Recommendations for identifying Crohn’s disease patients with poor prognosis

Abstract

Clinical presentation at diagnosis and the disease course of Crohn’s disease is heterogeneous and variable over time. The majority of patients with Crohn’s disease will develop at least one stricturing or perforating complication requiring surgery during follow-up. New data support a change in the natural history of the disease associated with the advent of biologicals and tailored treatment strategy. Therefore, it is important to identify patients at risk for disease progression as soon as possible. In recent years, much emphasis has been placed on determining important predictive factors. Complex evaluation of factors such as clinical and endoscopic presentation, fecal, serological and routine laboratory tests, and genetic factors is needed. This review summarizes the available evidence and will hopefully assist clinicians when choosing a treatment strategy in everyday practice.

Keywords::

• biomarkers
• clinical
• Crohn’s disease
• disease course
• predictive markers
• serology

Medscape: Continuing Medical Education Online

This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of Medscape, LLC and Expert Reviews Ltd. Medscape, LLC is accredited by the ACCME to provide continuing medical education for physicians.

Medscape, LLC designates this Journal-based CME activity for a maximum of 1 AMA PRA Category 1 Credit(s)^™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

All other clinicians completing this activity will be issued a certificate of participation. To participate in this journal CME activity: (1) review the learning objectives and author disclosures; (2) study the education content; (3) take the post-test with a 70% minimum passing score and complete the evaluation at www.medscape.org/journal/expertimmunology; (4) view/print certificate.

Release date: 21 December 2012; Expiration date: 21 December 2013

Learning objectives

Upon completion of this activity, participants will be able to:

• • Analyze the disease classification and clinical course of Crohn’s disease

• • Distinguish clinical factors which predict worse outcomes of Crohn’s disease

• • Assess endoscopic factors associated with the prognosis of Crohn’s disease

• • Evaluate biomarkers which might predict the severity of Crohn’s disease

Financial & competing interests disclosure

EDITOR

Elisa Manzotti

Publisher, Future Science Group, London, UK

Disclosure: Elisa Manzotti has disclosed no relevant financial relationships.

CME AUTHOR

Charles P Vega, MD

Health Sciences Clinical Professor; Residency Director, Department of Family Medicine, University of California, Irvine, CA, USA

Disclosure: Charles P Vega, MD, has disclosed no relevant financial relationships.

AUTHORS AND CREDENTIALS

Pal Miheller, MD

Second Department of Medicine, Semmelweis University, Budapest, Hungary

Disclosure: Pal Miheller, MD, has disclosed no relevant financial relationships.

Lajos S Kiss, MD

First Department of Medicine, Semmelweis University, Budapest, Hungary

Disclosure: Lajos S Kiss, MD, has disclosed no relevant financial relationships.

Mark Juhasz, MD, PhD

Second Department of Medicine, Semmelweis University, Budapest, Hungary

Disclosure: Mark Juhasz, MD, PhD, has disclosed no relevant financial relationships.

Michael Mandel, MD

First Department of Medicine, Semmelweis University, Budapest, Hungary

Disclosure: Michael Mandel, MD, has disclosed no relevant financial relationships.

Peter L Lakatos, MD, PhD

First Department of Medicine, Semmelweis University, Budapest, Hungary

Disclosure: Peter L Lakatos, MD, PhD, has disclosed no relevant financial relationships.

Inflammatory bowel diseases (IBDs) are a heterogeneous group of distinct, chronic inflammatory diseases primarily affecting the GI tract, including Crohn’s disease (CD) and ulcerative colitis (UC). These diseases are characterized according to their clinical, radiological, endoscopic and histological properties. Both IBD epidemiology and disease course have changed in recent decades.

The incidence of both CD and UC has dramatically changed over time [1], with both common and distinct developments. Most significant is the growing incidence of both diseases, alterations in the ratio of CD and UC and a reduction of geographical differences in disease incidence. An increased number of younger patients are diagnosed with IBD than in the past.

A global trend of increasing incidence and prevalence of CD and UC has been reported in a recent review [2]. The highest annual incidence of CD was 12.7:100,000 in Europe, 20.2:100,000 in North America and 5.5:100,000 in Asia and the Middle East. In addition, the annual incidence of UC was calculated to be 24.3:100,000 in Europe, 19.2:100,000 in North America and 6.3:100,000 in Asia and the Middle East. Geographical differences in the incidence of IBD seem to be less prevalent in recent decades, because of a recent increase in patient population in eastern and southern Europe. Growing incidence rates were also reported in eastern and southern Europe. Of note, one of the highest incidence rates of IBDs was reported from Australia with an incidence of 29.3 and 17.4 per 100,000 for CD and UC, respectively [3]. Cosnes et al. have reported prevalence of IBD as high as 0.5% in Canada [4].

Similarly, a recent review reported growing incidence rates in pediatric populations [5]. Abramson et al. observed changing epidemiology of pediatric IBD in an 11-year period [6]. During the study, annual incidence increased from 2.2 to 4.3 per 100,000 for CD (p = 0.09) and from 1.8 to 4.9 for UC (p <0.001). Overall, IBD is still more frequent in developed countries, with incidence growing parallel to the spread of western lifestyle.

Definition of disease phenotype & course

The phenotypic classification of CD is important when determining patient management and treatment strategy, and some of the variables may assist in predicting clinical disease course [7]. CD was classified in Vienna in 1998 according to patient age at diagnosis, disease location and disease behavior [8]. The cutoff point for age at disease onset was 40 years. Disease localization is based on endoscopic and imaging findings.

One of the most important components of this classification is disease behavior. The Vienna classification divides CD into three categories according to disease behavior at onset. Inflammatory disease is characterized by systemic complaints, including abdominal pain, diarrhea, weight loss, and in more severe cases, febrility. Stricturing disease results in luminal narrowing visualizable by radiology, endoscopy or surgery, demonstrating prestenotic dilatation or obstructive signs and symptoms without the presence of penetrating disease at any time. Penetrating disease is the occurrence of intra-abdominal or perianal fistulas, inflammatory masses or abscesses at any time in the disease course. Perianal ulcers were included in this category, but skin tags were excluded. These latter two phenotypes are defined as complicated.

In 2006, this classification was further refined and modified in Montreal [9]. Perhaps most noteworthy, perianal involvement was introduced as a new complementary factor. Upper gastrointestinal disease became classified as an independent location.

While the aforementioned clinical classifications provide a useful approach to patient risk assessment at a given time point, it has been shown that significant changes in disease behavior occur over time, whereas disease location remains relatively stable [10]. However, recent population-based studies report a more benign disease course in CD. A decade-long Norwegian prospective study categorized 237 patients into four groups based on their clinical course during follow-up [11]. Forty-three percent of patients experienced reduced bowel symptoms, whereas only 3% reported an increase in symptom severity. Chronic continuous symptoms and chronic relapsing symptoms were reported in 19 and 32% of patients, respectively. The overall percentage of patients with complicated disease was 36% at diagnosis, 49% at 5 years and 53% at 10 years (31% stricturing and 22% penetrating).

Why do we need prognostic factors?

A significant change in patient management and therapeutic strategy occurred in the last decade. Recent therapeutic goals extend beyond symptomatic control and include long-term clinical, biochemical and endoscopic remission, avoidance of surgery or hospitalization, and ultimately aim at changing the natural history by slowing down or halting disease progression. This also includes more sophisticated patient follow-up (tight control) [12] and early, aggressive, tailored therapy. Risk assessment and prognostication by means of complex clinical, biochemical and endoscopic markers has become key to patient management, therapy optimization and prediction of the outcome and side effects of medical therapy.

A practical question is whether a concrete definition of severe or mild clinical phenotype exists. Unfortunately, at present, there are no clear definitions, and the relative importance of factors discussed in the subsequent sections must be considered on a case-by-case basis.

Clinical & environmental predictors

Clinical features are useful medium and long-term prognostic factors of complicated disease course in IBD. In the landmark paper by Beaugerie et al., initial need for steroid use (odds ratio [OR]: 3.1; 95% CI: 2.2–4.4), age <40 years (OR: 2.1; 95% CI: 1.3–3.6), and the presence of perianal disease (OR: 1.8; 95% CI: 1.2–2.8) were associated with progression to disabling disease according to their definition in patients with CD [13]. The positive predictive value for patients with two and three predictive factors of disabling disease was as high as 0.91 and 0.93, respectively. The majority of patients had at least two of the predictive factors. Of note, the definition of disabling disease was arbitrary and included significantly different clinical scenarios (e.g., need for two or more steroids courses, further hospitalization or need for immunosuppressives). Some of these unquestionably represent therapeutic decisions by the treating physician (e.g., the point at which immunosuppressives are started) and should not be regarded as disabling outcomes. Similarly, steroid use and stricturing disease at diagnosis were also identified as predictors of complicated disease course in the pediatric patient populations [14].

Progression towards complicated disease was also more rapid in those with small bowel compared with colonic disease (p <0.001) in a New Zealand cohort [7], and perianal disease was a significant predictor of change in CD behavior (hazard ratio [HR]: 1.62; p <0.001). Thus, patients with small bowel involvement in particular should be observed closely.

In addition, a Belgian study showed that perianal lesions, the need for steroids to treat the first flare-up and ileocolonic location, but not age <40 years were confirmed as predictive markers for developing disabling disease at 5 years [15]. Stricturing behavior (HR: 2.11; 95% CI: 1.39–3.20) and weight loss (>5 kg; HR: 1.67; 95% CI: 1.14–2.45) at diagnosis were independently associated with time to development of severe disease. Finally, terminal ileal location (p <0.001), stricturing (p = 0.004), penetrating behavior (p <0.001) and age <40 years (p = 0.03) at diagnosis were independent risk factors for subsequent surgery in a prospective 10-year follow-up study by the IBSEN group [11].

Medical therapy may also affect prognosis in CD; early need for systemic steroids denotes a worse prognosis. In a Danish cohort of those patients who achieved complete or partial clinical remission of active CD with 1 mg/kg prednisolone induction therapy, nearly half had a relapse or developed corticosteroid dependency within 1 year of treatment initiation [16]. Similar figures were published from the Mayo clinic by Faubion et al. [17]. In summary, only 32% of patients with CD and 48% with UC were corticosteroid-free without operation after the 1-year observational period.

The effect of azathioprine (AZA) on disease prognosis was controversial until recently. AZA therapy was effective in achieving and maintaining remission and mucosal healing (MH) in CD [18,19]; but only recent population-based reports confirmed that early AZA use is associated with reduced need for surgery according to a Cox regression analysis and propensity score matching in two population-based cohorts from Wales and Hungary [20,21]. Of note, these studies analyzed the association between early AZA therapy and the need for surgery by using complex multivariate analysis, and in the second study even propensity score adjustment. The follow-up was also reasonably long (median: 12 and 5 years) in these studies, and finally, a significant proportion of the patients did not undergo surgery during follow-up (HR: 0.40 and 0.47). In another Hungarian study, it was reported that early AZA or biological therapy reduced the risk for change in disease behavior and the risk of first operation in a referral CD cohort [22,23]. Nonetheless, the most convincing data to support benefit from early use of AZA come from the pediatric literature [24]. In a randomized controlled trial in 55 children, the early use of 6-mercaptopurine was associated with a significantly lower relapse rate (only 9% compared with 47% of controls (p = 0.007). All these confirm that the natural history of the disease was influenced by the medical treatment strategy.

Early use of combination AZA and infliximab was shown to be superior compared with conventional management in recent-onset CD [25]. Patients were assigned to conventional management or combined immunosuppression (infliximab induction followed by maintenance AZA). Remission rates at week 52 were 61.5 and 42.2% (95% CI: 2.4–36.3; p = 0.027). Recently, the combined use of AZA and infliximab was also observed to be more efficacious than monotherapy in early CD patients in the SONIC study [26].

One of the most widely studied environmental factors related to IBD is smoking. In a recent review, it was shown that smoking was associated with a greater likelihood to progress to complicated disease, as defined by the development of strictures or fistulae [27], a higher relapse rate [28], increased risk of surgery, including reoperation [29] and need for steroids and immunosuppressants [30], although not in all studies [31]. Some data suggest that the deleterious effects of smoking can be at least partly neutralized by the use of immunomodulators [4]. In a referral CD cohort from a Hungarian study, the deleterious effects of smoking (disease behavior change and need for surgery) were only evident in patients without early thiopurine therapy [22,23].

Endoscopic factors

The clinical importance of MH on short- and long-term prognosis of CD was investigated in several settings; however, the definitions used for MH were quite heterogeneous [32]. MH may be defined as a complete absence of any characteristic endoscopic lesions in the gut, or may represent a significant decrease in any of the endoscopic severity indices for CD.

Due to the need for objectivity, scoring systems were developed to evaluate the severity of mucosal lesions. The CD Endoscopic Index of Severity (CDEIS) is a prospectively developed, reproducible, validated scoring system for classifying the alterations of the ileocolonic mucosa [33]. Poor correlation was observed between CDEIS and clinical activity [34], and steroid-induced remission. As CDEIS is time consuming and inconvenient in daily clinical practice, another simple endoscopic index of severity for CD (SES-CD) was proposed with the goal of simplifying mucosal evaluation in CD [35]. Reproducibility of the SES-CD results was comparable with that of CDEIS. Clinical correlations of SES-CD results were weak but significant (SES-CD to Crohn’s Disease Activity Index r = 0.390; SES-CD to C-reactive protein [CRP] r = 0.472). Of note, the size of ulcers and stenosis are the two major factors in endoscopic scores.

An expert panel of the European Crohn’s and Colitis Organization developed a consensus regarding predictive markers’ abilities to detect and monitor intestinal healing in IBD [36]. Both CDEIS and SES-CD scores were regarded as being highly reproducible, and they were prospectively validated. Attempts to define endoscopic remission or minimal activity led to the identification of CDEIS cutoff of lower than 3 points and of SES-CD cutoff of lower than 5 points, although in other studies, the best prognosis seemed to be associated with a CDEIS or SES-CD scores of 0 points. However, both were judged to be complicated. The consensus stated that none of the available scales assisted in estimating differences in prognosis, nor in establishing cutoff values for endoscopic remission or levels of endoscopic activity. Thus, it is still questionable how best to describe the severity of mucosal lesions and healing.

Despite inconsistent definitions of MH, the impact of MH on long-term outcomes, such as hospitalization, steroid use and clinical activity, has also been studied. In a landmark paper, Allez et al. reported that severe endoscopic lesions in patients with colonic CD were associated with an increased risk for colectomy after 1, 3 and 8 years of follow-up [37]. This was partially confirmed in a population-based follow-up study by the IBSEN group, in which MH in CD was not seen as a significant predictor for resective surgery at 5 years, but the risk of future steroid use was found to be decreased [38].

In a further study from the Leuven group, the need for surgery and hospitalization was evaluated in infliximab-treated CD patients. Interestingly, patients with MH had less need for resective surgery and less frequent hospitalizations compared with those without MH (14.1 vs 38.4%; p <0001 and 42.2 vs 59.3%; p = 0.018, respectively) [39]. Similarly, MH at 6 months following the start of scheduled infliximab maintenance therapy was associated with fewer major abdominal surgeries during follow-up [39].

Similar positive data were published in randomized clinical trials. In the step-up, top-down study, complete MH in patients with early CD was associated with significantly higher steroid-free remission rates 3 or 4 years after the start of therapy [40]. MH appeared to correlate with fewer hospitalizations in the ACCENT I study population, although these results were not statistically significant [41]. Notably, no strong relationship between clinical remission and complete MH was found.

The first randomized, double-blind, placebo-controlled trial to explore MH as a primary end point under anti-TNFα therapy was the EXTEND trial [42]. After the initial 160/80 mg adalimumab induction therapy, patients were randomized to subcutaneous 40 mg adalimumab or placebo every other week until week 52. The primary end point was MH at week 12. At week 52, rates of MH were 24 and 0%, respectively (p <0.001), and this was associated with risk of hospitalization and surgery.

In the STORI trial, a recent anti-TNFα cessation trial, clinical, laboratory and endoscopic variables were evaluated for association with time to relapse [43]. CDEIS and a complex set of other markers (including male gender, corticosteroid use 6 to 12 months before baseline, number of previous surgical resections, hemoglobin level, leukocyte count, fecal calprotectin concentration and infliximab trough level) were the most important predictors of relapse-risk in a multivariate model.

Finally, ileocolonoscopy and endoscopic healing was shown to be associated with the clinical outcome in the postoperative setting. The Rutgeerts score was developed to assess the severity of disease recurrence 1 year after ileal resection [44]. Severity of the endoscopic recurrence after ileocecal resection was predictive regarding the subsequent clinical course. The clinical relapse rate in patients with no or mild endoscopic relapse present in the first postoperative year was observed to be 9% at 7 years, while patients with severe endoscopic relapse had a clinical relapse within 4 years.

Biomarkers

Biomarkers can be divided into long-term markers (e.g., genetics and serology) influencing the clinical phenotype and short-term markers (e.g., CRP or calprotectin) that may be more useful for the prediction of flares.

C-reactive protein

CRP is useful in evaluating the severity of inflammation in IBD, but has some limitations. Elevated CRP is common in active small bowel disease and thus has more significant diagnostic value in CD, but septic complications, including abscesses and toxic colitis, may increase the CRP in both CD and UC.

In an early study by Fagan et al., CRP levels corresponded closely with clinical and pathological indices of relapse, remission and response to therapy in patients with CD [45]. These results were confirmed more recently from the Mayo clinic [46]. In CD patients, moderate-to-severe clinical activity (OR: 4.5; 95% CI: 1.1–18.3), active disease at colonoscopy (OR: 3.5; 95% CI: 1.4–8.9), and histologically severe inflammation (OR: 10.6; 95% CI: 1.1–104) were all significantly associated with CRP elevation. No differences in CRP levels at diagnosis were found between subgroups of patients with CD as defined according to the Vienna classification.

A simple biological score for prediction of short-term (12–18 months) relapse was created by the GETAID group in 2006 [47], based on the follow-up of 71 patients. CRP >20 mg/l and erythrocyte sedimentation rate >15 mm/h were regarded as a negative score, and values under these limits were regarded as a positive score. The relative risk of short-term relapse for patients with a positive dual score compared with those with negative scores was 8 (95% CI: 2.8–22.9) with a high sensitivity (89%) and low specificity (43%). A further Swiss study also showed CRP to be the second-best marker after calprotectin for identifying patients with active endoscopic disease [48].

However, the predictive value of CRP in long-term prognostication is more questionable. A subanalysis of the ACCENT I trial observed that a significant association was observed between baseline CRP levels and long-term clinical remission [49]. Decreased CRP at week 14, during infliximab treatment, was associated with a higher probability of sustained response (56.6% of patients with CRP <0.5 mg/dl vs 37.2% with higher CRP, p = 0.005) or remission (p = 0.052). No optimal cutoff value of CRP was determined.

A nationwide observational Hungarian study observed partly similar results in adalimumab-treated patients [50]. In this patient cohort, in a logistic-regression model, clinical efficacy of treatment and CRP at week 12, need for combined immunosuppression at induction, shorter disease duration and smoking were identified as independent predictors for 12-month clinical outcome. CRP at week 12, clinical remission at week 24 and nonsmoking status were associated with endoscopic improvement. Of note, authors used a higher upper limit of normal CRP (10 mg/dl) [50].

A significant association was also reported between CRP level at diagnosis and long-term risk of surgery in CD patients with terminal ileitis. The risk was increased when CRP levels were above 53 mg/l in this subgroup (OR: 6; 95% CI: 1.1–31.9; p = 0.03) in a Norwegian cohort [51]. In addition, high CRP (>20 mg/l) was found to be an independent predictor for relapse after AZA withdrawal in patients on AZA therapy for >42 months [52].

Of note, however, due to unknown reasons, a significant proportion of patients (~30%) do not mount a CRP response despite active disease. In these patients, CRP negativity is a constant finding in active disease at diagnosis and during follow-up [53]. Therefore, the accuracy of CRP may be increased by patient selection. In a referral study, active disease later during follow-up was more effectively identified by CRP in patients with an elevated high-sensitivity CRP (hs-CRP) at diagnosis (area under the curve: 0.92, cutoff: 10.3 mg/l). In addition, hs-CRP was an independent predictor of three- (p = 0.007) or 12-month (p = 0.001) clinical relapse for patients in remission who had an elevated hs-CRP at diagnosis. Thus, a tailored treatment strategy is appropriate, but monitoring IBD patients must be individualized based on disease phenotype and certain markers (CRP). Unfortunately, most of the previous studies assessed the accuracy of CRP in IBD cohorts without a stratification based on the initial CRP; therefore, confirmation of the aforementioned findings on the importance of patient stratification based on the initial CRP value is urgently awaited.

Calprotectin

Calprotectin is one of the most promising markers in identifying active inflammation in the gut. It is a calcium- and zinc-binding protein accounting for >50% of granulocyte cytosolic protein. The presence of calprotectin in feces can, therefore, be seen as directly proportional to neutrophil migration to the GI tract. Its fecal measurement is considered an accurate inflammatory marker of the GI tract, irrespective of etiology. Fecal calprotectin is a stable marker (>1 week at room temperature) and is resistant to degradation.

Besides being accurate in identifying active disease in both adults [54] and children [55] with IBD, one of the first publications to address the issue found fecal calprotectin valuable for predicting relapse in CD. In a study by Tibble et al., calprotectin levels of higher than 50 µg/g predicted a 13-fold increased risk for clinical relapse [56], and was confirmed in other studies using different cutoff values (150 µg/g) [57]. Of note, an optimal cutoff value was not yet identified. Although sensitivity was high for both CD (87%) and UC (89%), specificity was much lower in the case of CD (43%) compared with UC (82%).

García-Sánchez et al. observed a greater predictive value of fecal calprotectin regarding relapse of both CD and UC with colon involvement and inflammatory pattern, compared with ileal CD [58]. Using a cutoff value for calprotectin of 200 µg/g, relapse rates were fourfold higher than those patients with lower concentrations. In UC, calprotectin >120 µg/g was associated with a sixfold increase in the probability of disease exacerbation with 80% sensitivity and 60% specificity. The ability to predict relapse was lower in patients with ileal disease. However, some studies reported that the best discriminative accuracy exists during the first 3 months of follow-up, suggesting that calprotectin is more of a short-term marker of disease activity [59].

In postsurgical CD patients, calprotectin, at a cutoff value of 200 mg/l, 3 months postsurgery, was useful in predicting endoscopic postsurgical recurrence in asymptomatic patients with 63% sensitivity and 75% specificity [60]. Of note, in a study by Schoepfer et al., fecal calprotectin was the most accurate marker for the prediction of endoscopic severity in the colon of patients with CD [48].

A recent meta-analysis by Mao et al. summarized data regarding the value of calprotectin in predicting IBD relapse [61]. Data from 672 IBD patients (318 UC and 354 CD) were analyzed. The pooled sensitivity and specificity of fecal calprotectin for predicting relapse of quiescent IBD was 78% (95% CI: 72–83) and 73% (95% CI: 68–77), respectively. The utility of calprotectin for predicting relapse was observed to be similar in UC and CD. Despite the fact that isolated small bowel CD was not assessed due to insufficiency of available data, evaluating the data of enrolled CD patients, fecal calprotectin was shown to be more accurate in ileocolonic and colonic CD.

It is thus difficult to define cutoff values based on these studies. In addition to serum markers, fecal calprotectin also correlates well with endoscopic and histological activity in patients with UC and CD, and elevated calprotectin levels normalize once inflammation has resolved [48,62,63].

Serology markers

Serological markers are typically long-term markers and may be associated with complicated disease phenotype [64]. They may play only a marginal role in the diagnostic workup. However, whether a high titer of these antimicrobial markers indicates inflammation only, or whether they have an active role in the perpetuation of the inflammatory cascade, has not been clarified. Recent studies aimed to evaluate the role of serological markers in predicting the long-term course of IBD.

A conventional anti-Saccharomyces cerevisiae antibody (ASCA) positivity and perinuclear antineutrophil cytoplasmic antibody-negative phenotype was reported to be associated with small bowel involvement (with or without colonic disease), which is more typical than pure colonic disease (60–80 vs 30–45%) [65,66]. ASCAs have been associated with stricturing and penetrating disease and higher risk of small bowel resection [66,67]. An association between the presence of anti-outer membrane porin C (OmpC) in adult CD patients with penetrating disease has been reported [64], whereas in children, anti-OmpC has been associated with both the penetrating and stenosing forms [68]. A putative association exists between antibody positivity and more aggressive disease, including disease requiring surgical intervention. In adult CD patients, anti-I2, much like ASCA and OmpC, is apparently associated with increased risk for complications. Moreover, it is an independent risk factor for stenosing disease and need for surgical intervention. Anti-flagellin (anti-CBir1) antibody was also associated with ileal involvement in adult CD patients independently from other serological markers, and with predisposition for the development of both stenosing and penetrating forms [69]. This association was even more pronounced in young children with CD (age: 0–7 years) [70]. Finally, our group observed an association between the presence of pancreatic autoantibodies and perforating, perianal disease and extraintestinal manifestations [71].

The magnitude of serologic response was assessed by the number of antibody-positive patients or the sum of antibody titers. In CD, a positive correlation exists between the severity of the disease course and these markers [66]. The magnitude of immune response to microbial antigens, as indicated by ASCA, anti-OmpC, anti-I2 and anti-CBir1, was significantly associated with a more aggressive disease phenotype, according to prospective pediatric cohort studies by Dubinsky et al. [68]. As compared with seronegative patients, individuals who were seropositive for all four antimicrobial antibodies had an elevated risk of developing stricturing or penetrating CD, recently confirmed by the same group in a much larger IBD population [72].

The more newly developed antiglycan antibodies (including anti-laminarin and anti-chitin markers) provide other means of prognostication, as the magnitude of immune response as measured by these markers was also associated with age-at-onset, ileal involvement, stricturing or penetrating phenotype and risk for surgery [73,74]. Hungarian authors found that gASCA antibodies against a mannan epitope of S. cerevisiae, IgG and ASCA IgG were of comparable value in determining CD phenotype [74]. Nevertheless, a partially complementary role for the two tests was reported. The differentiation between colon-only CD and UC was also better [73,74].

Interestingly, serum ASCA levels remain stable after curative intestinal resection in CD [75], indicating the persistence of both the stimulus and immunological mechanisms operative in the production of ASCA even after complete surgical resection of macroscopically inflamed intestinal tissue, or alternatively indicating that longer time is needed for the loss of antibody response as suggested by the data from the celiac literature [76]. Similarly in a study by Rieder et al., it was observed that a variation in titer, but not marker positivity, was reported for antiglycan antibodies in medically or surgically induced remission [77]. Comparable findings were reported from the pediatric CD cohort from the same group [78].

Genetic markers

Genetic markers are also associated with disease phenotype and long-term evolution, but their value in everyday clinical practice is limited at the moment. NOD2/CARD15 on chromosome 16 in the IBD1 region has emerged as one of the most important candidate genes for CD, and has stimulated further research into the area of novel genetic determinants for IBD [79]. Phenotype–genotype associations were also reported. The three common NOD2/CARD15 mutations were reported to be associated with ileal disease and fibrostenosing behavior and need for surgery. On the contrary, in colonic and fistulizing disease, they were relatively less frequent [80,81]. IRGM variants were also reported to be associated with increased need for surgery in ileocolonic CD patients in a very recent study [82]. However, many controversial findings exist.

Recently, Weersma et al. performed a more detailed genotype–phenotype analysis using both novel markers (e.g., ATG16L1, IL23R) and earlier genetic markers (NOD2, IBD5 and DLG5) [83]. In this study, patients with CD with a more severe disease course, surgeries or an age at onset below 40 years, had more risk-associated alleles compared with nonstricturing, nonpenetrating behavior (p = 0.0008), no need for surgery (p = 0.02) or age at onset greater than 40 years (p = 0.028). However, with longer disease duration, the predictive potential of genetic factors became nonsignificant, confirming that other factors such as medical therapy and disease phenotype at diagnosis, among others, may contribute to the long-term progression of disease phenotype. A characteristic genetic background was also reported for early-onset IBD, thus confirming the importance of age at onset [84]. In concordance with these findings, a recent study reported an association between the nonsynonymous SNP (rs2302685; Ile1062Val) of another crucial Wnt factor, the coreceptor LRP6 and early-onset ileal CD (OR: 1.8; p = 0.00034. For homozygous carriers: OR: 4.1; p = 0.00004) and additionally with penetrating ileal CD behavior (OR: 1.3; p = 0.00917) [85]. By contrast, it was not linked to adult onset ileal CD, colonic CD or UC.

In a landmark study of new concept-based complex modeling, the importance of both genetic and clinical variables in a complex analysis assessing the complete follow-up period was assessed [86]. In summary, genetic factors were identified as independent predictors for some outcomes, for example, homozygosity for the rs1363670 G-allele in a gene encoding a hypothetical protein near the IL12B gene was associated with stricturing disease behavior, with shorter time to strictures, or male patients carrying at least one rs12704036 T-allele in a gene desert had the shortest time to nonperianal fistula. However, much more research is needed before the routine use of genetic markers can be recommended in the everyday clinical practice.

Finally, Lee et al. determined the transcriptional profile of circulating T cells isolated from patients with CD and UC [87]. Analogous CD8⁺ T-cell transcriptional signatures were identified that divided IBD patients into two otherwise indistinguishable subgroups with very different disease courses. A more aggressive disease course was experienced in the subgroup defined by elevated expression of genes involved in pathways previously associated with prognosis in autoimmune diseases.

Expert commentary & five-year view

Clinical presentation at diagnosis and disease course of CD remains variable. Unfortunately, the majority of patients with CD still develop a stricturing or perforating complication with a subsequent need for surgery during their disease course. Since timely introduction of immunomodulators or biologicals might be justified in patients at risk for disease progression, it is important to identify these patients as soon as possible.

Of note, patient management and monitoring has already changed in the past decade, and results from randomized controlled trials and long-term outcomes from inception cohorts have contributed significantly to our understanding. In the past few years, evidence is accumulating in support of a change in the natural history of the disease associated with the advent of biologicals and tailored treatment strategy. We have learned much about complex patient monitoring (see Table 1). Armed with this knowledge, we identified the importance of treatment goals beyond symptomatic control, including MH and normalization of biomarkers to be able to achieve less flares, less hospitalizations and ultimately less surgeries. We changed our management and treatment paradigms from step-up top-down approach to tailored treatment plan with tight control, where complex evaluation of clinical, endoscopic and molecular markers plays a very important part of patient monitoring.

The search for clinical, laboratory and molecular markers to define and predict disease outcome has moved forward rapidly. However, many questions remain unanswered. Limitations include the lack of uniform definitions for endoscopic improvement or healing or differences in cutoff values and the predictive potential of new molecular markers. A better definition of some short- and long-term outcomes is also needed. Moreover, it is currently not possible to predict a favorable disease course, as there is a paucity of data regarding this. This would urgently be needed to avoid overmedication and treatment-associated side effects. Of note, an ultimate definition of poor prognosis phenotype is not possible. Important clinical factors include ileal involvement, perianal disease, young age at onset and probably serology positivity. However, the relative importance of the above factors has to be evaluated on a case-by-case basis.

In addition, although the concept of ‘tight control’ is tempting, a word of caution is necessary, since it did not lead to superior outcomes in other chronic diseases (e.g., diabetes) [88]. On the contrary, frequent, invasive evaluation may potentially be associated with significant risks. Therefore, further research should be encouraged.

Over the next 5 years, we anticipate that results from hypothesis-driven randomized controlled trials will become available (e.g., CALM) that hopefully can clarify the clinical value of intensive patient control (including fecal, laboratory markers and endoscopic evaluation) in orchestrating therapeutic decisions, and risk–benefit evaluations will also be needed.

Nevertheless, the complex clinical and endoscopic evaluation, with fecal, serological and routine laboratory tests, as well as appropriate genetic testing is recommended. The ultimate goal is to identify individual patient profiles at the time of diagnosis that will allow us to choose the most appropriate management in terms of therapy, intensity of follow-up, and frequency of different investigations.

Table 1. Possible use of predictors for long- and short-term disease course in Crohn’s disease.

Marker name	Clinical outcome
Clinical markers
Young age at onset (pediatric or <40 years)	Disabling disease, surgery
Small bowel disease
Stricturing
Perianal disease
Weight loss >5 kg
Steroid need for the first flare at diagnosis
Early immunosuppression and/or biological therapy (protective?)
Endoscopy markers
Complete or partial mucosal healing (protective) according to CDEIS or SES-CD	Clinical flares, hospitalization and surgery
Biomarkers
Laboratory markers	Clinical flares, endoscopic activity, surgery?
CRP
ESR
Calprotectin
Serology markers	Complicated disease, surgery
ASCA, pANCA, glycans
Genetic markers NOD2/CARD15	Disease location/behavior/surgery in CD
TPMT	Azathioprine toxicity

ASCA: Anti-Saccharomyces cerevisiae antibody; CD: Crohn’s disease; CDEIS: Crohn’s Disease Endoscopic Index of Severity; ESR: Erythrocyte sedimentation rate; pANCA: Perinuclear antineutrophil cytoplasmic antibody; SES-CD: Simple endoscopic score for Crohn’s disease; TPMT: Thiopurine S-methyltransferase.

Key issues

• • Clinical presentation at diagnosis and disease course of Crohn’s disease is heterogeneous and variable over time.

• • The majority of patients with Crohn’s disease will develop a stricturing or perforating complication with a subsequent need for surgery during follow-up.

• • Adequate evaluation of clinical phenotype is of utmost importance.

• • An objective confirmation of disease activity is recommended beyond clinical symptoms.

• • A complex evaluation of clinical, laboratory and endoscopic markers is needed to adequately identify patients with active disease or at risk for disease progression.

• • Patients with young age at onset, small bowel disease, perianal lesions, deep ulceration at endoscopy and early need for steroids are at risk for developing disabling disease.

• • Serology (e.g., anti-Saccharomyces cerevisiae antibody, glycans) or genetic (e.g., NOD2/CARD15) markers may be of additional value for predicting the long-term disease course.

• • Additional research is needed to prove the superiority of the tight control concept.

References

• Lakatos PL. Recent trends in the epidemiology of inflammatory bowel diseases: up or down? World J. Gastroenterol. 12(38), 6102–6108 (2006).
   PubMed Web of Science ®Google Scholar
• Molodecky NA, Soon IS, Rabi DM et al. Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. Gastroenterology 142(1), 46–54.e42; quiz e30 (2012).
   PubMed Web of Science ®Google Scholar
• Wilson J, Hair C, Knight R et al. High incidence of inflammatory bowel disease in Australia: a prospective population-based Australian incidence study. Inflamm. Bowel Dis. 16(9), 1550–1556 (2010).
   PubMed Web of Science ®Google Scholar
• Cosnes J, Carbonnel F, Beaugerie L, Le Quintrec Y, Gendre JP. Effects of cigarette smoking on the long-term course of Crohn’s disease. Gastroenterology 110(2), 424–431 (1996).
   PubMed Web of Science ®Google Scholar
• Benchimol EI, Fortinsky KJ, Gozdyra P, Van den Heuvel M, Van Limbergen J, Griffiths AM. Epidemiology of pediatric inflammatory bowel disease: a systematic review of international trends. Inflamm. Bowel Dis. 17(1), 423–439 (2011).
   PubMed Web of Science ®Google Scholar
• Abramson O, Durant M, Mow W et al. Incidence, prevalence, and time trends of pediatric inflammatory bowel disease in northern California, 1996 to 2006. J. Pediatr. 157(2), 233–239.e1 (2010).
   PubMed Web of Science ®Google Scholar
• Tarrant KM, Barclay ML, Frampton CM, Gearry RB. Perianal disease predicts changes in Crohn’s disease phenotype – results of a population-based study of inflammatory bowel disease phenotype. Am. J. Gastroenterol. 103(12), 3082–3093 (2008).
   PubMed Web of Science ®Google Scholar
• Gasche C, Scholmerich J, Brynskov J et al. A simple classification of Crohn’s disease: report of the Working Party for the World Congresses of Gastroenterology, Vienna 1998. Inflamm. Bowel Dis. 6(1), 8–15 (2000).
   PubMed Web of Science ®Google Scholar
• Silverberg MS, Satsangi J, Ahmad T et al. Toward an integrated clinical, molecular and serological classification of inflammatory bowel disease: report of a Working Party of the 2005 Montreal World Congress of Gastroenterology. Can. J. Gastroenterol. 19(Suppl. A), 5–36 (2005).
   PubMed Web of Science ®Google Scholar
• Louis E, Collard A, Oger AF, Degroote E, Aboul Nasr El Yafi FA, Belaiche J. Behaviour of Crohn’s disease according to the Vienna classification: changing pattern over the course of the disease. Gut 49(6), 777–782 (2001).
   PubMed Web of Science ®Google Scholar
• Solberg IC, Vatn MH, Høie O et al.; IBSEN Study Group. Clinical course in Crohn’s disease: results of a Norwegian population-based ten-year follow-up study. Clin. Gastroenterol. Hepatol. 5(12), 1430–1438 (2007).
   PubMed Web of Science ®Google Scholar
• Panaccione R, Hibi T, Peyrin-Biroulet L, Schreiber S. Implementing changes in clinical practice to improve the management of Crohn’s disease. J. Crohns. Colitis 6(Suppl. 2), S235–S242 (2012).
   Google Scholar
• Beaugerie L, Seksik P, Nion-Larmurier I, Gendre JP, Cosnes J. Predictors of Crohn’s disease. Gastroenterology 130(3), 650–656 (2006).
   PubMed Web of Science ®Google Scholar
• Vernier-Massouille G, Balde M, Salleron J et al. Natural history of pediatric Crohn’s disease: a population-based cohort study. Gastroenterology 135(4), 1106–1113 (2008).
   PubMed Web of Science ®Google Scholar
• Loly C, Belaiche J, Louis E. Predictors of severe Crohn’s disease. Scand. J. Gastroenterol. 43(8), 948–954 (2008).
   PubMed Web of Science ®Google Scholar
• Munkholm P, Langholz E, Davidsen M, Binder V. Frequency of glucocorticoid resistance and dependency in Crohn’s disease. Gut 35(3), 360–362 (1994).
   PubMed Web of Science ®Google Scholar
• Faubion WA Jr, Loftus EV Jr, Harmsen WS, Zinsmeister AR, Sandborn WJ. The natural history of corticosteroid therapy for inflammatory bowel disease: a population-based study. Gastroenterology 121(2), 255–260 (2001).
   PubMed Web of Science ®Google Scholar
• D’Haens G, Geboes K, Ponette E, Penninckx F, Rutgeerts P. Healing of severe recurrent ileitis with azathioprine therapy in patients with Crohn’s disease. Gastroenterology 112(5), 1475–1481 (1997).
   PubMed Web of Science ®Google Scholar
• D’Haens G, Geboes K, Rutgeerts P. Endoscopic and histologic healing of Crohn’s (ileo-) colitis with azathioprine. Gastrointest. Endosc. 50(5), 667–671 (1999).
   PubMed Web of Science ®Google Scholar
• Lakatos PL, Golovics PA, David G et al. Has there been a change in the natural history of Crohn’s disease? Surgical rates and medical management in a population-based inception cohort from western Hungary between 1977–2009. Am. J. Gastroenterol. 107(4), 579–588 (2012).
   PubMed Web of Science ®Google Scholar
• Ramadas AV, Gunesh S, Thomas GA, Williams GT, Hawthorne AB. Natural history of Crohn’s disease in a population-based cohort from Cardiff (1986–2003): a study of changes in medical treatment and surgical resection rates. Gut 59(9), 1200–1206 (2010).
   PubMed Web of Science ®Google Scholar
• Lakatos PL, Czegledi Z, Szamosi T et al. Perianal disease, small bowel disease, smoking, prior steroid or early azathioprine/biological therapy are predictors of disease behavior change in patients with Crohn’s disease. World J. Gastroenterol. 15(28), 3504–3510 (2009).
   PubMed Web of Science ®Google Scholar
• Szamosi T, Banai J, Lakatos L et al. Early azathioprine/biological therapy is associated with decreased risk for first surgery and delays time to surgery but not reoperation in both smokers and nonsmokers with Crohn’s disease, while smoking decreases the risk of colectomy in ulcerative colitis. Eur. J. Gastroenterol. Hepatol. 22(7), 872–879 (2010).
   PubMed Web of Science ®Google Scholar
• Markowitz J, Grancher K, Kohn N, Lesser M, Daum F. A multicenter trial of 6-mercaptopurine and prednisone in children with newly diagnosed Crohn’s disease. Gastroenterology 119(4), 895–902 (2000).
   PubMed Web of Science ®Google Scholar
• D’Haens G, Baert F, van Assche G et al.; Belgian Inflammatory Bowel Disease Research Group; North-Holland Gut Club. Early combined immunosuppression or conventional management in patients with newly diagnosed Crohn’s disease: an open randomised trial. Lancet 371(9613), 660–667 (2008).
   PubMed Web of Science ®Google Scholar
• Colombel JF, Sandborn WJ, Reinisch W et al.; SONIC Study Group. Infliximab, azathioprine, or combination therapy for Crohn’s disease. N. Engl. J. Med. 362(15), 1383–1395 (2010).
   PubMed Web of Science ®Google Scholar
• Mahid SS, Minor KS, Stevens PL, Galandiuk S. The role of smoking in Crohn’s disease as defined by clinical variables. Dig. Dis. Sci. 52(11), 2897–2903 (2007).
   PubMedGoogle Scholar
• Picco MF, Bayless TM. Tobacco consumption and disease duration are associated with fistulizing and stricturing behaviors in the first 8 years of Crohn’s disease. Am. J. Gastroenterol. 98(2), 363–368 (2003).
   PubMed Web of Science ®Google Scholar
• Lindberg E, Järnerot G, Huitfeldt B. Smoking in Crohn’s disease: effect on localisation and clinical course. Gut 33(6), 779–782 (1992).
   PubMed Web of Science ®Google Scholar
• Cosnes J. Tobacco and IBD: relevance in the understanding of disease mechanisms and clinical practice. Best Pract. Res. Clin. Gastroenterol. 18(3), 481–496 (2004).
   PubMed Web of Science ®Google Scholar
• Aldhous MC, Drummond HE, Anderson N, Smith LA, Arnott ID, Satsangi J. Does cigarette smoking influence the phenotype of Crohn’s disease? Analysis using the Montreal classification. Am. J. Gastroenterol. 102(3), 577–588 (2007).
   PubMed Web of Science ®Google Scholar
• Peyrin-Biroulet L, Ferrante M, Magro F et al.; Scientific Committee of the European Crohn’s and Colitis Organization. Results from the 2nd Scientific Workshop of the ECCO. I: impact of mucosal healing on the course of inflammatory bowel disease. J. Crohns. Colitis 5(5), 477–483 (2011).
   PubMed Web of Science ®Google Scholar
• Mary JY, Modigliani R. Development and validation of an endoscopic index of the severity for Crohn’s disease: a prospective multicentre study. Groupe d’Etudes Thérapeutiques des Affections Inflammatoires du Tube Digestif (GETAID). Gut 30(7), 983–989 (1989).
   PubMed Web of Science ®Google Scholar
• Cellier C, Sahmoud T, Froguel E et al. Correlations between clinical activity, endoscopic severity, and biological parameters in colonic or ileocolonic Crohn’s disease. A prospective multicentre study of 121 cases. The Groupe d’Etudes Thérapeutiques des Affections Inflammatoires Digestives. Gut 35(2), 231–235 (1994).
   PubMed Web of Science ®Google Scholar
• Daperno M, D’Haens G, Van Assche G et al. Development and validation of a new, simplified endoscopic activity score for Crohn’s disease: the SES-CD. Gastrointest. Endosc. 60(4), 505–512 (2004).
   PubMed Web of Science ®Google Scholar
• Daperno M, Castiglione F, de Ridder L et al.; Scientific Committee of the European Crohn’s and Colitis Organization. Results of the 2nd part Scientific Workshop of the ECCO. II: measures and markers of prediction to achieve, detect, and monitor intestinal healing in inflammatory bowel disease. J. Crohns. Colitis 5(5), 484–498 (2011).
   PubMed Web of Science ®Google Scholar
• Allez M, Lemann M, Bonnet J, Cattan P, Jian R, Modigliani R. Long term outcome of patients with active Crohn’s disease exhibiting extensive and deep ulcerations at colonoscopy. Am. J. Gastroenterol. 97(4), 947–953 (2002).
   PubMed Web of Science ®Google Scholar
• Frøslie KF, Jahnsen J, Moum BA, Vatn MH; IBSEN Group. Mucosal healing in inflammatory bowel disease: results from a Norwegian population-based cohort. Gastroenterology 133(2), 412–422 (2007).
   PubMed Web of Science ®Google Scholar
• Schnitzler F, Fidder H, Ferrante M et al. Long-term outcome of treatment with infliximab in 614 patients with Crohn’s disease: results from a single-centre cohort. Gut 58(4), 492–500 (2009).
   PubMed Web of Science ®Google Scholar
• Baert F, Moortgat L, Van Assche G et al.; Belgian Inflammatory Bowel Disease Research Group; North-Holland Gut Club. Mucosal healing predicts sustained clinical remission in patients with early-stage Crohn’s disease. Gastroenterology 138(2), 463–8; quiz e10 (2010).
   PubMed Web of Science ®Google Scholar
• Rutgeerts P, Diamond RH, Bala M et al. Scheduled maintenance treatment with infliximab is superior to episodic treatment for the healing of mucosal ulceration associated with Crohn’s disease. Gastrointest. Endosc. 63(3), 433–42; quiz 464 (2006).
   PubMed Web of Science ®Google Scholar
• Rutgeerts P, Van Assche G, Sandborn WJ et al.; EXTEND Investigators. Adalimumab induces and maintains mucosal healing in patients with Crohn’s disease: data from the EXTEND trial. Gastroenterology 142(5), 1102–1111.e2 (2012).
   PubMed Web of Science ®Google Scholar
• Louis E, Mary JY, Vernier-Massouille G et al.; Groupe D’etudes Thérapeutiques Des Affections Inflammatoires Digestives. Maintenance of remission among patients with Crohn’s disease on antimetabolite therapy after infliximab therapy is stopped. Gastroenterology 142(1), 63–70.e5; quiz e31 (2012).
   PubMed Web of Science ®Google Scholar
• Rutgeerts P, Geboes K, Vantrappen G, Beyls J, Kerremans R, Hiele M. Predictability of the postoperative course of Crohn’s disease. Gastroenterology 99(4), 956–963 (1990).
   PubMed Web of Science ®Google Scholar
• Fagan EA, Dyck RF, Maton PN et al. Serum levels of C-reactive protein in Crohn’s disease and ulcerative colitis. Eur. J. Clin. Invest. 12(4), 351–359 (1982).
   PubMed Web of Science ®Google Scholar
• Solem CA, Loftus EV Jr, Tremaine WJ, Harmsen WS, Zinsmeister AR, Sandborn WJ. Correlation of C-reactive protein with clinical, endoscopic, histologic, and radiographic activity in inflammatory bowel disease. Inflamm. Bowel Dis. 11(8), 707–712 (2005).
   PubMed Web of Science ®Google Scholar
• Consigny Y, Modigliani R, Colombel JF, Dupas JL, Lémann M, Mary JY; Groupe d’Etudes Thérapeutiques des Affections Inflammatoires Digestives. A simple biological score for predicting low risk of short-term relapse in Crohn’s disease. Inflamm. Bowel Dis. 12(7), 551–557 (2006).
   PubMed Web of Science ®Google Scholar
• Schoepfer AM, Beglinger C, Straumann A et al. Fecal calprotectin correlates more closely with the Simple Endoscopic Score for Crohn’s disease (SES-CD) than CRP, blood leukocytes, and the CDAI. Am. J. Gastroenterol. 105(1), 162–169 (2010).
   PubMed Web of Science ®Google Scholar
• Reinisch W, Wang Y, Oddens BJ, Link R. C-reactive protein, an indicator for maintained response or remission to infliximab in patients with Crohn’s disease: a post-hoc analysis from ACCENT I. Aliment. Pharmacol. Ther. 35(5), 568–576 (2012).
   PubMed Web of Science ®Google Scholar
• Kiss LS, Szamosi T, Molnar T et al.; Hungarian IBD Study Group. Early clinical remission and normalisation of CRP are the strongest predictors of efficacy, mucosal healing and dose escalation during the first year of adalimumab therapy in Crohn’s disease. Aliment. Pharmacol. Ther. 34(8), 911–922 (2011).
   PubMed Web of Science ®Google Scholar
• Henriksen M, Jahnsen J, Lygren I et al.; IBSEN Study Group. C-reactive protein: a predictive factor and marker of inflammation in inflammatory bowel disease. Results from a prospective population-based study. Gut 57(11), 1518–1523 (2008).
   PubMed Web of Science ®Google Scholar
• Lémann M, Mary JY, Colombel JF et al.; Groupe D’Etude Thérapeutique des Affections Inflammatoires du Tube Digestif. A randomized, double-blind, controlled withdrawal trial in Crohn’s disease patients in long-term remission on azathioprine. Gastroenterology 128(7), 1812–1818 (2005).
   PubMed Web of Science ®Google Scholar
• Kiss LS, Papp M, Lovasz BD et al. High-sensitivity C-reactive protein for identification of disease phenotype, active disease, and clinical relapses in Crohn’s disease: a marker for patient classification? Inflamm. Bowel Dis. 18(9), 1647–1654 (2012).
   PubMed Web of Science ®Google Scholar
• Langhorst J, Elsenbruch S, Koelzer J, Rueffer A, Michalsen A, Dobos GJ. Noninvasive markers in the assessment of intestinal inflammation in inflammatory bowel diseases: performance of fecal lactoferrin, calprotectin, and PMN-elastase, CRP, and clinical indices. Am. J. Gastroenterol. 103(1), 162–169 (2008).
   PubMed Web of Science ®Google Scholar
• Walkiewicz D, Werlin SL, Fish D, Scanlon M, Hanaway P, Kugathasan S. Fecal calprotectin is useful in predicting disease relapse in pediatric inflammatory bowel disease. Inflamm. Bowel Dis. 14(5), 669–673 (2008).
   PubMed Web of Science ®Google Scholar
• Tibble JA, Sigthorsson G, Bridger S, Fagerhol MK, Bjarnason I. Surrogate markers of intestinal inflammation are predictive of relapse in patients with inflammatory bowel disease. Gastroenterology 119(1), 15–22 (2000).
   PubMed Web of Science ®Google Scholar
• Costa F, Mumolo MG, Ceccarelli L et al. Calprotectin is a stronger predictive marker of relapse in ulcerative colitis than in Crohn’s disease. Gut 54(3), 364–368 (2005).
   PubMed Web of Science ®Google Scholar
• García-Sánchez V, Iglesias-Flores E, González R et al. Does fecal calprotectin predict relapse in patients with Crohn’s disease and ulcerative colitis? J. Crohns. Colitis 4(2), 144–152 (2010).
   PubMed Web of Science ®Google Scholar
• Gisbert JP, Bermejo F, Pérez-Calle JL et al. Fecal calprotectin and lactoferrin for the prediction of inflammatory bowel disease relapse. Inflamm. Bowel Dis. 15(8), 1190–1198 (2009).
   PubMed Web of Science ®Google Scholar
• Orlando A, Modesto I, Castiglione F et al. The role of calprotectin in predicting endoscopic post-surgical recurrence in asymptomatic Crohn’s disease: a comparison with ultrasound. Eur. Rev. Med. Pharmacol. Sci. 10(1), 17–22 (2006).
   PubMedGoogle Scholar
• Mao R, Xiao YL, Gao X et al. Fecal calprotectin in predicting relapse of inflammatory bowel diseases: a meta-analysis of prospective studies. Inflamm. Bowel Dis. 18(10), 1894–1899 (2012).
   PubMed Web of Science ®Google Scholar
• Røseth AG, Aadland E, Grzyb K. Normalization of faecal calprotectin: a predictor of mucosal healing in patients with inflammatory bowel disease. Scand. J. Gastroenterol. 39(10), 1017–1020 (2004).
   PubMed Web of Science ®Google Scholar
• D’Haens G, Ferrante M, Vermeire S et al. Fecal calprotectin is a surrogate marker for endoscopic lesions in inflammatory bowel disease. Inflamm. Bowel. Dis. 18(12), 2218–2224 (2012).
   PubMed Web of Science ®Google Scholar
• Lakatos PL, Papp M, Rieder F. Serologic antiglycan antibodies in inflammatory bowel disease. Am. J. Gastroenterol. 106(3), 406–412 (2011).
   PubMed Web of Science ®Google Scholar
• Vermeire S, Peeters M, Vlietinck R et al. Anti-Saccharomyces cerevisiae antibodies (ASCA), phenotypes of IBD, and intestinal permeability: a study in IBD families. Inflamm. Bowel Dis. 7(1), 8–15 (2001).
   PubMed Web of Science ®Google Scholar
• Papp M, Altorjay I, Norman GL et al.; Hungarian IBD Study Group. Seroreactivity to microbial components in Crohn’s disease is associated with ileal involvement, noninflammatory disease behavior and NOD2/CARD15 genotype, but not with risk for surgery in a Hungarian cohort of IBD patients. Inflamm. Bowel Dis. 13(8), 984–992 (2007).
   PubMed Web of Science ®Google Scholar
• Mow WS, Vasiliauskas EA, Lin YC et al. Association of antibody responses to microbial antigens and complications of small bowel Crohn’s disease. Gastroenterology 126(2), 414–424 (2004).
   PubMed Web of Science ®Google Scholar
• Dubinsky MC, Lin YC, Dutridge D et al.; Western Regional Pediatric IBD Research Alliance. Serum immune responses predict rapid disease progression among children with Crohn’s disease: immune responses predict disease progression. Am. J. Gastroenterol. 101(2), 360–367 (2006).
   PubMed Web of Science ®Google Scholar
• Papadakis KA, Yang H, Ippoliti A et al. Anti-flagellin (CBir1) phenotypic and genetic Crohn’s disease associations. Inflamm. Bowel Dis. 13(5), 524–530 (2007).
   PubMed Web of Science ®Google Scholar
• 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. 15(5), 714–719 (2009).
   PubMed Web of Science ®Google Scholar
• 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. 15(3), 365–374 (2009).
   PubMed Web of Science ®Google Scholar
• 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. 6(10), 1105–1111 (2008).
   PubMed Web of Science ®Google Scholar
• Rieder F, Schleder S, Wolf A et al. Association of the novel serologic anti-glycan antibodies anti-laminarin and anti-chitin with complicated Crohn’s disease behavior. Inflamm. Bowel Dis. 16(2), 263–274 (2010).
   PubMed Web of Science ®Google Scholar
• Papp M, Altorjay I, Dotan N et al.; Hungarian IBD Study Group. New serological markers for inflammatory bowel disease are associated with earlier age at onset, complicated disease behavior, risk for surgery, and NOD2/CARD15 genotype in a Hungarian IBD cohort. Am. J. Gastroenterol. 103(3), 665–681 (2008).
   PubMed Web of Science ®Google Scholar
• Eser A, Papay P, Primas C et al. The impact of intestinal resection on serum levels of anti-Saccharomyces cerevisiae antibodies (ASCA) in patients with Crohn’s disease. Aliment. Pharmacol. Ther. 35(2), 292–299 (2012).
   PubMed Web of Science ®Google Scholar
• Papp M, Foldi I, Altorjay I et al. Anti-microbial antibodies in celiac disease: trick or treat? World J. Gastroenterol. 15(31), 3891–3900 (2009).
   Google Scholar
• Rieder F, Lopez R, Franke A et al. Characterization of changes in serum anti-glycan antibodies in Crohn’s disease – a longitudinal analysis. PLoS ONE 6(5), e18172 (2011).
   PubMed Web of Science ®Google Scholar
• Rieder F, Hahn P, Finsterhoelzl L et al. Clinical utility of anti-glycan antibodies in pediatric Crohn’s disease in comparison with an adult cohort. Inflamm. Bowel Dis. 18(7), 1221–1231 (2012).
   PubMed Web of Science ®Google Scholar
• Hampe J, Cuthbert A, Croucher PJ et al. Association between insertion mutation in NOD2 gene and Crohn’s disease in German and British populations. Lancet 357(9272), 1925–1928 (2001).
   PubMed Web of Science ®Google Scholar
• Ahmad T, Armuzzi A, Bunce M et al. The molecular classification of the clinical manifestations of Crohn’s disease. Gastroenterology 122(4), 854–866 (2002).
   PubMed Web of Science ®Google Scholar
• Lakatos PL, Lakatos L, Szalay F et al.; Hungarian IBD Study Group. Toll-like receptor 4 and NOD2/CARD15 mutations in Hungarian patients with Crohn’s disease: phenotype–genotype correlations. World J. Gastroenterol. 11(10), 1489–1495 (2005).
   PubMed Web of Science ®Google Scholar
• Sehgal R, Berg A, Polinski JI et al. Mutations in IRGM are associated with more frequent need for surgery in patients with ileocolonic Crohn’s disease. Dis. Colon Rectum 55(2), 115–121 (2012).
   PubMed Web of Science ®Google Scholar
• Weersma RK, Stokkers PC, van Bodegraven AA et al.; Dutch Initiative on Crohn and Colitis (ICC). Molecular prediction of disease risk and severity in a large Dutch Crohn’s disease cohort. Gut 58(3), 388–395 (2009).
   PubMed Web of Science ®Google Scholar
• Imielinski M, Baldassano RN, Griffiths A et al.; Western Regional Alliance for Pediatric IBD; International IBD Genetics Consortium; NIDDK IBD Genetics Consortium; Belgian-French IBD Consortium; Wellcome Trust Case Control Consortium. Common variants at five new loci associated with early-onset inflammatory bowel disease. Nat. Genet. 41(12), 1335–1340 (2009).
   PubMed Web of Science ®Google Scholar
• Koslowski MJ, Teltschik Z, Beisner J et al. Association of a functional variant in the Wnt co-receptor LRP6 with early onset ileal Crohn’s disease. PLoS Genet. 8(2), e1002523 (2012).
   PubMed Web of Science ®Google Scholar
• Henckaerts L, Van Steen K, Verstreken I et al. Genetic risk profiling and prediction of disease course in Crohn’s disease patients. Clin. Gastroenterol. Hepatol. 7(9), 972–980.e2 (2009).
   PubMed Web of Science ®Google Scholar
• Lee JC, Lyons PA, McKinney EF et al. Gene expression profiling of CD8+ T cells predicts prognosis in patients with Crohn disease and ulcerative colitis. J. Clin. Invest. 121(10), 4170–4179 (2011).
   PubMed Web of Science ®Google Scholar
• Wiener RS, Wiener DC, Larson RJ. Benefits and risks of tight glucose control in critically ill adults: a meta-analysis. JAMA 300(8), 933–944 (2008).
   PubMed Web of Science ®Google Scholar

Recommendations for identifying Crohn’s disease patients with poor prognosis

To obtain credit, you should first read the journal article. After reading the article, you should be able to answer the following, related, multiple-choice questions. To complete the questions (with a minimum 70% passing score) and earn continuing medical education (CME) credit, please go to www.medscape.org/journal/expertimmunology. Credit cannot be obtained for tests completed on paper, although you may use the worksheet below to keep a record of your answers. You must be a registered user on Medscape.org. If you are not registered on Medscape.org, please click on the New Users: Free Registration link on the left hand side of the website to register. Only one answer is correct for each question. Once you successfully answer all post-test questions you will be able to view and/or print your certificate. For questions regarding the content of this activity, contact the accredited provider, [email protected]. For technical assistance, contact [email protected]. American Medical Association's Physician's Recognition Award (AMA PRA) credits are accepted in the US as evidence of participation in CME activities. For further information on this award, please refer to http://www.ama-assn.org/ama/pub/category/2922.html. The AMA has determined that physicians not licensed in the USA who participate in this CME activity are eligible for AMA PRA Category 1 Credits™. Through agreements that the AMA has made with agencies in some countries, AMA PRA credit may be acceptable as evidence of participation in CME activities. If you are not licensed in the USA, please complete the questions online, print the AMA PRA CME credit certificate and present it to your national medical association for review.

Activity Evaluation: Where 1 is strongly disagree and 5 is strongly agree

	1	2	3	4	5
1. The activity supported the learning objectives.
2. The material was organized clearly for learning to occur.
3. The content learned from this activity will impact my practice.
4. The activity was presented objectively and free of commercial bias.

1. You are seeing a 35-year-old woman with a recent diagnosis of Crohn’s disease, and she has multiple questions about her condition. Which of the following statements regarding the classification and prognosis of Crohn’s disease is most accurate?

• □ A The Vienna classification requires the diagnosis of Crohn’s disease be made by age 55 years

• □ B The Vienna classification divides Crohn’s disease into 6 categories

• □ C Disease location remains relatively constant in Crohn’s disease

• □ D Crohn disease invariably becomes more severe over time

2. The patient wants to better understand the prognosis of her Crohn’s disease. Which of the following clinical factors is most significant in promoting a worse prognosis of Crohn’s disease?

• □ A Early treatment with corticosteroids

• □ B Early treatment with azathioprine

• □ C Onset of disease over the age of 40 years

• □ D Alcohol use

3. What should you consider regarding endoscopic signs and the prognosis of Crohn’s disease?

• □ A The Crohn’s Disease Endoscopic Index of Severity (CDEIS) is the closest correlate with the clinical severity of Crohn’s disease

• □ B The degree of inflammation is the most critical factor in endoscopic severity scores

• □ C There is now good agreement on the definition of mucosal healing

• □ D Mucosal healing is associated with fewer hospitalizations and less surgery

3. What should you consider regarding biomarkers as you evaluate this patient?

• □ A C-reactive protein (CRP) is universally elevated in cases of Crohn’s disease

• □ B Fecal levels of calprotectin reflect the degree of neutrophil migration to the gastrointestinal tract

• □ C Calprotectin levels remain high even after Crohn’s disease improves

• □ D Anti-Saccharomyces cerevisiae antibody (ASCA) is associated with better clinical outcomes in Crohn’s disease