Clinical utility of serodiagnostic testing in pediatric inflammatory bowel disease

  • Darja Urlep-Žužej
  • Jernej Dolinšek
  • Dušanka Mičetić-Turk
  • Evgenija Homšak
  • Boris Zagradišnik
Keywords: serological markers, inflammatory bowel disease, children, adolescents, Crohn’s disease, ulcerative colitis, NOD2/CARD15 mutations

Abstract

Background: Among children and adolescents, the diagnosis of inflammatory bowel disease (IBD) is often missed or delayed because of the nonspecific nature of the clinical symptoms. In such instances noninvasive and accurate diagnostic tests that would accurately distinguish IBD from functional disorders would be most valuable to clinicians. Several serological markers have been used as non-invasive diagnostic tools in IBD pediatric patients. The aim of our study was to determine the prevalence and diagnostic accuracy of perinuclear antineutrophil cytoplasmic antibodies (p-ANCA), anti-Saccharomyces cerevisiae antibodies (ASCA), anti-exocrine pancreatic antibodies (PAB) and anti-goblet cells antibodies (GAB) alone and in combination in children and adolescents with IBD.

Patients and methods: Serum specimens were analyzed for p-ANCA, ASCA IgG, ASCA IgA, PAB and GAB antibodies in 49 children and adolescents with confirmed IBD and 53 non-IBD controls. P-ANCA, PAB and GAB antibodies were determined by indirect immunofluorescent test and ASCA by enzyme-linked immunosorbent assay. All patients with Crohn’s disease (CD) had genotyping performed using a sequence specific PCR directed against the wild type and the three principal mutations of NOD2/CARD15 gene. Disease location, body mass index (BMI) and disease activity by pediatric Crohn’s disease activity index (PCDAI) at the time of diagnosis were determined in CD patients.

Results: The prevalence of p-ANCA in patients with UC and ASCA in CD patients was high (82.3 % and 67.9 %, respectively). Positivity for PAB antibodies in CD and GAB in UC was lower (35.7 % and 23.5 %, respectively). Accuracy data (sensitivity, specificity, PPV, NPV, respectively) for differentiating IBD from non-IBD controls were as follows: p-ANCA: 82 %, 100 %, 100 %, 94 %; ASCA IgG: 68 %, 94 %, 86 %, 84 %; ASCA IgA: 54 %, 100 %, 100 %, 80 %; PAB: 36 %, 98 %, 91 %, 74 %; GAB: 23 %, 100 %, 100 %, 80 %. In distinguishing CD from UC we found out the following accuracy data (sensitivity, specificity, PPV, NPV, respectively): p-ANCA: 82 %, 82 %, 74 %, 88 %; ASCA IgG: 68 %, 100 %, 100 %, 65 %; ASCA IgA: 54 %, 100 %, 100 %, 57 %; PAB: 36 %, 100 %, 100 %, 49 %; GAB: 23 %, 100 %, 100 %, 68 %. There were no significant association between ASCA positivity and the three major mutations of NOD2/CARD15 gene, disesase location and family history in CD patients, however an association between BMI and disease activity at the time of diagnosis was found out.

Conclusions: Specificity and positive predictive value of serological markers p-ANCA, ASCA IgG, ASCA IgA, PAB and GAB for IBD alone and in combination are high and which make them useful in diagnosis of inflammatory bowel disease in day-to-day clinical practice, particulary in making decision about performing invasive diagnostic procedures. Because of low sensitivity they are less useful as screening tests for inflammatory bowel disease in pediatric population.

Downloads

Download data is not yet available.

References

Baldassano RN, Piccoli DA. Inflammatory bowel disease in pediatric and adolescent patients. Gastroenterol Clin North Am 1999; 28: 445–58.
Urlep D, Mamula P, Baldassano R. Extraintestinal manifestations of inflammatory bowel disease. Minerva Gastroenterol Dietol 2005; 51: 147–63.
Saxon A, Shanahan F, Landers C, Ganz T, Targan SA. Distinct subset of antineutrophil cytoplasmic antibodies is associated with inflammatory bowel disease. J Allergy Clin Immunol 1990; 86: 202–10.
Panaccione R, Sandborn WJ. Is antibody testing for inflammatory bowel disease clinically useful? Gastroenterology 1999; 116: 1001–8.
Brimnes J, Nielsen OH, Wiik A, Heegaard NHH. Autoantibodies to molecular targets in neutrophils in patients with ulcerative colitis. Dig Dis Sci 1999; 44: 415–23.
Frenzer A, Fierz W, Rundler E, Hammer B, Binek J. Atypical, cytoplasmic and perinuclear anti-neutrophil cytoplasmic antibodies in patients with inflammatory bowel disease. J Gastroenterol Hepatol 1998; 13: 950–54.
Cambridge G, Rampton DS, Stevens TRJ, McCarthy DA, Kamm M, Leaker B. Anti-neutrophil antibodies in inflammatory bowel disease: prevalence and diagnostic role. Gut 1992; 33: 668–74.
Proujansky R, Fawcett PT, Gibney KM, Treem WR, Hyams JS. Examination of anti-neutrophil cytoplasmic antibodies in childhood inflammatory bowel disease. J Ped Gastroenterol Nutr 1993; 17: 193–7.
Broekroelofs J, Mudler AHL. Anti-neutrophil cytoplasmic antibodies (ANCA) in sera from patiens with inflammatory bowel disease (IBD). Dig Dis Sci 1994; 39: 545–9.
Winter HS, Landers CJ, Winkelstein A, Vidrich A, Targan SR. Antineutrophil cytoplasmic antibodies in children with ulcerative colitis. J Pediatr 1994; 125: 707–11.
Targan SR, Lander CJ, Cobb L, MaccDermott RP, Vidrich A. Perinuclear anti-neutrophil cytoplasmic antibodies are spontaneously produced by mucosal B cells of ulcerative colitis patients. J Immunol 1995; 155: 3262–7.
Sobajima J, Ozaki S, Osakada F, Uesugi H, Shirakawa H, Yoshida M, Nakao K. Novel autoantigens of perinuclear anti-neutrophil cytoplasmic antibodies (p-ANCA) in ulcerative colitis: non-histone chromosomal proteins:HMG1 and HMG2. Clin Exp Immunol 1997; 107: 135–40.
Terjung B, Spengler U, Sauerbruch T, Worman HJ. Atypical pANCA in IBD and hepatobiliary disorders react with a 50-kilodalton nuclear envelope protein of neutrophils and myeloid cell lines. Gastroenterology 2000; 119: 310–22.
Mallolas J, Esteve M, Rius E, Cabre E, Gassull MA. Antineutrophill antibodies associated with ulcerative colitis interact with the antigen(s) during the process of apoptosis. Gut 2000; 47: 74–8.
Reumaux D, Colombel JF, Masy E, Duclos B, Heresbach D, Belaiche J, et al. Anti-neutrophil cytoplasmic auto-antibodies (ANCA) in ulcerative colitis (UC): no relationship with disease activity. Inflamm Bowel Dis 2000; 6: 270–4.
Main J, McKenzie H, YeamanGR, Kerr MA, Robson D, Pennington CR, Parrat D. Antibody to Saccharomyces cerevisiae (baker’s yeast) in Crohn’s disease. Br Med J 1988; 297: 1105–6.
Quinton JF, Sendid B, Reumaux D, Duthilleul P, Cortot A, Grandbastien B, et al. Anti-Saccharomyces cerevisiae mannan antibodies combined with antineutrophil cytoplasmatic autoantibodies in inflammatory bowel disease: prevalence and diagnostic role. Gut 1998; 42: 788–91.
Ruemmele FM, Targan SR, Levy G, Dubinsky M, Jonathan B, Seidman EG. Diagnostic accuracy of serological assays in pediatric inflammatory bowel disease. Gastroenterology 1998; 115: 822–9.
Peeters M, Joossens S, Vermeire S, Vlietinck R, Bossuyt X, Rutgeerts P. Diagnostic value of anti-Saccharomyces cerevisiae and antineutrophil cytoplasmic autoantibodies in inflammatory disease. Am J Gastroenterol 2001; 96: 730–34.
Nielsen OH, Vainer B, Madsen SM, Seidelin JB, Heegaard NHH. Established and emerging biological activity markers of inflammatory bowel disease. Am J Gastroenterol 2000; 95: 395–67.
Conrad K, Schmecta H, Klafki A, Lobeck G, Uhlig HH, Gerdi S, Henker J. Serological differentiation of inflammatory bowel diseases. Eur J Gastroenterol Hepatol 2002; 14: 129–35.
Lerner A, Shoenfeld Y. Serological markers in inflammatory bowel disease. The pros and cons. Eur J Gastroenterol Hepatol 2002; 14: 103–5.
Bernstein CN, Orr K, Blanchard JF, Sargent M, Workman D. Development of an assay for antibodies to Saccharomyces cerevisiae: Easy, cheap and specific for Crohn’s disease. Can J Gastroenterol 2001; 15: 499–504.
Rutgeerts P, Vermeire S. Serological diagnosis of inflammatory bowel disease. Lancet 2000; 356: 2117–18.
Dubinsky MC, Ofman JJ, Urman M, Targan SR, Seidman EG. Clinical utility of serodiagnostic testing in suspected pediatric inflammatory bowel disease. Am J Gastroenterol 2001; 96: 758– 65.
Sendid B, Colombel JF, Jacquinot PM, Faille C, Fruit J, Cortot A. Specific antibody response to oligomannoside epitopes in Crohn’s disease. Clin Diagn Lab Immunol 1996; 3: 219–26.
Sutton CL, Yang H, Li Z, Rotter JI, Targan SR, Braun J. Familial expression of anti-Saccharomyces cerevisiae mannan antibodies in affected and unaffected relatives of patients with Crohn’s disease. Gut 2000; 46: 58–63.
Annesse V, Andreoli A, Andriulli A, Dinca R, Gionchetti P, Latiano A, et al. Familial expression of anti-Saccharomyces cerevisiae Mannan antibodies in Crohn’s disease and ulcerative colitis: a GISC study. Am J Gastroenterol 2001; 96: 2407–12.
Vermeire S, Peeters M, Vlietinck R, Joossens S, Den Hond E, Bulteel V, et al. Anti-Saccharomyces cerecvisiae Antibodies (ASCA), Phenotypes of IBD, and Intestinal permeability. A study in IBD families. Inflamm Bowel Dis 2001; 7: 8–15.
Stocker W, Otte M, Ulrich S, Normann D, Stocker K, Jantschek G. Autoantibodies against the exocrine pancreas and against intestinal goblet cells in the diagnosis of Crohn’s disease and ulcerative colitis. Deutsch Med Wochenschr 1984; 109: 1963–9.
Stocker W, Ote M, Ulrich S, Normann D, Stocker K, Jantschek G, Scriba PC. Autoimmunity to pancreatic juice in Crohn’s disease. Results of an autoantibody screening in patients with chronic inflammatory bowel disease. Scand J Gastroenterol 1987; 139: 41–52.
Seibold F, Weber P, Jennss H, Wiedmann KH. Antibodies to a trysin sensitive pancreatic antigen in chronic inflammatory bowel disease: specific markers for a subgroup of patients with Crohn’s disease. Gut 1991; 32: 1192–7.
Homšak E. Prevalenca in diagnostična vrednost avtoprotiteles PAB, GAB in p-ANCA pri kronični vnetni črevesni bolezni. [Magistrsko delo.] Ljubljana: Medicinska fakulteta; 2002. p. 1–73.
Joossens S, Vermeire S, Steen KV, Godefridis G, Claessens G, Pierik M, et al. Pancreatic autoantibodies in inflammatory bowel disease. Inflamm Bowel Dis 2004; 10: 771–7.
Fricke H, Birkhofer A, Folwaczny C, Meister W, Scriba PC. Characterization of antigens from the human exocrine pancreatic tissue (Pag) relevant as target antigens for autoantibodies in Crohn’s disease. Eur J Clin Invest 1999; 29: 41–5.
Folwaczny C, Noehl N, Tschop K, Endres SP, Heldwein W, Koeschke K, Fricke H. Goblet cell autoantibodies in patients with inflammatory bowel disease and their first degree relatives. Gastroenterology 1997; 113: 101–6.
Hibi T, Ohara M, Kobayahi K, Brown BR, Takaishi K, Takaishi K, et al. Enzyme linked immunosorbent assay (ELISA) and immunoprecipitation studies on anti-goblet cell antibody using a mucin producing cell line in patients with inflammatory bowel disease. Gut 1994; 35: 224–30.
Laurence IC, Hall A, Leong R, Pearce C, Murray K. A comparative study of goblet cell and pancreatic exocrine autoantibodies combined with ASCA and p-ANCA in Chinese and Caucasian patients with IBD. Inflamm Bowel Dis 2005; 11: 890–7.
Hugot JP, Zouali H, Lesage S. Lessons to be learned from the NOD2 gene in Crohn’s disease. Eur J Gastroenterol Hepatol 2003; 15: 593–7.
Cho JH. Significant role of genetics in IBD: The NOD2 gene. Rev Gastroenetrol Disord 2003; 3 suppl 1: S18–22.
Moore MM, Fabricatorian D, Selby WS. Assessment and relevance of enzyme-linked immunosorbent assay for antibodies to Saccharomyces cerevisiae in Australian patients with inflammatory bowel disease. Intern Med J 2002; 32: 349–52.
Joossens S, Reinisch W, Vermeire S, Sendid B, Poulain D, Peeters M, et al. The value of serologic markers in indeterminate colitis. A prospective folow up study. Gastroenterology 2002; 122: 1242– 47.
Kaila B, Orr K, Bernstein CN. The anti-saccharomyces cerevisiae antibody assay in a province-wide practice: accurate in identifying cases of Crohn’s disease and predicting inflammatory disease. Can J Gastroenterol 2005; 19: 717–21.
Torok HP, Glas J, Hollay HC, Gruber R, Osthoff M, Tonenchi L, et al. Serum antibodies in first-degree relatives of patients with IBD: a marker of disease suspectibility? A follow-up pilot study after 7 years. Digestion 2005; 72: 119–23.
Vermeire S, Joossens S, Peeters M, Monsuur F, Marien G, Bossuyt X, et al. Comparative study of ASCA (Anti-saccharomyces cerevisiae antibody) assays in inflammatory bowel disease. Gastroenterology 2001; 120: 827–33.
Vasiliauskas EA, Kam LY, Karp LC, Gaienniwe J, Yang H, Targan SR. Marker antibody expression stratifies Crohn’s disease into immunologically homogeneous subgroups with distinct clinical characteristics. Gut 2000; 47: 487–96.
Sandborn WJ, Loftus EV, Colombel JF, Fleming KA, Seibold F, Homburger HA, et al. Evaluation of serologic disease markers in a population-based cohort of patients with ulcerative colitis and Crohn’s disease. Inflamm Bowel Dis 2001; 7: 192–201.
Zholudev A, Zurakowski D, Young W, Leichner A, Bousvaros A. Serologic testing with ANCA, ASCA, anti-OmpC in children and young adults with Crohn’s disease and ulcerative colitis: diagnostic value and correlation with disease phenotype. Am J Gastroenterol 2004; 99: 2235–41.
Konrad A, Rutten C, Flogerzi B, Styner M, Goke B, Seibold F. Immune sensitisation to yeast antigens in ASCA-positive patients with Crohn’s disease. Inflamm Bowel Dis 2004; 10: 97–105.
Arnott ID, Landers CJ, Nimmo EJ, Drummond HE, Smith BK, Targan SR, Satsangi J. Sero-reactivity to microbial components in Crohn’s disease is associated with disease severity and progression, but not NOD2/CARD15 genotype. AM J Gastroenterol 2004; 99: 2376–84.
Published
2016-08-29
How to Cite
1.
Urlep-Žužej D, Dolinšek J, Mičetić-Turk D, Homšak E, Zagradišnik B. Clinical utility of serodiagnostic testing in pediatric inflammatory bowel disease. TEST ZdravVestn [Internet]. 29Aug.2016 [cited 5Aug.2024];75. Available from: http://vestnik-dev.szd.si/index.php/ZdravVest/article/view/2066
Section
Research article

Most read articles by the same author(s)