Novel Serum Biomarkers Show Potential for Diagnosing, Monitoring Axial Spondyloarthritis

A recent review highlighted several candidate biomarkers for diagnosing axial spondyloarthritis (axSpA) associated with inflammatory bowel disease (IBD) in early phases.¹ The review, published in the journal Autoimmunity Reviews, included a range of genetic biomarkers, markers of disease activity, biochemical biomarkers, immunological biomarkers, and markers for structural changes that have been linked with both axial axSpA and idiopathic intestinal inflammation.

“While the prevalence of SpA in the general population is relatively high (approximately 1.5%), there still exists a diagnostic delay, and achieving early diagnosis for axial spondyloarthritis remains a challenge,” the authors wrote. “The main reason contributing to this delay is the difficulty in identifying patients with chronic low back pain, which can be one of the nonspecific symptoms initially. Moreover, there are currently limited biomarkers with adequate sensitivity and specificity for assessing the risk of developing and achieving early diagnosis of axSpA.”

SpA comprises a group of chronic inflammatory immune-mediated rheumatic diseases affecting the spine, and the main symptom for most patients is pain in the low back.² This most often occurs in axSpA, and many patients with axSpA progress to some degree of ankylosing spondylitis with some degree of spinal fusion. Diagnosing SpA entails imaging and blood tests, with a key aspect being sacroiliac joint changes seen in X-rays.

The review authors noted that recent efforts have focused on biomarkers that may offer predictive insights into the onset, activity, and progression of axSpA associated with IBD.¹

Red blood drop with double helix | Image credit: Елена Бутусова-stock.adobe.com

“Biomarkers serve as important indicators of disease risk and should exhibit ample accuracy, reproducibility, and non-invasiveness,” the author wrote. “Moreover, biomarkers can be categorized into genetic, biochemical, immunologic antibodies, markers of disease activity and structural progression.”

Currently, the most notable genetic biomarker associated with SpA is human leukocyte antigen 27 (HLA-B27), which is a risk factor for SpA and is positive in about 85% of patients with ankylosing spondylitis. Still, only 5% of those with HLA-B27 go on to develop ankylosing spondylitis.

A cytoplasmic protein called endoplasmic reticulum aminopeptidase (ERAP-1 and ERAP-2) is another potential marker, with the ERAP-1 gene variant being specific to patients with HLA-B27 and the ERAP-2 gene variant linked with disease onset regardless of HLA-B27 status. Additionally, ERAP-1 polymorphism in IBD may influence ulcerative colitis pathogenesis in axSpA.

Gene variants associated with the IL-17/IL-23 signaling pathway have also been linked to SpA and IBD. Although IL-23 polymorphism may potentially hold predictive significance for IBD and ankylosing spondylitis, its exact role is not yet known. The NOD2 gene on chromosome 16, also known as CARD15, was also highlighted in the review as a potential factor in innate immune responses in the gut.

Regarding biochemical markers, the authors highlighted acute phase reactants, which currently encompass C-reactive protein (CRP) and erythrocyte sedimentation rate in clinical practice, that serve as markers for systemic inflammatory response. These are key parameters for monitoring axSpA activity, they noted.

“In patients with IBD, CRP levels exhibit a correlation with disease activity and response to treatment. Currently, acute phase reactants are the only biochemical markers used to assess disease activity in ankylosing spondylitis,” the authors wrote.

Additionally, they noted serum amyloid A, cytokines, serum calprotectin (CLP), and fecal CLP as potential biochemical markers of interest. Serum CLP, in particular, is considered an independent predictor of X-ray progression in axSpA. Serum antibodies have also been studied in IBD, with several showing potential diagnostic significance, notably anti-saccharomyces cerevisiae antibodies (ASCA), immunoglobulin A antibodies, and perinuclear antineutrophil cytoplasmic antibodies (pANCA). ASCA and pANCA are currently the most reliable methods to diagnose ulcerative colitis and Crohn disease, the authors noted.

Biomarkers for structural changes in recent research include Dickkopf-related protein 1 (DKK-1), sclerostin and anti-sclerostin, the adipokine visfatin, and the extracellular glycoprotein tenascin (TNC). Studies have shown elevated DKK-1 in patients with of ankylosing spondylitis, low serum sclerostin has been correlated with radiographic progression, visfatin has been found elevated in patients with axSpA vs healthy individuals, and TNC may be a marker for early stages of ankylosing spondylitis.

The authors also noted composite disease activity indices as key tools for clinical practice, where axSpA disease activity is commonly assessed using numerical scoring scales.

“In conclusion, there are several candidate biomarkers for AxSpA associated with IBD. However, despite extensive analysis, this topic remains the subject of ongoing research,” the authors wrote.

References

1. Ondrejčáková L, Gregová M, Bubová K, Šenolt L, Pavelka K. Serum biomarkers and their relationship to axial spondyloarthritis associated with inflammatory bowel diseases. Autoimmun Rev. 2024;23(3):103512. doi:10.1016/j.autrev.2023.103512

2. Crow C. Spondyloarthritis. American College of Rheumatology. Updated February 2023. Accessed May 30, 2024. https://rheumatology.org/patients/spondyloarthritis