REVIEW URRENT C OPINION
Serological studies in inflammatory bowel disease: how important are they? Maria Papp a and Peter L. Lakatos b
Purpose of review Serum antibodies have the potential role to assist in the diagnosis, disease stratification and prognostication of inflammatory bowel disease (IBD). Understanding antibody formation might provide insight into the dysregulated immunological response to the gut microbiota in IBD. This review summarizes recent evidence regarding the role of serology in IBD. Recent findings There is accumulating evidence from cross-sectional and longitudinal studies and from recent meta-analyses that supports the value of serological markers in identifying patients with complicated disease phenotype and increased risk of surgery in patients with Crohn’s disease. Anti-Saccharomyces cerevisiae antibody remains the most accurate single marker, and recently identified exocrine pancreas antibodies (GP2 and CUZD1) have been suggested as evidence for a role of antibodies in the pathogenesis of Crohn’s disease. Summary Despite these various developments, the use of the serum antibodies remains complementary in clinical practice. New markers are being currently evaluated that may reflect events relevant to the pathogenesis of IBD. Keywords Crohn’s disease, diagnosis, pathogenesis, prediction, serological antibodies
INTRODUCTION Inflammatory bowel disease (IBD) is a term referring to chronic inflammatory disorders of the gastrointestinal tract consisting of ulcerative colitis and Crohn’s disease. Clinical presentation is greatly heterogeneous and variable both at diagnosis and during the disease course. Serum antibodies have a potential role in the diagnosis, differential diagnosis and prediction of either disease course or response to therapy in IBD [1 ]. Table 1 summarizes the presumed antigens and the reported prevalence of serum antibodies in IBD. The presence and probably the significance of these antibodies vary to some extent ethnically; their frequency may differ particularly in nonCaucasians [1 ,2]. Age-associated differences also exist (e.g. anti-CBir1) [3–5] and optimal cut-off values for serologic antibodies in children differ from those in the adult population [6 ]. &&
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DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS OF INFLAMMATORY BOWEL DISEASE Serum antibodies, individually or in combination, have limited clinical value in the primary diagnostic workup of IBD patients because of their moderate
sensitivity and negative predictive value (NPV). However, their high specificity and positive predictive value (PPV) make them useful in selected cases. ASCAþ/pANCA (anti-Saccharomyces cerevisiae antibody and atypical perinuclear antineutrophil cytoplasmatic antibody) is the most accurate combination for distinguishing Crohn’s disease and colonic Crohn’s disease from ulcerative colitis (specificity: 91–94% and PPV: 77–95%). Nonetheless, sensitivity is low in colonic Crohn’s disease (30–38%) [1 ]. In recent publications, the addition of anti-L and anti-C to gASCA IgG and pANCA improved differentiation between Crohn’s disease and ulcerative colitis. Combination of positivity of two or more antiglycan markers including gASCA, ACCA, ALCA and AMCA without pANCA did not &&
a Department of Gastroenterology, Institute of Medicine, University of Debrecen, Debrecen and b1st Department of Medicine, Semmelweis University, Budapest, Hungary
Correspondence to Peter L. Lakatos, MD, PhD, 1st Department of Medicine, Semmelweis University, Koranyi S 2A, Budapest H-1083, Hungary. Tel: +36 1 4591500 51500 51520; fax: +36 1 313 0250; e-mail: [email protected] Curr Opin Gastroenterol 2014, 30:359–364 DOI:10.1097/MOG.0000000000000076
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Inflammatory bowel disease
KEY POINTS Serum antibodies provide additional evidence for the presence of a dysregulated immune response in the development of IBDs. The presence of serum antibodies may at times precede clinical evidence of IBD, and the evaluation of antibodies may assist in diagnosis and differential diagnosis. Accumulating evidence suggests that serological markers can identify, and according to more recent findings may predict, the development of complicated disease in patients with Crohn’s disease, whereas their role is limited in patients with ulcerative colitis. ASCA remains the most accurate single marker, and a combination of multiple markers is only slightly superior to predict the disease course.
yield higher diagnostic value than ASCA for differentiating Crohn’s disease from ulcerative colitis [diagnostic odds ratio (DOR): 10.2 for both] [7 ], whereas ASCA has the highest accuracy for differentiating IBD patients from healthy individuals (OR: 21.1). Anti-OmpC, anti-I2 and anti-CBir1 (antibodies against porin protein C of Escherichia coli; associated with anti-Pseudomonas activity and antiflagellin) failed to provide additional differential diagnostic value. In contrast, adding PAB (glycoprotein targets of exocrine pancreas autoantibodies) to ASCA/pANCA combination further enhanced the specificity and predictive value in both clinical situations [8]. No relevant study targeted the accuracy of novel serologic antibodies in the further differentiation of patients with IBD-unclassified (IBD-U). Antimicrobial antibodies are present in diseases other than IBD and can be associated to sustained bacterial translocation of the gut microflora. Significant antiglycan antibody expression was reported in celiac disease [9], AIDS [10], cystic fibrosis [11], antiGP2 antibodies in celiac disease [12], and ASCA, antiOMP [13] and ANCA [5] expression in cirrhosis. Interestingly, patients with isolated active ileitis (IAI) did not show significant serum antibody expression even in patients with NOD2 mutations [14 ]. Recently discovered serologic candidates like Crohn’s disease peptide (ACP) [15] and agalactosylIgG [16 ] in Crohn’s disease or proteinase-3 (PR3)ANCA [17 ,18] and anti-HMGB1/HMGB2 antibodies in ulcerative colitis [19] are promising, but need further validation in various IBD populations. &&
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PREDICTION OF INFLAMMATORY BOWEL DISEASE DEVELOPMENT Recent reports suggest that the presence of serum markers may precede IBD diagnosis and is predictive 360
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of future IBD in asymptomatic individuals. In the European Prospective Investigation into Cancer and Nutrition (EPIC) study, 39% of Crohn’s disease and 35% of ulcerative colitis patients were positive for a panel of serologic markers (ASCA IgA and IgG, antiCBir1, anti-OmpC and pANCA, respectively) with a mean interval of 4.5 and 4.4 years before IBD diagnosis [20 ]. ASCA [21], other antiglycans [22] and anti-OmpC antibodies are more prevalent in firstdegree relatives of Crohn’s disease patients, and this may be regarded as an at-risk status in unaffected family members [23]. &&
RISK FOR COMPLICATED DISEASE IN CROHN’S DISEASE AND ULCERATIVE COLITIS Association of serum antibodies and clinical phenotype of Crohn’s disease was extensively assessed in cross-sectional single time point studies as summarized in Table 1. In most of these studies, ASCAs were linked to complicated disease behavior (stricturing or penetrating disease) as well as Crohn’s disease-related surgery. A recent meta-analysis [24 ] confirmed that ASCA-positive status was a significant risk factor for complicated disease behavior (OR: 2.09–2.13), perianal disease (OR: 1.49–1.96), and surgery (OR:1.61– 1.71). DORs of complicated disease and surgical intervention were also evaluated for other antiglycan antibodies and compared with that of ASCA [7 ]. Presence of ASCA was also linked to risk of growth impairment in pediatric Crohn’s disease [25]. Data regarding PAB are controversial. PABpositive patients were found to have complicated disease phenotype more frequently as compared with PAB-negative patients in some studies, including the one with the largest IBD cohort [26]. Other studies, however, failed to show a correlation in adult or pediatric settings [26]. In addition, the presence of anti-GP2 antibodies was associated to stricturing behavior with perianal disease in most [27–29] but not all studies [30]. When combining a panel of antiglycan or other antimicrobial antibodies, increasing number or magnitude of seropositivity has yielded higher association with complications and need for surgery than single markers in most individual studies [31]. However, in the recent meta-analysis by Kaul et al. [7 ], the combination of 2 or more antiglycan markers performed only slightly better in predicting need for surgery but not complicated disease phenotype compared with any individual marker. Moreover, interpretation of quartiles sum requires caution, as serum antibody status (positive versus negative) is generally stable during the disease course, but a marked fluctuation was reported in antibody levels and thus the quartile sum score [32]. &
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Type
IgA
IgG
IgG
IgA
IgA
ACCA
ALCA
AMCA
Anti-C
Anti-L
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Anti-CBir1
IgAa/IgG
IgA/IgG
PAB
IgG
Atypical P-ANCA
Autoantibodies
IgA
IgA
Anti-OMP
Anti-I2
IgA
Anti-OmpC
Antipeptide antibodies
IgA/IgG
ASCA
Antiglycan antibodies
Antibody
Glycosylated membrane proteins of acinar secretory storage granules of exocrine pancreas
Unidentified nuclear or nuclear-associated cytoplasmic
Pseudomonas-associated sequence I2 Bacterial flagellin CBir1
Multiple, non-Escherichia coli-derived bacterial proteins of two but undefined intestinal bacteria
Outer membrane protein C transport protein of Escherichia coli
Laminarin
Chitin
Mannobioside
Laminaribiosid
Chitobioside
Cell wall carbohydrate epitopes found in bacteria and fungi Phosphopeptideomannan cell wall carbohydrate epitopes of Saccharomyces cerevisiae or Candida albicans
Presumed antigen
14–42
2–28
50–57
38–60
29–31
24–55
10–25
18–26
12–28
19–31
8–25
29–69
Crohn’s disease
0–23
45–82
6–16
42
20–24
5–28
2–15
3–15
7–15
3–15
5–19
5–15
Ulcerative colitis
Prevalence (%)
Table 1. Prevalence and clinical significance of IBD associated serum antibodies
0–8 nd
1–7
8–15
15
7–20
3–5
2–12
1–10
7–9
2–4
1–12
5–10
Healthy controls
No
–
þ
No
No
No
No
No
?
?
No
þ
Early age at onset
No
Colon only
Small bowel
No
No
Ileocolonic
Small bowel
No
No
?
No
Small bowel, upper GID, oral
Location
þ (?)
–
þ
þ
No
þ
þ
þ
þ
þ
þ
þ
Complicated disease behavior
Association with the clinical phenotype of Crohn’s disease
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(Continued )
No
nd
No
þ
No
þ
þ
þ
þ
þ
þ
þ
Need for surgery in Crohn’s disease
Serology in inflammatory bowel disease Papp and Lakatos
361
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ACCA, antichitobioside carbohydrate antibody; ALCA, antilaminaribiosid carbohydrate antibody; AMCA, antimannobioside carbohydrate antibody; anti-C, antichitin carbohydrate antibody; anti-GP2, antiglycoprotein 2; anti-L, antilaminarin carbohydrate antibody; anti-OmpC, antiouter membrane protein antibody; ASCA, anti-Saccharomyces cerevisiae antibody; atypical P-ANCA, anti-perinuclear anti-neutrophil cytoplasmic antibodies; CUB, complement subcomponents C1r/C1sC1s, Uegf, bone morphogenetic protein; GID, gastrointestinal disease; þ, positive association; –, negative association; no, no association; nd, no data available; ?, inconsistent; PAB, antipancreatic antibodies. a IgA type antibodies were rarely assessed.
nd nd nd 20 CUB/zona pellucida-like domain-containing protein Anti-CUZD1
IgA/IgG
2–12 Glycoprotein 2 Anti-GP2
IgA/IgG
21–38
nd
nd
nd
No þ Ileocolonic, upper GI
Location
þ
Early age at onset Healthy controls Ulcerative colitis Crohn’s disease Presumed antigen Type Antibody
Prevalence (%)
Table 1 (Continued) 362
1–8
Complicated disease behavior
Association with the clinical phenotype of Crohn’s disease
Need for surgery in Crohn’s disease
Inflammatory bowel disease
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In addition, the extrapolation of findings in cross-sectional single point studies requires caution, as these studies combine different patient cohorts with early or advanced disease. Longitudinal followup studies are still rare. Prospective studies, mainly from the pediatric setting, support the findings of cross-sectional studies. Increasing immune reactivity to antimicrobial epitopes was able to predict faster progression to complicated disease and surgery in newly diagnosed Crohn’s disease patients [33]; however, their predictive power is too low for routine clinical use. A very recent study by the Inflammatory Bowel South-Eastern Norway (IBSEN) group suggested the use of serum markers as part of a complex matrix model. A set of clinical variables (age, disease location and need for systemic steroids) and ASCA status was included in a 5-year and 10-year prediction model. The probabilities of advanced disease and Crohn’s disease-related surgery during this period varied from 8.6–92.0% to 12.4–96.7% depending on the combination of predictors [34 ]. The predictive potential of antimicrobial antibodies in the postoperative setting in Crohn’s disease is even more controversial. In a recent study, neither preoperative ASCA status nor ASCA levels was able to predict the risk of surgical recurrence during long-term follow-up [35]. In ulcerative colitis, association of serological markers with disease extent or course is still questionable. In a recent meta-analysis [36 ], ANCA positivity was associated with 76% higher odds of chronic pouchitis than ANCA negativity. &
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FROM THE FORMATION TO THE PATHOGENIC ROLE For several years, the exact mechanisms responsible for the induction and generation of serum antibodies remained unclear. Antibody formation appears to be the result of an enhanced microbial challenge. In IBD, contrary to other disorders, this process is not solely dependent on the inflammatory activity or the mucosal barrier defect, but could partly reflect the nature of the disease. Of note, serum antibody status remains largely unaffected by the actual inflammatory burden and is not altered by anti-inflammatory therapy [32] or after curative surgical resection [35], and association between serum markers and variants in the pattern recognition receptors and autophagy genes was reported [37 ]. Recently, humoral autoreactivity to GP2 was recognized. This has been proposed as evidence that antibodies may be actively involved in the gut inflammatory process [28,38]. GP2 seems to exert an immunomodulatory effect and antimicrobial function in the intestine and thus might be an &
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Serology in inflammatory bowel disease Papp and Lakatos
important factor in maintaining the balance between tolerance to commensal bacteria and immune response against pathogens. After the loss of tolerance toward GP2, it is hypothesized that anti-GP2 IgG diminishes the suppressive effect of GP2 on T-cell activation and proliferation facilitating intestinal inflammation.
CONCLUSION Since the identification of pANCA and ASCA, investigations of serum markers became an important part of biomarker studies in IBD. They may assist the diagnosis of IBDs in selected cases and their presence may even precede the development of symptomatic disease. In Crohn’s disease, but not in ulcerative colitis, serum markers have been associated with and prediction of aggressive disease phenotype (complicated disease, need for surgery). ASCA remains the most accurate single marker (with some variation according to age at onset) and a combination of the markers is only slightly superior in the disease course prediction. Currently, their use is restricted in clinical practice to cases with an indefinite diagnosis or indeterminate disease phenotype. In the future, they could be useful elements of complex matrix models, together with other genetic and biomarkers in combination with clinical markers in the prediction of intermediate and long-term disease course. Finally, serum antibodies provide further evidence for the importance of a dysregulated immune response in the development of IBDs. Acknowledgements M.P. was supported by the Janos Bolyai Research Scholarship of the Hungarian Academy of Sciences and Internal Research Grant of University of Debrecen. Disclosure: none Conflicts of interest There are no conflicts of interest.
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27. Bogdanos DP, Roggenbuck D, Reinhold D, et al. Pancreatic-specific autoantibodies to glycoprotein 2 mirror disease location and behaviour in younger patients with Crohn’s disease. BMC Gastroenterol 2012; 12:102; PubMed PMID: 22866900; PubMed Central PMCID:MC3449192. 28. Pavlidis P, Romanidou O, Roggenbuck D, et al. Ileal inflammation may trigger the development of GP2-specific pancreatic autoantibodies in patients with Crohn’s disease. Clin Dev Immunol 2012; 2012:640835. doi: 10.1155/ 2012/640835; Epub 2012 Oct 17. PubMed PMID: 23118780; PubMed Central PMCID: PMC3483735. 29. Somma V, Ababneh H, Ababneh A, et al. The novel Crohn’s disease marker anti-GP2 antibody is associated with ileocolonic location of disease. Gastroenterol Res Pract 2013; 2013:683824. doi: 10.1155/2013/683824; Epub 2013 May 15. PubMed PMID: 23762038; PubMed Central PMCID: PMC3671301. 30. Op De Bee´ck K, Vermeire S, Rutgeerts P, Bossuyt X. Antibodies to GP2, the major zymogen granule membrane glycoprotein, in inflammatory bowel diseases. Gut 2012; 61:162–164; author reply 164-5. doi: 10.1136/ gut.2010.233148. Epub 2010Dec 29. PubMed PMID: 21193445. 31. Siegel CA, Siegel LS, Hyams JS, et al. Real-time tool to display the predicted disease course and treatment response for children with Crohn’s disease. Inflamm Bowel Dis 2011; 17:30–38. doi: 10.1002/ibd.21386. Epub 2010 Sep 1. PubMed PMID: 20812335. 32. Rieder F, Lopez R, Franke A, et al. Characterization of changes in serum antiglycan antibodies in Crohn’s disease–a longitudinal analysis. PLoS One 2011; 6:e18172. doi: 10.1371/journal.pone.0018172; PubMed PMID: 21573154; PubMed Central PMCID: PMC3089599. 33. Dubinsky MC, Kugathasan S, Mei L, et al., Western Regional Pediatric IBD Research Alliance; Pediatric IBD Collaborative Research Group; Wisconsin Pediatric IBD Alliance. Increased immune reactivity predicts aggressive complicating Crohn’s disease in children. Clin Gastroenterol Hepatol 2008; 6:1105–1111. doi: 10.1016/j.cgh.2008.04.032. Epub 2008 Jul 10. 34. Solberg IC, Cvancarova M, Vatn MH, Moum B. IBSEN Study Group risk matrix & for prediction of advanced disease in a population-based study of patients with Crohn’s disease (the IBSEN Study). Inflamm Bowel Dis 2014; 20:60–68. This is an interesting study by the IBSEN group proposing a complex matrix model including ASCA and clinical markers for the prediction of the probability of developing complicated disease. 35. Eser A, Papay P, Primas C, et al. The impact of intestinal resection on serum levels of anti-Saccharomycescerevisiae antibodies (ASCA) in patients with Crohn’s disease. Aliment Pharmacol Ther 2012; 35:292–299. doi: 10.1111/ j.1365-2036 2011.04932.x.; Epub 2011 Dec 6. PubMed PMID: 22146122. 36. Singh S, Sharma PK, Loftus EV Jr, Pardi DS. Meta-analysis: serological & markers and the risk of acute and chronic pouchitis. Aliment Pharmacol Ther 2013; 37:867–875. doi: 10.1111/apt.12274; Epub 2013 Mar 11. Review. PubMed PMID: 23480145. In this meta-analysis, the authors analyzed 14 studies and evaluated the association of ANCA and ASCA status with the risk of acute and chronic pouchitis in ulcerative colitis patients who underwent IPAA. 37. Murdoch TB, Xu W, Stempak JM, et al. Pattern recognition receptor and & autophagy gene variants are associated with development of antimicrobial antibodies in Crohn’s disease. Inflamm Bowel Dis 2012; 18:1743–1748. doi: 10.1002/ibd.22884; Epub 2012 Jan 24. PubMed PMID: 22275320; PubMed Central PMCID: PMC3418471. In a large cohort of Crohn’s disease patients, the authors confirmed the previous association between NOD2 variants and the presence of ASCA. 3020insC variant and, to a lesser degree, G908R are largely driving the associations between pooled NOD2 variants and ASCA in previous reports. Variants in TLR5 and IRGM were associated with changes in antiflagellin reactivity. NOD2 and ATG16L1 variants appeared to synergistically influence ASCA development. In contrast, variants in the interleukin-23 signaling pathway (IL12B, IL23R and STAT3) did not influence the development of antimicrobial antibodies. 38. Roggenbuck D, Reinhold D, Werner L, et al. Glycoprotein 2 antibodies in Crohn’s disease. Adv Clin Chem 2013; 60:187–208; Review. PubMed PMID: 23724745.
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Serological studies in inflammatory bowel disease: how important are they? Maria Papp a and Peter L. Lakatos b
Purpose of review Serum antibodies have the potential role to assist in the diagnosis, disease stratification and prognostication of inflammatory bowel disease (IBD). Understanding antibody formation might provide insight into the dysregulated immunological response to the gut microbiota in IBD. This review summarizes recent evidence regarding the role of serology in IBD. Recent findings There is accumulating evidence from cross-sectional and longitudinal studies and from recent meta-analyses that supports the value of serological markers in identifying patients with complicated disease phenotype and increased risk of surgery in patients with Crohn’s disease. Anti-Saccharomyces cerevisiae antibody remains the most accurate single marker, and recently identified exocrine pancreas antibodies (GP2 and CUZD1) have been suggested as evidence for a role of antibodies in the pathogenesis of Crohn’s disease. Summary Despite these various developments, the use of the serum antibodies remains complementary in clinical practice. New markers are being currently evaluated that may reflect events relevant to the pathogenesis of IBD. Keywords Crohn’s disease, diagnosis, pathogenesis, prediction, serological antibodies
INTRODUCTION Inflammatory bowel disease (IBD) is a term referring to chronic inflammatory disorders of the gastrointestinal tract consisting of ulcerative colitis and Crohn’s disease. Clinical presentation is greatly heterogeneous and variable both at diagnosis and during the disease course. Serum antibodies have a potential role in the diagnosis, differential diagnosis and prediction of either disease course or response to therapy in IBD [1 ]. Table 1 summarizes the presumed antigens and the reported prevalence of serum antibodies in IBD. The presence and probably the significance of these antibodies vary to some extent ethnically; their frequency may differ particularly in nonCaucasians [1 ,2]. Age-associated differences also exist (e.g. anti-CBir1) [3–5] and optimal cut-off values for serologic antibodies in children differ from those in the adult population [6 ]. &&
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DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS OF INFLAMMATORY BOWEL DISEASE Serum antibodies, individually or in combination, have limited clinical value in the primary diagnostic workup of IBD patients because of their moderate
sensitivity and negative predictive value (NPV). However, their high specificity and positive predictive value (PPV) make them useful in selected cases. ASCAþ/pANCA (anti-Saccharomyces cerevisiae antibody and atypical perinuclear antineutrophil cytoplasmatic antibody) is the most accurate combination for distinguishing Crohn’s disease and colonic Crohn’s disease from ulcerative colitis (specificity: 91–94% and PPV: 77–95%). Nonetheless, sensitivity is low in colonic Crohn’s disease (30–38%) [1 ]. In recent publications, the addition of anti-L and anti-C to gASCA IgG and pANCA improved differentiation between Crohn’s disease and ulcerative colitis. Combination of positivity of two or more antiglycan markers including gASCA, ACCA, ALCA and AMCA without pANCA did not &&
a Department of Gastroenterology, Institute of Medicine, University of Debrecen, Debrecen and b1st Department of Medicine, Semmelweis University, Budapest, Hungary
Correspondence to Peter L. Lakatos, MD, PhD, 1st Department of Medicine, Semmelweis University, Koranyi S 2A, Budapest H-1083, Hungary. Tel: +36 1 4591500 51500 51520; fax: +36 1 313 0250; e-mail: [email protected] Curr Opin Gastroenterol 2014, 30:359–364 DOI:10.1097/MOG.0000000000000076
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Inflammatory bowel disease
KEY POINTS Serum antibodies provide additional evidence for the presence of a dysregulated immune response in the development of IBDs. The presence of serum antibodies may at times precede clinical evidence of IBD, and the evaluation of antibodies may assist in diagnosis and differential diagnosis. Accumulating evidence suggests that serological markers can identify, and according to more recent findings may predict, the development of complicated disease in patients with Crohn’s disease, whereas their role is limited in patients with ulcerative colitis. ASCA remains the most accurate single marker, and a combination of multiple markers is only slightly superior to predict the disease course.
yield higher diagnostic value than ASCA for differentiating Crohn’s disease from ulcerative colitis [diagnostic odds ratio (DOR): 10.2 for both] [7 ], whereas ASCA has the highest accuracy for differentiating IBD patients from healthy individuals (OR: 21.1). Anti-OmpC, anti-I2 and anti-CBir1 (antibodies against porin protein C of Escherichia coli; associated with anti-Pseudomonas activity and antiflagellin) failed to provide additional differential diagnostic value. In contrast, adding PAB (glycoprotein targets of exocrine pancreas autoantibodies) to ASCA/pANCA combination further enhanced the specificity and predictive value in both clinical situations [8]. No relevant study targeted the accuracy of novel serologic antibodies in the further differentiation of patients with IBD-unclassified (IBD-U). Antimicrobial antibodies are present in diseases other than IBD and can be associated to sustained bacterial translocation of the gut microflora. Significant antiglycan antibody expression was reported in celiac disease [9], AIDS [10], cystic fibrosis [11], antiGP2 antibodies in celiac disease [12], and ASCA, antiOMP [13] and ANCA [5] expression in cirrhosis. Interestingly, patients with isolated active ileitis (IAI) did not show significant serum antibody expression even in patients with NOD2 mutations [14 ]. Recently discovered serologic candidates like Crohn’s disease peptide (ACP) [15] and agalactosylIgG [16 ] in Crohn’s disease or proteinase-3 (PR3)ANCA [17 ,18] and anti-HMGB1/HMGB2 antibodies in ulcerative colitis [19] are promising, but need further validation in various IBD populations. &&
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PREDICTION OF INFLAMMATORY BOWEL DISEASE DEVELOPMENT Recent reports suggest that the presence of serum markers may precede IBD diagnosis and is predictive 360
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of future IBD in asymptomatic individuals. In the European Prospective Investigation into Cancer and Nutrition (EPIC) study, 39% of Crohn’s disease and 35% of ulcerative colitis patients were positive for a panel of serologic markers (ASCA IgA and IgG, antiCBir1, anti-OmpC and pANCA, respectively) with a mean interval of 4.5 and 4.4 years before IBD diagnosis [20 ]. ASCA [21], other antiglycans [22] and anti-OmpC antibodies are more prevalent in firstdegree relatives of Crohn’s disease patients, and this may be regarded as an at-risk status in unaffected family members [23]. &&
RISK FOR COMPLICATED DISEASE IN CROHN’S DISEASE AND ULCERATIVE COLITIS Association of serum antibodies and clinical phenotype of Crohn’s disease was extensively assessed in cross-sectional single time point studies as summarized in Table 1. In most of these studies, ASCAs were linked to complicated disease behavior (stricturing or penetrating disease) as well as Crohn’s disease-related surgery. A recent meta-analysis [24 ] confirmed that ASCA-positive status was a significant risk factor for complicated disease behavior (OR: 2.09–2.13), perianal disease (OR: 1.49–1.96), and surgery (OR:1.61– 1.71). DORs of complicated disease and surgical intervention were also evaluated for other antiglycan antibodies and compared with that of ASCA [7 ]. Presence of ASCA was also linked to risk of growth impairment in pediatric Crohn’s disease [25]. Data regarding PAB are controversial. PABpositive patients were found to have complicated disease phenotype more frequently as compared with PAB-negative patients in some studies, including the one with the largest IBD cohort [26]. Other studies, however, failed to show a correlation in adult or pediatric settings [26]. In addition, the presence of anti-GP2 antibodies was associated to stricturing behavior with perianal disease in most [27–29] but not all studies [30]. When combining a panel of antiglycan or other antimicrobial antibodies, increasing number or magnitude of seropositivity has yielded higher association with complications and need for surgery than single markers in most individual studies [31]. However, in the recent meta-analysis by Kaul et al. [7 ], the combination of 2 or more antiglycan markers performed only slightly better in predicting need for surgery but not complicated disease phenotype compared with any individual marker. Moreover, interpretation of quartiles sum requires caution, as serum antibody status (positive versus negative) is generally stable during the disease course, but a marked fluctuation was reported in antibody levels and thus the quartile sum score [32]. &
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Type
IgA
IgG
IgG
IgA
IgA
ACCA
ALCA
AMCA
Anti-C
Anti-L
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Anti-CBir1
IgAa/IgG
IgA/IgG
PAB
IgG
Atypical P-ANCA
Autoantibodies
IgA
IgA
Anti-OMP
Anti-I2
IgA
Anti-OmpC
Antipeptide antibodies
IgA/IgG
ASCA
Antiglycan antibodies
Antibody
Glycosylated membrane proteins of acinar secretory storage granules of exocrine pancreas
Unidentified nuclear or nuclear-associated cytoplasmic
Pseudomonas-associated sequence I2 Bacterial flagellin CBir1
Multiple, non-Escherichia coli-derived bacterial proteins of two but undefined intestinal bacteria
Outer membrane protein C transport protein of Escherichia coli
Laminarin
Chitin
Mannobioside
Laminaribiosid
Chitobioside
Cell wall carbohydrate epitopes found in bacteria and fungi Phosphopeptideomannan cell wall carbohydrate epitopes of Saccharomyces cerevisiae or Candida albicans
Presumed antigen
14–42
2–28
50–57
38–60
29–31
24–55
10–25
18–26
12–28
19–31
8–25
29–69
Crohn’s disease
0–23
45–82
6–16
42
20–24
5–28
2–15
3–15
7–15
3–15
5–19
5–15
Ulcerative colitis
Prevalence (%)
Table 1. Prevalence and clinical significance of IBD associated serum antibodies
0–8 nd
1–7
8–15
15
7–20
3–5
2–12
1–10
7–9
2–4
1–12
5–10
Healthy controls
No
–
þ
No
No
No
No
No
?
?
No
þ
Early age at onset
No
Colon only
Small bowel
No
No
Ileocolonic
Small bowel
No
No
?
No
Small bowel, upper GID, oral
Location
þ (?)
–
þ
þ
No
þ
þ
þ
þ
þ
þ
þ
Complicated disease behavior
Association with the clinical phenotype of Crohn’s disease
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(Continued )
No
nd
No
þ
No
þ
þ
þ
þ
þ
þ
þ
Need for surgery in Crohn’s disease
Serology in inflammatory bowel disease Papp and Lakatos
361
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ACCA, antichitobioside carbohydrate antibody; ALCA, antilaminaribiosid carbohydrate antibody; AMCA, antimannobioside carbohydrate antibody; anti-C, antichitin carbohydrate antibody; anti-GP2, antiglycoprotein 2; anti-L, antilaminarin carbohydrate antibody; anti-OmpC, antiouter membrane protein antibody; ASCA, anti-Saccharomyces cerevisiae antibody; atypical P-ANCA, anti-perinuclear anti-neutrophil cytoplasmic antibodies; CUB, complement subcomponents C1r/C1sC1s, Uegf, bone morphogenetic protein; GID, gastrointestinal disease; þ, positive association; –, negative association; no, no association; nd, no data available; ?, inconsistent; PAB, antipancreatic antibodies. a IgA type antibodies were rarely assessed.
nd nd nd 20 CUB/zona pellucida-like domain-containing protein Anti-CUZD1
IgA/IgG
2–12 Glycoprotein 2 Anti-GP2
IgA/IgG
21–38
nd
nd
nd
No þ Ileocolonic, upper GI
Location
þ
Early age at onset Healthy controls Ulcerative colitis Crohn’s disease Presumed antigen Type Antibody
Prevalence (%)
Table 1 (Continued) 362
1–8
Complicated disease behavior
Association with the clinical phenotype of Crohn’s disease
Need for surgery in Crohn’s disease
Inflammatory bowel disease
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In addition, the extrapolation of findings in cross-sectional single point studies requires caution, as these studies combine different patient cohorts with early or advanced disease. Longitudinal followup studies are still rare. Prospective studies, mainly from the pediatric setting, support the findings of cross-sectional studies. Increasing immune reactivity to antimicrobial epitopes was able to predict faster progression to complicated disease and surgery in newly diagnosed Crohn’s disease patients [33]; however, their predictive power is too low for routine clinical use. A very recent study by the Inflammatory Bowel South-Eastern Norway (IBSEN) group suggested the use of serum markers as part of a complex matrix model. A set of clinical variables (age, disease location and need for systemic steroids) and ASCA status was included in a 5-year and 10-year prediction model. The probabilities of advanced disease and Crohn’s disease-related surgery during this period varied from 8.6–92.0% to 12.4–96.7% depending on the combination of predictors [34 ]. The predictive potential of antimicrobial antibodies in the postoperative setting in Crohn’s disease is even more controversial. In a recent study, neither preoperative ASCA status nor ASCA levels was able to predict the risk of surgical recurrence during long-term follow-up [35]. In ulcerative colitis, association of serological markers with disease extent or course is still questionable. In a recent meta-analysis [36 ], ANCA positivity was associated with 76% higher odds of chronic pouchitis than ANCA negativity. &
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FROM THE FORMATION TO THE PATHOGENIC ROLE For several years, the exact mechanisms responsible for the induction and generation of serum antibodies remained unclear. Antibody formation appears to be the result of an enhanced microbial challenge. In IBD, contrary to other disorders, this process is not solely dependent on the inflammatory activity or the mucosal barrier defect, but could partly reflect the nature of the disease. Of note, serum antibody status remains largely unaffected by the actual inflammatory burden and is not altered by anti-inflammatory therapy [32] or after curative surgical resection [35], and association between serum markers and variants in the pattern recognition receptors and autophagy genes was reported [37 ]. Recently, humoral autoreactivity to GP2 was recognized. This has been proposed as evidence that antibodies may be actively involved in the gut inflammatory process [28,38]. GP2 seems to exert an immunomodulatory effect and antimicrobial function in the intestine and thus might be an &
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Serology in inflammatory bowel disease Papp and Lakatos
important factor in maintaining the balance between tolerance to commensal bacteria and immune response against pathogens. After the loss of tolerance toward GP2, it is hypothesized that anti-GP2 IgG diminishes the suppressive effect of GP2 on T-cell activation and proliferation facilitating intestinal inflammation.
CONCLUSION Since the identification of pANCA and ASCA, investigations of serum markers became an important part of biomarker studies in IBD. They may assist the diagnosis of IBDs in selected cases and their presence may even precede the development of symptomatic disease. In Crohn’s disease, but not in ulcerative colitis, serum markers have been associated with and prediction of aggressive disease phenotype (complicated disease, need for surgery). ASCA remains the most accurate single marker (with some variation according to age at onset) and a combination of the markers is only slightly superior in the disease course prediction. Currently, their use is restricted in clinical practice to cases with an indefinite diagnosis or indeterminate disease phenotype. In the future, they could be useful elements of complex matrix models, together with other genetic and biomarkers in combination with clinical markers in the prediction of intermediate and long-term disease course. Finally, serum antibodies provide further evidence for the importance of a dysregulated immune response in the development of IBDs. Acknowledgements M.P. was supported by the Janos Bolyai Research Scholarship of the Hungarian Academy of Sciences and Internal Research Grant of University of Debrecen. Disclosure: none Conflicts of interest There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Prideaux L, De Cruz P, Ng SC, Kamm MA. Serological antibodies in inflammatory bowel disease: a systematic review. Inflamm Bowel Dis 2013; 18:1340–1355. doi: 10.1002/ibd.21903; Epub 2011 Nov 8. Review. PubMed PMID: 22069240. In this detailed review, the authors processed the data of 204 articles in the period of 1970–2011 focusing on 10 particular serum antibodies. They discussed their prevalence in IBD and healthy controls, role in disease diagnosis and risk stratification, stability over time, presence in unaffected relatives, association with genetic variants and differences between ethnic groups.
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2. Prideaux L, Kamm MA, De Cruz P, et al. Inflammatory bowel disease serology in Asia and the West. World J Gastroenterol 2013; 19:6207–6213. doi: 10.3748/wjg.v19.i37.6207; PubMed PMID: 24115818; PubMed Central PMCID: PMC3787351. 3. Kovacs M, Muller KE, Papp M, et al. New serological markers in pediatric patients with inflammatory bowel disease. World J Gastroenterol (in press). 4. Saadah OI, Al-Mughales JA. Serological markers of inflammatory bowel diseasein children from the Western region of Saudi Arabia. Arab J Gastroenterol 2013; 14:78–82. doi: 10.1016/j.ajg.2013.05.004; Epub 2013 Jun 6. PubMed PMID:23820506. 5. Markowitz J, Kugathasan S, Dubinsky M, et al. Age of diagnosis influences serologic responses in children with Crohn’s disease: a possible clue to etiology? Inflamm Bowel Dis 2009; 15:714–719. doi: 10.1002/ibd.20831; PubMed PMID: 19107777;PubMed Central PMCID: PMC2726983. 6. Rieder F, Hahn P, Finsterhoelzl L, et al. Clinical utility of antiglycan antibodies & in pediatric Crohn’s disease in comparison with an adult cohort. Inflamm Bowel Dis 2012; 18:1221–1231. doi: 10.1002/ibd.21854; Epub 2011 Dec 6. PubMed PMID: 22147427. This study is the first to investigate antiglycan antibodies in a pediatric IBD cohort. The authors performed comparative analysis assessing the accuracy of these markers in adult versus pediatric population. The cut-off values, calculated by receiver-operating characteristic curve analysis, were strikingly lower for all antiglycan markers in the pediatric population. However, the overall performance of markers and association with Crohn’s disease behavior was not affected by the age of sample procurement. 7. Kaul A, Hutfless S, Liu L, et al. Serum antiglycan antibody biomarkers for && inflammatory bowel disease diagnosis and progression: a systematic review and meta-analysis. Inflamm Bowel Dis 2012; 18:1872–1884. doi: 10.1002/ ibd.22862; Epub 2012 Jan 31. Review. PubMed PMID: 22294465; PubMed Central PMCID: PMC3342398. This meta-analysis and systemic review includes nine and 14 studies and aimed at comparing diagnostic value of individual and combinations of antiglycan markers and their association with disease course (complication and/or need for surgery). 8. Lakatos PL, Altorjay I, Szamosi T, et al., Hungarian IBD Study Group. Pancreatic autoantibodies are associated with reactivity to microbial antibodies, penetrating disease behavior, perianal disease, and extraintestinal manifestations, but not with NOD2/CARD15 or TLR4 genotype in a Hungarian IBD cohort. Inflamm Bowel Dis 2009; 15:365–374. doi: 10.1002/ ibd.20778; PubMed PMID: 18972554. 9. Papp M, Foldi I, Altorjay I, et al. Antimicrobial antibodies in celiac disease: trick or treat? World J Gastroenterol 2009; 15:3891–3900; PubMed PMID: 19701969; PubMed Central PMCID: PMC2731251. 10. Kamat A, Ancuta P, Blumberg RS, Gabuzda D. 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PLoS One 2010; 5:e12957. doi: 10.1371/journal.pone.0012957; PubMed PMID: 20886039; PubMed Central PMCID: PMC2944893. 14. O’Donnell S, Crotty PL, O’Sullivan M, et al. Isolated active ileitis: is it a mild && subtype of Crohn’s disease? Inflamm Bowel Dis 2013; 19:1815–1822. doi:10.1097/MIB.0b013e31828dc68b; PubMed PMID: 23751397. IAIisdefinedbymildterminalilealinflammationwithoutfulfillmentofhistologiccriteriaof Crohn’s disease. In this study, IAI shared similar genetic but not serologic profile with Crohn’s disease. NOD2 carriage was identical, whereas prevalence of pANCA, ASCA,anti-OmpCandanti-CBir1wassignificantlylower inIAIcomparedwithCrohn’s disease. During the 38-month follow-up, 14% of IAI cases developed definite Crohn’s disease. Unfortunately, the authors did not report whether the serologic profile of this subgroup was predictive for the development Crohn’s disease by chance. 15. Mitsuyama K, Niwa M, Masuda J, et al., The Kyushu ACP Study Group. Possible diagnostic role of antibodies to Crohn’s disease peptide (ACP): results of a multicenter study in a Japanese cohort. J Gastroenterol 2013. [Epub ahead of print] PubMed PMID: 24297319. 16. Shinzaki S, Kuroki E, Iijima H, et al. Lectin-based immunoassay for aberrant & IgG glycosylation as the biomarker for Crohn’s disease. Inflamm Bowel Dis 2013; 19:321–331. doi: 10.1097/MIB.0b013e318280eade. PubMed PMID: 23287897. Agalactosyl (Agal) fraction among fucosylated IgG oligosaccharides was described as a novel marker of Crohn’s disease facilitating antibody-dependent phagocytosis. In this study, the establishment of a simple detection system for aberrant glycosylated IgG based on lectin–oligosaccharide interactions was reported (lectin-antibody enzyme immunoassay). Validation analysis of a large cohort of IBD patients showed that Agal IgG was increased not only in Japanese, but also in American Crohn’s disease patients. Combination of ASCA and Agal-IgG increased the accuracy of differentiation Crohn’s disease from ulcerative colitis.
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Inflammatory bowel disease 17. Mahler M, Bogdanos DP, Pavlidis P, et al. PR3-ANCA: a promising biomarker for ulcerative colitis with extensive disease. Clin Chim Acta 2013; 424:267– 273. doi: 10.1016/j.cca.2013.06.005; Epub 2013 Jun 24. PubMed PMID: 23806819. This study reported the development of a novel chemiluminescence assay (CIA) that was able to recognize conformational epitopes of PR3-ANCA. This new test showed similar sensitivity, but somewhat higher specificity compared with immunofluorescence ANCA determination and was superior to PR3-ANCA enzyme-linked immunosorbent assay. Particularly, the association between PR3-ANCA CIA and pANCA immunofluorescence was not strong. The majority of PR3-ANCA samples showed a strong pANCA but not C-ANCA pattern. These findings suggest that in a significant proportion of ulcerative colitis patients, at least two independent ANCA specificities might exist. 18. Arias-Loste MT, Bonilla G, Moraleja I, et al. Presence of antiproteinase 3 antineutrophil cytoplasmic antibodies (anti-PR3 ANCA) as serologic markers in inflammatory bowel disease. Clin Rev Allergy Immunol 2013; 45:109–116. doi: 10.1007/s12016-012-8349-4; PubMed PMID: 23345025. 19. Takaishi H, Kanai T, Nakazawa A, et al. Antihigh mobility group box 1 and box 2 nonhistone chromosomal proteins (HMGB1/HMGB2) antibodies and antiSaccharomyces cerevisiae antibodies (ASCA): accuracy in differentially diagnosing UC and CD and correlation with inflammatory bowel disease phenotype. J Gastroenterol 2012; 47:969–977. doi: 10.1007/s00535-0120566-3; Epub 2012 May 30. PubMed PMID: 22644337. 20. van Schaik FD, Oldenburg B, Hart AR, et al. Serological markers predict && inflammatory bowel disease years before the diagnosis. Gut 2013; 62:683– 688. doi: 10.1136/gutjnl 2012 302717; Epub 2012 Jul 26. PubMed PMID: 22842615. In this case –control study, 244 individuals not having Crohn’s disease or ulcerative colitis at recruitment later developed IBD, and twice as many randomly selected matched controls were identified from the EPIC study and tested for a panel of serologic markers. The authors demonstrated the value of the combination of various serologic markers in predicting Crohn’s disease or ulcerative colitis years before the diseases became clinically overt. They also provided future perspectives for pathogenetic studies in a ‘prediagnostic IBD phase’. 21. Vasseur F, Sendid B, Jouault T, et al. Variants of NOD1 and NOD2 genes display opposite associations with familial risk of Crohn’s disease and antisaccharomyces cerevisiae antibody levels. Inflamm Bowel Dis 2012; 18:430–438. doi: 10.1002/ibd.21817; Epub 2011 Jul 7. PubMed PMID: 21739538. 22. Michielan A, Basso D, Martinato M, et al. Increased antibody response to microbial antigens in patients with Crohn’s disease and their unaffected firstdegree relatives. Dig Liver Dis 2013; 45:894–898. doi: 10.1016/ j.dld.2013.01.017; Epub 2013 Mar 7. PubMed PMID: 23477870. 23. Hedin CR, Stagg AJ, Whelan K, Lindsay JO. Family studies in Crohn’s disease: new horizons in understanding disease pathogenesis, risk and prevention. Gut 2012; 61:311–318. doi: 10.1136/gut.2011.238568; Epub 2011 May 11. Review. PubMed PMID: 21561876. 24. Zhang Z, Li C, Zhao X, et al. Anti-Saccharomyces cerevisiae antibodies & associate with phenotypes and higher risk for surgery in Crohn’s disease: a meta-analysis. Dig Dis Sci 2012; 57:2944–2954. doi:10.1007/s10620012-2244-y; Epub 2012 Jun 6. PubMed PMID: 22669207. This meta-analysis included 10 cohort studies (n ¼ 2365) and 14 case–control studies (n ¼ 1887) to investigate the association of ASCA status with phenotypes and risk of surgery in Crohn’s disease. 25. Trauernicht AK, Steiner SJ. Serum antibodies and anthropometric data at diagnosis in pediatric Crohn’s disease. Dig Dis Sci 2012; 57:1020–1025. doi: 10.1007/s10620-011-1954-x; Epub 2011 Nov 11. PubMed PMID: 22075854. 26. Bogdanos DP, Rigopoulou EI, Smyk DS, et al. Diagnostic value, clinical utility and pathogenic significance of reactivity to the molecular targets of Crohn’s disease specific-pancreatic autoantibodies. Autoimmun Rev 2011; 11:143– 148. doi: 10.1016/j.autrev.2011.09.004; Epub 2011 Sep 29. Review. PubMed PMID: 21983481. &
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27. Bogdanos DP, Roggenbuck D, Reinhold D, et al. Pancreatic-specific autoantibodies to glycoprotein 2 mirror disease location and behaviour in younger patients with Crohn’s disease. BMC Gastroenterol 2012; 12:102; PubMed PMID: 22866900; PubMed Central PMCID:MC3449192. 28. Pavlidis P, Romanidou O, Roggenbuck D, et al. Ileal inflammation may trigger the development of GP2-specific pancreatic autoantibodies in patients with Crohn’s disease. Clin Dev Immunol 2012; 2012:640835. doi: 10.1155/ 2012/640835; Epub 2012 Oct 17. PubMed PMID: 23118780; PubMed Central PMCID: PMC3483735. 29. Somma V, Ababneh H, Ababneh A, et al. The novel Crohn’s disease marker anti-GP2 antibody is associated with ileocolonic location of disease. Gastroenterol Res Pract 2013; 2013:683824. doi: 10.1155/2013/683824; Epub 2013 May 15. PubMed PMID: 23762038; PubMed Central PMCID: PMC3671301. 30. Op De Bee´ck K, Vermeire S, Rutgeerts P, Bossuyt X. Antibodies to GP2, the major zymogen granule membrane glycoprotein, in inflammatory bowel diseases. Gut 2012; 61:162–164; author reply 164-5. doi: 10.1136/ gut.2010.233148. Epub 2010Dec 29. PubMed PMID: 21193445. 31. Siegel CA, Siegel LS, Hyams JS, et al. Real-time tool to display the predicted disease course and treatment response for children with Crohn’s disease. Inflamm Bowel Dis 2011; 17:30–38. doi: 10.1002/ibd.21386. Epub 2010 Sep 1. PubMed PMID: 20812335. 32. Rieder F, Lopez R, Franke A, et al. Characterization of changes in serum antiglycan antibodies in Crohn’s disease–a longitudinal analysis. PLoS One 2011; 6:e18172. doi: 10.1371/journal.pone.0018172; PubMed PMID: 21573154; PubMed Central PMCID: PMC3089599. 33. Dubinsky MC, Kugathasan S, Mei L, et al., Western Regional Pediatric IBD Research Alliance; Pediatric IBD Collaborative Research Group; Wisconsin Pediatric IBD Alliance. Increased immune reactivity predicts aggressive complicating Crohn’s disease in children. Clin Gastroenterol Hepatol 2008; 6:1105–1111. doi: 10.1016/j.cgh.2008.04.032. Epub 2008 Jul 10. 34. Solberg IC, Cvancarova M, Vatn MH, Moum B. IBSEN Study Group risk matrix & for prediction of advanced disease in a population-based study of patients with Crohn’s disease (the IBSEN Study). Inflamm Bowel Dis 2014; 20:60–68. This is an interesting study by the IBSEN group proposing a complex matrix model including ASCA and clinical markers for the prediction of the probability of developing complicated disease. 35. Eser A, Papay P, Primas C, et al. The impact of intestinal resection on serum levels of anti-Saccharomycescerevisiae antibodies (ASCA) in patients with Crohn’s disease. Aliment Pharmacol Ther 2012; 35:292–299. doi: 10.1111/ j.1365-2036 2011.04932.x.; Epub 2011 Dec 6. PubMed PMID: 22146122. 36. Singh S, Sharma PK, Loftus EV Jr, Pardi DS. Meta-analysis: serological & markers and the risk of acute and chronic pouchitis. Aliment Pharmacol Ther 2013; 37:867–875. doi: 10.1111/apt.12274; Epub 2013 Mar 11. Review. PubMed PMID: 23480145. In this meta-analysis, the authors analyzed 14 studies and evaluated the association of ANCA and ASCA status with the risk of acute and chronic pouchitis in ulcerative colitis patients who underwent IPAA. 37. Murdoch TB, Xu W, Stempak JM, et al. Pattern recognition receptor and & autophagy gene variants are associated with development of antimicrobial antibodies in Crohn’s disease. Inflamm Bowel Dis 2012; 18:1743–1748. doi: 10.1002/ibd.22884; Epub 2012 Jan 24. PubMed PMID: 22275320; PubMed Central PMCID: PMC3418471. In a large cohort of Crohn’s disease patients, the authors confirmed the previous association between NOD2 variants and the presence of ASCA. 3020insC variant and, to a lesser degree, G908R are largely driving the associations between pooled NOD2 variants and ASCA in previous reports. Variants in TLR5 and IRGM were associated with changes in antiflagellin reactivity. NOD2 and ATG16L1 variants appeared to synergistically influence ASCA development. In contrast, variants in the interleukin-23 signaling pathway (IL12B, IL23R and STAT3) did not influence the development of antimicrobial antibodies. 38. Roggenbuck D, Reinhold D, Werner L, et al. Glycoprotein 2 antibodies in Crohn’s disease. Adv Clin Chem 2013; 60:187–208; Review. PubMed PMID: 23724745.
Volume 30 Number 4 July 2014
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