Calprotectin and spondyloarthritis

KEYWORDS:

• Spondyloarthritis
• calprotectin
• gut
• disease activity
• prognosis

Spondyloarthritis is a chronic inflammatory disease with several phenotypes (including axial and peripheral), and possible extra-rheumatologic manifestations such as uveitis, psoriasis or inflammatory bowel disease (IBD). With an onset in young adults and a prevalence of approximately 1% of the adult population [1], the disease is associated with quality of life and functional impairments, leading to socioeconomic consequences. Several tools have been proposed for the evaluation of the disease, but the most currently used, particularly in axial disease, are the Bath Ankylosing Spondylitis Disease Index (BASDAI) and the Ankylosing Spondylitis Disease Activity Score (ASDAS), the latter of which incorporates the acute phase reactant C-reactive protein (CRP). CRP is the most widely used biomarker in current practice and clinical trials, but it has performance limitations [2]. Currently there is an unmet need for a simple reliable biomarker of disease activity and prognosis in spondyloarthritis [2]. Many candidate biomarkers may arise from the growing immunopathologic knowledge of the disease [3]. The pathogenesis of the disease involves genetic and environmental factors [1], leading to the activation of the IL-23/Th17 pathway [4]. The gut plays a major role in this scenario [5], representing a large immunological interface between environmental factors represented by gut microbiota modifications or dysbiosis, and the immune system, with data illustrating the relationship between dysbiosis, gut and IL-23/Th17 axis activation [5]. The presence of this gut involvement is also supported by the finding of ileocolonic histologic inflammation in approximately half of the patients with axial spondyloarthritis [1,5] and an association between chronic gut inflammation and inflammatory scores on sacroiliac MRI [5]. Inflammatory lesions found on MRI may secondarily evolve toward ossification, which is associated with functional consequences in this disease.

Calprotectin is a member of the S100 protein family and is a heterodimeric complex of S100A8 and S100A9 proteins (calgranulin A and B, part of the Alarmins) [6]. Calprotectin is a calcium and zinc binding protein in the cytosol of monocytes, macrophages and neutrophil granulocytes. In local inflammation, activated cells migrate to the inflammatory site and release calprotectin locally; in the case of gut inflammation, calprotectin is released into the gut lumen and into the feces [7]. Fecal calprotectin is a biomarker that is frequently used in inflammatory bowel disease (IBD) [7], for the assessment of disease activity and response to treatment and in the prediction of disease relapse or postoperative recurrence [7]. Serum calprotectin may have similar relevance in IBD [8].

There is some evidence in the literature supporting the potential of calprotectin as a disease biomarker in spondyloarthritis.

Hammer et al. [9] found in 52 cases of reactive arthritis followed over 104 weeks that plasma calprotectin was well correlated with CRP and disease activity and was the first biomarker to return to normal levels during recovery. Klingberg et al. [10] showed that fecal calprotectin was elevated in 68% of 205 ankylosing spondylitis patients and was not associated with gastrointestinal symptoms, whereas serum calprotectin levels remained low or normal in 98% of these cases. In this study, fecal calprotectin was higher in patients treated with nonsteroidal anti-inflammatory drugs (NSAID) and proton pump inhibitors, and lower in patients treated with a TNF blocker or with methotrexate. Another study evaluating 39 ankylosing spondylitis patients and 42 controls found elevated levels of fecal calprotectin in 41% of the patients and 10% of the controls [11], and no differences between fecal calprotectin-positive and negative patients in NSAID or anti-TNF use. In this study, an association was found between fecal calprotectin positivity and elevated levels of other biomarkers of gut inflammation, namely ASCA and Cbir1. Oktayoglu et al. [12] confirmed higher levels of serum calprotectin in 31 patients with ankylosing spondylitis in comparison to 45 healthy controls, but without correlation with disease activity (assessed by BASDAI and ASDAS), function, metrology, radiographic score or CRP. Increased levels of serum calprotectin were confirmed again by Turina et al. [13] in 37 patients with spondyloarthritis compared to 20 healthy controls. Moreover, they found a significant decrease in serum calprotectin after 2 weeks of treatment with the anti-TNF infliximab (n = 18), whereas there was no change with placebo (n = 19). A significant reduction in serum calprotectin levels was also demonstrated after 4 weeks of treatment with the TNF blocker etanercept in another group of 20 patients with peripheral spondyloarthritis [13]. In axial spondyloarthritis, it was found that the serum calprotectin level was an independent marker for radiographic spinal progression because baseline levels were significantly higher in patients with a worsening of the radiographic score (n = 15) compared to those without worsening (n = 61), after adjustment for factors of radiographic progression (CRP, smoking, syndesmophyte presence at baseline, levels of VEGF) [14].

Finally, Cypers et al. [15] evaluated serum calprotectin and ileocolonoscopy in a cohort of 125 patients with spondyloarthritis and assessed fecal calprotectin in 44 of these patients. Microscopic gut inflammation was present in 42% of the patients; high levels of serum calprotectin, as well as fecal calprotectin, were associated with microscopic gut inflammation. Of the patients with both high levels of serum calprotectin and CRP, 64% exhibited gut inflammation, whereas 25% of patients with low levels of these two biomarkers exhibited gut inflammation.

Considering all of these findings, we can summarize key aspects of calprotectin evaluation and conclude that serum levels can more easily be evaluated than fecal dosage for the assessment of spondyloarthritis.

A majority of studies indicate that calprotectin is elevated in patients with spondyloarthritis compared to healthy controls. In some studies, serum levels of calprotectin were associated with disease activity assessed using CRP [9,10] or the BASDAI [11] and functional impairment measured using the Bath ankylosing spondylitis functional index (BASFI) [11]. In one study, calprotectin demonstrated an interesting sensitivity to short-term improvement under anti-TNF therapy, with a better standardized response mean than hs-CRP [13]. Moreover, calprotectin levels may have potential prognostic value, since elevated levels are associated with radiographic progression [14] and predictive of microscopic gut inflammation, which may aid in selecting patients who should undergo ileocolonoscopy [15].

However, the findings on calprotectin are not homogeneous, and the analysis of this literature has some limitations. In some studies, calprotectin levels did not correlate with disease activity [12], and anti-TNF therapy was not always associated with a reduction in calprotectin levels [11]. The use of NSAIDs, the first line therapy in spondyloarthritis, may influence fecal calprotectin: one study found higher levels of fecal calprotectin in patients taking NSAIDs [10], but this finding was not confirmed in other studies [11]. Moreover, elevated levels of serum calprotectin were found in several other inflammatory diseases [15] and may also reflect nonspecific inflammation, regardless of gut involvement.

In conclusion, calprotectin may be an interesting disease biomarker in spondyloarthritis, but the results should be confirmed using larger samples of patients with different phenotypes of the disease. Comparisons with other biomarkers on sensitivity, specificity, sensitivity to change and prognosis should also be performed. The quest for an ideal biomarker for spondyloarthritis continues.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This article was not funded.