much less reliable using MRI, while assessment using radiography lacks sensitivity to change. Assessment of disease modification therefore remains a principle challenge in the development of new therapies for ankylosing spondylitis. Ultrasound may be the preferred approach to the assessment of peripheral inflammation, especially enthesitis. Scintigraphy and computed tomography offer few advantages over MRI

Biomarkers for Diagnosis of Axial Spondyloarthritis, Disease Activity, Prognosis, and Prediction of Response to Therapy

There exists a major unmet need for biomarkers that can identify axial spondyloarthritis (axSpA) early after disease onset because of the availability of highly effective therapies. Several recent reports have examined the autoantibody response in patients with axSpA through the use of protein microarrays and protein-protein interactions although diagnostic performance of biomarkers identified to date has been inadequate. An example of such a biomarker is protein phosphatase magnesium-dependent 1A. Antibodies to the human leukocyte antigen class II-associated invariant chain peptide (anti-CD74) are candidate diagnostic biomarkers but sensitivity declines with increasing duration of disease. Metabolomic studies have employed nuclear magnetic resonance (NMR) spectrometry to identify disease-specific metabolites related to fat metabolism and intestinal microbial metabolism. A second major unmet need exists for biomarkers of disease activity that have superiority over standard C-reactive protein assessment and reflect MRI inflammation in the axial spine. Several biomarkers reflecting inflammation (calprotectin), angiogenesis (vasoactive endothelial growth factor), and connective tissue turnover (C2M, C3M, and citrullinated metalloproteinase degraded fragment of vimentin) have recently been shown to reflect disease activity when compared with clinical outcomes but comparisons with MRI inflammation are very limited. With increasing availability of highly effective but costly therapies, a third unmet need is biomarkers that can predict response to therapies with different mechanisms of action and are superior to C-reactive protein. Calprotectin is currently the only candidate. Although there are as yet no proven therapies for preventing progression of disease there is an unmet need for biomarkers of prognosis that are more responsive than radiography. Aside from CRP no consistent candidates have emerged. Future studies will need to be prospective, include consecutive patients presenting with undiagnosed back pain, and use more reliable and objective endpoints such as MRI inflammation. Moreover, it has become evident that targeted biomarker studies have not been successful in identifying clinically useful biomarkers and technologies that can simultaneously assess “multiomic” markers will need to be analyzed for future advances. These include more sophisticated metabolomic profiling and universal metabolome-standard (UMS) methodology, next generation RNA sequencing, and affinity-based quantitative proteomics based on the use of nucleic acid binders such as the aptamer-based SOMAscan assay

The impact of MRI on the clinical management of inflammatory arthritides

In the past two decades, MRI has gained a major role in research and clinical management of patients with inflammatory arthritides, particularly in spondyloarthritis (SpA), rheumatoid arthritis (RA), and osteoarthritis (OA). MRI is regarded as the most sensitive imaging modality for detecting early SpA in young patients with inflammatory back pain and normal radiographs of the sacroiliac joints. The recently published Assessment of SpondyloArthritis International Society classification criteria for axial SpA include for the first time a positive MRI demonstrating sacroiliitis as an imaging criterion indicative of SpA together with at least one clinical feature of SpA. Recent data show that systematic assessment of sacroiliitis displayed on MRI has much greater diagnostic utility than previously reported and highlight the diagnostic relevance of structural lesions. In RA, MRI has predictive value for the development of disease in new onset undifferentiated arthritis, and MR pathology at disease onset is a highly significant predictor of radiographic erosions. Consequently MRI has been credited with an important role in the new ACR/EULAR 2010 classification criteria for RA. In OA, bone marrow edema (BME) and synovitis may serve as biomarkers in interventional trials. Treatment interventions targeting BME and synovitis observed on MRI in inflammatory arthritides may have a disease-modifying effect as these lesions are potentially reversible and have been shown to be associated with structural progression. Research should focus on the prognostic significance of MRI lesions in larger cohorts and whether adding MRI to routine care improves clinical and radiographic outcome in patients with inflammatory arthritide

Tumor necrosis factor inhibitor therapy but not standard therapy is associated with resolution of erosion in the sacroiliac joints of patients with axial spondyloarthritis

INTRODUCTION: Radiography is an unreliable and insensitive tool for the assessment of structural lesions in the sacroiliac joints (SIJ). Magnetic resonance imaging (MRI) detects a wider spectrum of structural lesions but has undergone minimal validation in prospective studies. The Spondyloarthritis Research Consortium of Canada (SPARCC) MRI Sacroiliac Joint (SIJ) Structural Score (SSS) assesses a spectrum of structural lesions (erosion, fat metaplasia, backfill, ankylosis) and its potential to discriminate between therapies requires evaluation. METHODS: The SSS score assesses five consecutive coronal slices through the cartilaginous portion of the joint on T1-weighted sequences starting from the transitional slice between cartilaginous and ligamentous portions of the joint. Lesions are scored dichotomously (present/absent) in SIJ quadrants (fat metaplasia, erosion) or halves (backfill, ankylosis). Two readers independently scored 147 pairs (baseline, 2 years) of scans from a prospective cohort of patients with SpA who received either standard (n = 69) or tumor necrosis factor alpha (TNFα) inhibitor (n = 78) therapy. Smallest detectable change (SDC) was calculated using analysis of variance (ANOVA), discrimination was assessed using Guyatt’s effect size, and treatment group differences were assessed using t-tests and the Mann–Whitney test. We identified baseline demographic and structural damage variables associated with change in SSS score by univariate analysis and analyzed the effect of treatment by multivariate stepwise regression adjusted for severity of baseline structural damage and demographic variables. RESULTS: A significant increase in mean SSS score for fat metaplasia (P = 0.017) and decrease in mean SSS score for erosion (P = 0.017) was noted in anti-TNFα treated patients compared to those on standard therapy. Effect size for this change in SSS fat metaplasia and erosion score was moderate (0.5 and 0.6, respectively). Treatment and baseline SSS score for erosion were independently associated with change in SSS erosion score (β = 1.75, P = 0.003 and β = 0.40, P < 0.0001, respectively). Change in ASDAS (β = −0.46, P = 0.006), SPARCC MRI SIJ inflammation (β = −0.077, P = 0.019), and baseline SSS score for fat metaplasia (β = 0.085, P = 0.034) were independently associated with new fat metaplasia. CONCLUSION: The SPARCC SSS method for assessment of structural lesions has discriminative capacity in demonstrating significantly greater reduction in erosion and new fat metaplasia in patients receiving anti-TNFα therapy

Clinical and MRI responses to etanercept in early non-radiographic axial spondyloarthritis : 48-week results from the EMBARK study

Objective: To evaluate the efficacy and safety of etanercept (ETN) after 48 weeks in patients with early active non-radiographic axial spondyloarthritis (nr-axSpA). Methods: Patients meeting Assessment of SpondyloArthritis international Society (ASAS) classification criteria for axSpA, but not modified New York radiographic criteria, received double-blind ETN 50 mg/week or placebo (PBO) for 12 weeks, then open-label ETN (ETN/ETN or PBO/ETN). Clinical, health, productivity, MRI and safety outcomes were assessed and the 48-week data are presented here. Results: 208/225 patients (92%) entered the open-label phase at week 12 (ETN, n=102; PBO, n=106). The percentage of patients achieving ASAS40 increased from 33% to 52% between weeks 12 and 48 for ETN/ETN and from 15% to 53% for PBO/ETN (within-group p value <0.001 for both). For ETN/ETN and PBO/ETN, the EuroQol 5 Dimensions utility score improved by 0.14 and 0.08, respectively, between baseline and week 12 and by 0.23 and 0.22 between baseline and week 48. Between weeks 12 and 48, MRI Spondyloarthritis Research Consortium of Canada sacroiliac joint (SIJ) scores decreased by -1.1 for ETN/ETN and by -3.0 for PBO/ETN, p<0.001 for both. Decreases in MRI SIJ inflammation and C-reactive protein correlated with several clinical outcomes at weeks 12 and 48. Conclusions: Patients with early active nr-axSpA demonstrated improvement from week 12 in clinical, health, productivity and MRI outcomes that was sustained to 48 weeks

Assessment of radiographic progression in the spines of patients with ankylosing spondylitis treated with adalimumab for up to 2 years

Ankylosing spondylitis (AS) is a chronic rheumatic disease associated with spinal inflammation that subsequently leads to progression of structural damage and loss of function. The fully human anti-tumor necrosis factor (anti-TNF) antibody adalimumab reduces the signs and symptoms and improves overall quality of life in patients with active AS; these benefits have been maintained through 2 years of treatment. Our objective was to compare the progression of structural damage in the spine in patients with AS treated with adalimumab for up to 2 years versus patients who had not received TNF antagonist therapy. Radiographs from patients with AS who received adalimumab 40 mg every other week subcutaneously were pooled from the Adalimumab Trial Evaluating Long-Term Efficacy and Safety for Ankylosing Spondylitis (ATLAS) study and a Canadian AS study (M03-606). Radiographic progression from baseline to 2 years in the spine of adalimumab-treated patients from these two studies (adalimumab cohort, n = 307) was compared with an historic anti-TNF-naïve cohort (Outcome in AS International Study [OASIS], n = 169) using the modified Stoke AS Spine Score (mSASSS) method. mSASSS results were not significantly different between the adalimumab cohort and the OASIS cohort, based on baseline and 2-year radiographs. Mean changes in mSASSS from baseline to 2 years were 0.9 for the OASIS cohort and 0.8 for the adalimumab cohort (P = 0.771), indicating similar radiographic progression in both groups. When results for patients in the OASIS cohort who met the baseline disease activity criteria for the ATLAS and Canadian studies (OASIS-Eligible cohort) were analyzed, there was no significant difference in mean change in mSASSS from baseline to 2 years between OASIS-Eligible patients and adalimumab-treated patients; the mean changes in mSASSS were 0.9 for the OASIS-Eligible cohort and 0.8 for the adalimumab cohort (P = 0.744). Two years of treatment with adalimumab did not slow radiographic progression in patients with AS, as assessed by the mSASSS scoring system, when compared with radiographic data from patients naïve to TNF antagonist therap