The Role of Serological Testing in the Diagnosis and Management of Patients with Inflammatory Bowel Disease

Crohn’s disease (CD) and ulcerative colitis (UC) are chronic, idiopathic, and clinically heterogenous intestinal disorders collectively known as inflammatory bowel disease (IBD). CD may affect any part of the digestive tract, is segmental in its distribution, and shows a transmural and often granulomatous inflammation.¹ The most common site of involvement is the distal small bowel, either as distal ileitis or ileocolitis (65%). Isolated involvement of the colon is present in a quarter of patients.² In contrast, UC involves the superficial layers of the colonic mucosa with continuous inflammatory lesions extending proximally from the rectum.¹ Most patients will present with either proctosigmoiditis or left-sided disease extending to the splenic flexure. Although pancolitis is present in only 20% of patients at the time of diagnosis, extensive colonic disease is generally associated with an increased risk of colectomy. Indeed, up to 40% of patients with pancolitis will require colectomy, the majority within 10 years of diagnosis.³ Although the distinction between UC and CD would seem clear based on the combination of clinical, endoscopic, and radiological criteria,¹ indeterminate colitis is present in up to 10 and 20% of adult and pediatric patients with isolated colitis, respectively.^4,5 Serological testing is a non-invasive method of diagnosing IBD and in separating UC from CD.⁶ These antibodies are produced on intestinal exposure to normal commensal bacteria in genetically susceptible individuals. Although these antibodies are non-pathogenic, they are specific to patients with either CD or UC and may reflect a dysregulated immune inflammatory response to intestinal bacterial antigens. This article will discuss the clinical application of serological testing in the diagnosis and management of patients with IBD, the most salient diagnostic and therapeutic issues concerning patients with either CD or UC, and the purported role of antibody monitoring in clinical practice.

Serology Testing
Several experimental animal models of IBD have led to the theory that the pathogenesis of IBD is the result of an aberrant immune response to normal commensal bacteria in genetically susceptible individuals. Although the CARD15/NOD2 gene has been associated with CD,⁷ the mechanism of immune activation is yet to be understood.⁸ Nevertheless, the role of the intestinal microflora in the pathogenesis of IBD has been defined through the presence of several serological markers to bacterial antigens, including oligomanna—anti-Saccharomyces cerevisiae (ASCA)—outer membrane porin C (OmpC), Pseudomonas fluorescens bacterial sequence I2 (anti-I2), and, most recently, bacterial flagellin (CBir1).^9-12 The CBir1 flagellin has been shown to elicit a strong CD4 T-cell lymphocyte response in the CRH/HeJBir colitic mouse and can induce colitis when these activated lymphocytes are transferred to severe combined immunodeficiency disease (SCID) mice.¹³ Flagellin has been defined as a ligand to TLR5, the activation of which culminates in the activation of NFKB.¹⁴ The induction of colitis on exposure to this antigen is unique among all the other bacterial antigens listed above where an antibody response has been associated with intestinal disease. Indeed, the lack of an association with NOD2 gene mutations would suggest that the presence of CBir antibodies may reflect a unique adaptive immune response in a particular subset of patients with CD (see Figure 1).¹⁵ Interestingly, CBir has been linked to an important subset of perinuclear anti-neutrophil cytoplasmic antibody (pANCA)-positive patients with CD, as will be discussed below.¹⁶ All of these antibodies show preponderance in patients with CD. However, ASCA has been identified in up to 5% of patients with UC.⁶ IBD-specific pANCA was first described in 1990. Although generally considered an auto-antibody, the specific antigenic stimulation for pANCA production remains unclear. This auto-antibody is present in up to 70% of patients with UC and in up to 20% of patients with CD.¹⁷ The presence of CBir antibodies has been shown to associate well with a sub-group (44%) of exclusively pANCA-positive patients with CD. In comparison, just 4% of patients with pANCA-positive UC develop CBir1 antibodies.¹⁸ Collectively, these antibodies are not generally present in either children or adults with non-IBD disease and may represent serological markers of intestinal inflammation specific to UC and CD.