Systematic review: New serological markers (anti-glycan, anti-GP2, anti-GM-CSF Ab) in the prediction of IBD patient outcomes

Abstract

Traditionally, IBD diagnosis is based on clinical, radiological, endoscopic, and histological criteria. Biomarkers are needed in cases of uncertain diagnosis, or to predict disease course and therapeutic response. No guideline recommends the detection of antibodies (including ASCA and ANCA) for diagnosis or prognosis of IBD to date. However, many recent data suggest the potential role of new serological markers (anti-glycan (ACCA, ALCA, AMCA, anti-L and anti-C), anti-GP2 and anti-GM-CSF Ab). This review focuses on clinical utility of these new serological markers in diagnosis, prognosis and therapeutic monitoring of IBD. Literature review of anti-glycan, anti-GP2 and anti-GM-CSF Ab and their impact on diagnosis, prognosis and prediction of therapeutic response was performed in PubMed/MEDLINE up to June 2014. Anti-glycan, anti-GP2 and anti-GM-CSF Ab are especially associated with CD and seem to be correlated with complicated disease phenotypes even if results differ between studies. Although anti-glycan Ab and anti-GP2 Ab have low sensitivity in diagnosis of IBD, they could identify a small number of CD patients not detected by other tests such as ASCA. Anti-glycan Abs are associated with a progression to a more severe disease course and a higher risk for IBD-related surgery. Anti-GP2 Ab could particularly contribute to better stratify cases of pouchitis. Anti-GM-CSF Ab seems to be correlated with disease activity and could help predict relapses. These new promising biomarkers could particularly be useful in stratification of patients according to disease phenotype and risk of complications. They could be a valuable aid in prediction of disease course and therapeutic response but more prospective studies are needed.

Introduction

Crohn's disease (CD) and ulcerative colitis (UC) are inflammatory bowel diseases (IBD) which are chronic diseases of the gastrointestinal tract. Although the etiology of IBD is still only partially understood, three factors seem to be involved in the pathogenesis of these diseases: environment (gut flora and microbial pathogens), genetic susceptibility (predisposing factors) and dysregulation of the immune system. The presence of environmental factors in a particular genetic background will lead to the activation of an inappropriate immune response inducing destruction of the mucosa and thus an increase in intestinal permeability which is one of the mechanisms that may explain the presence of antibodies (Abs) found in IBD and which could constitute biomarkers [1], [2], [3], [4]. Traditionally, IBD diagnosis is based on clinical, endoscopic, radiological, and histological criteria [5], [6]. In some cases, treatment of IBD could fail, so it is necessary to find predictors of non-response [7]. Biomarkers are needed in cases of uncertain diagnosis, or to predict disease course and therapeutic response. Their clinical utility is based on their effectiveness in distinguishing IBD compared to other non-IBD diseases with a similar clinical presentation and in the distinction between CD and UC. Their usefulness also includes their prognostic value and their role in the monitoring of disease activity reflecting therapeutic response.

Among many known serological markers, only anti-neutrophilic cytoplasmic antibodies (ANCA) and anti-Saccharomyces cerevisiae antibodies (ASCA) have demonstrated a diagnostic utility. Their simultaneous use improves the specificity in the distinction between CD and UC. Thus, the ASCA +/ANCA− profile has a sensitivity of about 50% and specificity of more than 90% for the diagnosis of CD [8]. However, ASCA and ANCA have many limitations, especially their moderate sensitivity. In addition, these Abs are not established predictive markers of disease activity. In one study, baseline ASCA IgA positivity significantly predicted a more relapsing disease course in pediatric CD [9]. In 279 CD patients under infliximab therapy, patients who had a serologic profile ASCA −/ANCA + before treatment showed a trend toward a lower response to infliximab but this finding lacked significance [10]. ANCA positivity has been reported to be associated with refractory left-sided UC [11]. However, there are conflicting results among studies [12]. The need to better diagnose and stratify IBD has led investigators to search for other serological markers such as anti-microbial antigen Ab [12]. These anti-microbial antigen antibodies, including anti-Escherichia coli outer membrane porin C (anti-OmpC) [13], anti-I2 Pseudomonas fluorescens sequence [14], [15], and anti-CBir1 flagellin [16], are particularly associated with distinct CD phenotypes, especially those associated with fibrostenotic and penetrating complications. However, given their low sensitivities, the role of these antibodies in both the diagnosis and prognostication of IBD remains controversial [13], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38], [39], [40] (Table 1). More recently, Abs against 2 other flagellins (A4-Fla2, Fla-X) have been identified and seem to be associated with complications [41].

Besides ASCA directed against S. cerevisiae mannan, new anti-glycan Abs have been recently described in IBD and include: anti-chitobioside carbohydrate Ab (GlcNAc (β1, 4) GlcNAc (β)) (ACCA) IgA, anti-laminaribioside carbohydrate Ab (Glc (β1, 3) Glc (β)) (ALCA) IgG, anti-mannobioside carbohydrate Ab (Man (α, 3) Manα) (AMCA) IgG, anti-laminarin Ab (Glc (β1, 3)) 3n (Glc (β1, 6))n (anti-L), and anti-chitin Ab (GlcNAc (β1, 4))n (anti-C) IgA. The evaluation of anti-glycan Ab is possible by enzyme-linked immunosorbent assay (ELISA) (IBDX/Glycominds ®) [42]. gASCA is an improved ASCA assay based on covalently immobilized purified mannan polysaccharide, found to be comparable with conventional ASCA and more recently studied [43].

More recently, other antibodies such as anti-glycoprotein 2 (anti-GP2) Ab and anti-granulocyte macrophage colony-stimulating factor (anti-GM-CSF) Ab have been identified in IBD and may play a key role in the pathogenesis of IBD.

Glycoprotein 2 (GP2) is the major autoantigen of exocrine pancreas auto-Ab (PAB) involved in IBD [44], [45]. GP2 is present on the surface of microfold (M) cells of intestinal Peyer's patches (PP), and could play an immunomodulatory role in the intestinal immune system [46], [47], [48]. GP2 can interact with FimH adhesin of enterobacteria and may introduce the presentation of these pathogens to mucosa-associated lymphoid tissue (MALT) via transcytosis and plays a role in the initiation of mucosal immune responses by mediating the bacteria uptake through intestinal M cells of PP [46], [48], [49], [50]. Elevated expression of GP2 has been found in intestinal biopsy samples from CD patients in contrast to UC patients [44], [46]. Anti-GP2 IgG may neutralize the immunomodulatory effect of GP2, and anti-GP2 IgA may facilitate the binding of the GP2-bacteria complex to M cells and thus promotes transcytosis, which may result in an increase of bacterial load in intestinal mucosa and causes an increased inflammatory phenomenon [46], [48], [49], [50]. ELISA tests have been developed for the routine determination of anti-GP2 Ab using human recombinant GP2 as solid-phase antigen [51].

Granulocyte macrophage colony-stimulating factor (GM-CSF) is a cytokine that promotes myeloid cell maturation and is necessary for anti-microbial functions of myeloid cells and homeostatic responses to tissue damage. It has an important role in the regulation of intestinal mucosal damage, and in intestinal immunity and inflammatory responses [52], [53], [54], [55]. GM-CSF therapy improved mucosal repair and could have a role in clinical improvement in CD [52], [53], [54], [55], [56]. Jurickova et al. showed that anti-GM-CSF Abs were produced by lamina propria mononuclear cells isolated from CD ileal resection specimens and that peripheral blood contains GM-CSF neutralizing capacity [57]. High levels of anti-GM-CSF Ab are associated with a reduced bioactivity of GM-CSF, of neutrophil bacterial killing, and an increase in intestinal permeability [57], [58].

There are other antibodies that have been studied in IBD, such as anti-goblet cell (Gab) [59], [60], anti-endothelial cell [61], anti-Mycobacterium avium paratuberculosis [62], anti-OmpW Bacteroides caccae porin [35], [63], or anti-ubiquitination factor E4A [64]. They have no currently clear role in diagnosis or disease stratification and/or have been poorly studied. Besides antibodies there are other biomarkers that are currently studied in IBD such as serum matrix metalloproteinase 9, or interleukin 22 [65] and that could be promising markers but more studies are needed.

Because of low specificity and sensitivity of specific antibodies, and lack of target values, no national, European or international guidelines recommend the routine detection of antibodies (including ASCA and ANCA) for the diagnosis or prognosis of IBD to date. However, many recent data suggest the potential benefits of using new serological markers (new anti-glycan ACCA, ALCA, AMCA, anti-L, anti-C, anti-GP2 and anti-GM-CSF Ab). This review focuses on their clinical utility in the diagnosis, prognosis and therapeutic monitoring of IBD.