Biomarkers for Diagnosis of Axial Spondyloarthritis

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In a recent edition of Frontiers in Immunology, Dr. Walter Maksymowych, University of Alberta, reviews the use of biomarkers for diagnosis and prognosis in axial spondyloarthritis. Maksymowych points out a major unmet need for appropriate biomarkers that can identify early axial spondyloarthritis (axSpA).

Axial spondyloarthritis (axSpA) is a inflammatory disorder of the sacroiliac joint and spine that also may manifest in extra articular sites such as the anterior uvea and aorta. Formation of new bone leads to functional disability and pain. Striking patients in their 30s and 40s, axSpA may also lead to significant loss of work-related productivity.

Owing to non-specific early symptoms, diagnosis is often significantly delayed in axSpA leading to delays in treatment and more advanced disease progression. Once treatment is started, monitoring efficacy is paramount highlighting the need for biomarkers to aid in this effort since serial MRI scans for surveillance is impractical and very expensive. Thankfully there have been recent advances in the field of biomarkers for axSpA.

Dr. Maksymowych points out that, “Any diagnostic test for axSpA should be supported by metrics such as a positive predictive value (PPV) of greater than 80 percent and positive likelihood ratio (LR) of greater than 5.”

He further adds,  “Conversely, because referral for back pain is so common in the age group that develops axSpA it is important that such a biomarker can effectively rule out disease with performance metrics such as greater than 80 percent negative predictive value (NPV) and negative LR of less than 0.2.”

The International Soluble Biomarker Working Group for the Outcome Measures in Rheumatology Consortium further states that additional performance characteristics are essential for a diagnostic biomarker such that they have well-defined standards, and limited variability due to age, gender, diurnal factors, body mass index, ethnicity, and disease duration.

Next page:  Recent Advances in Biomarkers for axSpA

Recent Advances in Biomarkers for axSpA

Antibody-Based Diagnostic BiomarkersAnti-CD74

CD74 is involved in the assembly of human histocompatibility leukocyte antigen (HLA) class II molecules and its extracellular portion includes thyroglobulin type 1 and class II-associated invariant chain peptide (CLIP) domains. Anti-CD74 may influence B cell differentiation and in turn expression of pro-inflammatory mediators.

ELISA studies looking at CD74 have demonstrated reactivity in 56% and 69% of patients with axSpA. Sensitivity was 85.1% and specificity 92.2% while the positive LR for anti-CLIP antibodies to diagnose axSpA was 10.9 and the negative LR was 0.08.

Unfortunately screening for IgA anti-CD74 antibodies resulted in a PPV of 58.8% and an NPV of 59.1%, which is of insufficient diagnostic value in patients with early axSpA.

Antibodies to Microbes and Quantitative Metagenomics

Recent research has focused on differences in gut microbes when compared to healthy people. Quantitative metagenomics of gut microbial DNA from 211 Chinese individuals demonstrated that 23,709 genes and 12 metagenomic species were differentially expressed between patients with axSpA and healthy controls.

With further research diagnostic algorithms with high discriminatory capacity could be developed using a subset of these gut microbial biomarkers.

Antibodies to Protein Phosphatase Magnesium-Dependent 1A (PPM1A)


Antibodies targeting protein phosphatase magnesium-dependent 1A (PPM1A), a Serine/Threonine protein phosphatase, have been identified in patients with axSpA. One study found that sensitivity and specificity were 66.7 and 73.3% for axSpA, respectively, when anti-PPM1A antibodies >2 SD above control were considered positive. Unfortunately, the performance of this assay is insufficient for diagnostic purposes.

See next page:  Candidate Diagnostic Biomarkers From Expression and Metabolomics Profiling

Candidate Diagnostic Biomarkers From Expression and Metabolomics Profiling

Gene Expression

A meta-analysis of datasets based on publicly available gene expression arrays identified 905 differentially expressed genes in patients with axSpA compared to healthy controls.  These candidate biomarkers require further validation in longitudinal studies of patients with unselected back pain.

Metabolomics

Several studies have assessed the metabolome using mass spectrometry to identify diagnostic profiles in serum, plasma, urine, and ligament tissues of hip joints from patients with axial SpA. By looking at differences between the metabolites produced by gut bacteria and comparing AS patients with healthy controls a diagnostic profile for AS could be developed. Further research is needed. 

See next page:  Disease Activity Biomarkers

Disease Activity Biomarkers

Markers of inflammation such as C-reactive protein (CRP) have long been utilized along with other acute phase reactants. Unfortunately traditional biomarkers such as CRP lack sufficient sensitivity but lay a foundation to the search for more sensitive and responsive measures of inflammation.

Biomarker Mediators of Inflammation

Calprotectin

Calprotectin is a calcium-binding protein that has been examined in the joint fluid of patients with axSpA. Studies have linked higher levels of calprotectin fecal matter with inflammatory bowel disease and AS. Unfortunately correlations between changes in biomarker levels and disease activity were not reported. The strongest correlation found was between calprotectin levels and Crohn’s disease.

Cytokines

When combined with CRP levels, several cytokines including interleukins correlated with inflammation in axSpA. However, the association did not remain independently of CRP.  Currently no cytokine is consistently associated with parameters of inflammation, especially MRI.

Tissue Turnover Biomarkers

Tissue remodeling leads to the presence of protein fragments. Biomarkers such as metalloproteinases and antibodies to these fragments have been weakly associated with disease activity but not to MRI inflammation. Further longitudinal studies of the biomarkers are needed.

See next page:  Candidate Disease Activity Biomarkers

Candidate Disease Activity Biomarkers

It has been found that miRNA expressed in patients with axSpA correlates with parameters of disease activity such as the CRP and disease activity scoring measures. While promising, further validation is needed.

Theragnostic Biomarkers

CRP is the only biomarker currently used in clinical practice to help select patients for treatment and when combined with MRI inflammation has been shown to predict treatment response to a TNFi. Calprotectin, and immunologic cells such as natural killer cells show promise in predicting response to treatment with TNFi drugs.

See next page:  Prognostic Biomarkers

Prognostic Biomarkers

Radiography is the primary prognostic tool in ankylosis even though it has limited sensitivity to changes in disease activity. Efforts are in the works to find biomarkers that can pick up short-term changes and predict long-term treatment response. The C-telopeptide of type I collagen is such a biomarker as it predicts fracture with sensitivity and correlates well with bone mineral density.

Biomarkers Related to Inflammation

Do to the lack of prospective investigation, data are lacking linking serum markers such as CRP, IL6, and calprotectin to prognosis.

Cytokines

Levels of IL31 and sCD40L were increased in axSpA patients and were associated with less structural damage.

Tissue Turnover Biomarkers

Tissue turnover associated citrullinated metalloproteinase degradation fragments are independently predictive of disease progression but cannot be stored for long.

Bone Formation Biomarkers

Conflicting data exist with regards to bone formation markers such as DKK-1 and sclerostin correlating with disease progression.

Adipokines

Visfatin and leptin have been shown to predict radiographic progression in axSpA independently of CRP however, lower levels in men have confounded these studies.

Candidate Prognostic Biomarkers

Changes in miRNA have been identified using gene expression array analysis with several proteins being implicated in the pathogenesis of autoimmune diseases. Several of these proteins are implicated in cell death and tissue damage. The diagnostic and prognostic potential for miRNA shows promise.

See next page:  Final Thoughts

Final Thoughts

From time to time clinicians and basic scientists alike require reviews so that we can see what our colleagues are doing. Since it is impossible for everyone to read everything, concise reviews of topics such as the current state of biomarker science in axSpA is necessary.

While the majority of this information is beyond the scope of the primary care provider, recognizing the progress and having a glimpse of what is coming in the future helps us prepare and stay abreast. Life long learning is essential for clinicians and researchers alike.

REFERENCE

Walter P. Maksymowych. Biomarkers for Diagnosis of Axial Spondyloarthritis, Disease Activity, Prognosis, and Prediction of Response to Therapy. Front Immunol. 2019;10:305. Published 2019 Mar 7. doi:10.3389/fimmu.2019.00305