Crohn’s Cartography: Mapping Disease Patterns and Trajectories Using the Lémann Index—Are We Finding Our Way?

Over a lifetime, an individual with Crohn’s disease may accumulate a broad assortment of physical insults that contribute to worsening health including gastrointestinal injuries, infections, and surgical interventions. A prolonged disease course often snowballs over time, provoking pain, diarrhea, fatigue, and other symptoms that are not necessarily associated with the characteristic intestinal inflammation of Crohn’s disease. This long-term, collective assault can result in decreased gastrointestinal function and increased chronic morbidity. Quantifying the overall impact of Crohn’s disease in a clinically useful way remains a challenge. Short-term measures of disease activity, such as the Crohn’s Disease Activity Index or the Harvey Bradshaw Index, focus on immediate symptoms connected largely to inflammation but fail to capture cumulative disease burden. Desirable and basic characteristics for measuring longer-term trajectories in Crohn’s disease include instruments with: (1) ease of use, (2) adaptability to account for individual variation and disease heterogeneity, (3) summarizable scoring systems that allow for meaningful comparisons among individuals, (4) capacity to capture responsiveness to change in clinical conditions beyond immediate measures of inflammatory activity, and (5) clinical utility as a prognostic tool. The creation of the Lémann Index, named in memory of Dr Marc Lémann—a renowned inflammatory bowel disease (IBD) researcher and clinician—reflects a recent effort to develop a metric for assessing long-term damage and disability in Crohn’s disease. Crohn’s disease generally begins as an inflammatory process that can lead to destructive and potentially irreversible organ damage and disease-related complications; these include strictures, fistula, and/or abscesses that often require surgical intervention, the ultimate manifestation of bowel injury. Consequences of disease progression related to inflammation, fibrosis, or surgery can adversely impact the quality of life in IBD patients and may precipitate decrements of functioning or disability.1–4 Efforts to organize patterns and quantify involvement in Crohn' disease have undergone considerable evolution. Our current classification of Crohn’s disease encompasses such features as disease location and behavior, with attention to disease progression, the latter of which is generally defined as an alteration from nonstricturing, nonpenetrating to stricturing, penetrating phenotype based on Vienna5 or Montreal6 classifications. Disease activity indexes can be used in conjunction with these classification schemes to evaluate fluctuations in inflammation-related symptoms. Variability in the presentation and clinical course of Crohn’s disease lends to the continued development of a scoring system such as the Lémann Index that aims to quantify the broader effect of disease on an individual over time. The Lémann Index, or Crohn’s Disease Digestive Damage Score, can be used to measure cumulative structural bowel damage (including stricturing lesions, penetrating lesions, and prior surgical resection) within the entire gastrointestinal tract and to monitor treatment effects over time.7 This may be particularly useful in striving toward the modern treatment paradigm of deep remission, a composite of clinical and biologic quiescence and endoscopic mucosal healing.7–12 Identifying patients at high risk for rapid progression and anticipating disease trajectories based on the Lémann Index scoring scale may not only alter the natural history and phenotypic variability of Crohn’s disease but may also substantiate treatment goals to prevent collateral bowel damage and defer surgery. A prospective, multicenter, international cross-sectional study was undertaken to develop the Lémann Index and to determine its ability to measure cumulative structural bowel damage among 138 Crohn’s disease patients stratified for disease location (24, 115, 92 and 59 with upper tract, small bowel, colon/rectum, and anus locations, respectively) and duration (<2 y since diagnosis, 2 to 10 y since diagnosis, and >10 y since diagnosis). This study found good correlation between predicted Lémann indexes and investigator-based damage evaluations, with unbiased correlation coefficients of 0.85, 0.98, 0.90, and 0.82 for upper tract, small bowel, colon/rectum, and anus locations, respectively, and 0.84 globally. The Lémann Index appeared to increase with Crohn’s disease duration, from a mean score of 6.3 for disease duration <2 years to a mean score of 19.0 for disease duration >10 years.13 Subsequent studies have further investigated the Lémann Index in the context of its responsiveness to change over time. A retrospective cohort study of 221 patients diagnosed with Crohn’s disease from 2004 to 2011 found that almost two thirds of patients had significant bowel damage (defined as Lémann Index >2) at 2 to 10 years following diagnosis. Median Lémann Index scores increased significantly at each stage of evaluation compared with initial or previous values, from a measurement of 2.3 [interquartile range (IQR), 1.2 to 3.9] at first evaluation, to 3.5 (IQR, 1.2 to 8.6) at 2 to 5 years after diagnosis, and 8.3 (IQR, 1.2 to 12.1) at 5 to 10 years after diagnosis (P<0.0001). Factors associated with progressive bowel damage over time included high Lémann Index scores at initial evaluation, ongoing clinical disease activity, and intestinal resection.14 However, as intestinal resection is a component of the Lémann Index, the validity of using this measure as a predictor of bowel damage warrants further investigation. A retrospective observational study in a cohort of 30 patients with Crohn’s disease (involving the upper digestive tract in 6.6%, small bowel in 96.6%, colon in 16.6%, and anus in 6.6%), used the Lémann Index to assess the evolution of digestive tract damage at 2 time points separated by at least 12 months. At initial evaluation, the median disease duration was 7 years. During a median follow-up period of 23 months, the Lémann Index appeared to increase in 36.0% of patients, decrease in 16.0% of patients, and remain stable in 46.7% of patients. The increase in Lémann Index was significantly related to disease duration.15 There are no definitive recommendations on the appropriate time interval for assessing progressive bowel damage, although this study suggests that repeat digestive tract evaluations using the Lémann Index should be adequately spaced over time. Recent clinical studies have used the change in Lémann Index to investigate the impact of medical therapy on bowel damage progression in Crohn’s disease. A single-center study prospectively following 30 Crohn’s disease subjects who achieved clinical remission with anti-tumor necrosis factor (TNF) agents (infliximab, n=13; adalimumab, n=17) over a median of 32.5 months found that anti-TNF therapy contributed to the reversal of bowel damage as measured by the Lémann Index in 83% of subjects responding to anti-TNF agents and also significantly reduced Lémann Index at 1 year (P=0.007). Progressive bowel damage was experienced in 17% of subjects and was predictive for major abdominal surgery through the follow-up period [hazard ratio (HR), 0.19; P=0.005].16 A retrospective observational analysis performed to investigate the effect of various medical therapies on Lémann Index reduction in 88 Crohn’s disease subjects over a median follow-up period of 26 months revealed that anti-TNF monotherapy was associated with a significantly higher reduction in Lémann Index compared with azathioprine therapy or 5-aminosalicylic acid therapy (P<0.05).17 Change in Lémann Index was assessed in the context of surgery in a retrospective cohort analysis of 39 subjects who underwent intestinal resection for Crohn’s disease (excluding patients with active perianal disease) from 2007 to 2013. Patients were evaluated with endoscopy and magnetic resonance enterography within 6 and 12 months postoperatively at the same time point (±60 d) and reassessed every 12 to 18 months with the same examinations over a median follow-up of 29 months. Within 12 months of surgery, 53.8% of patients had an increase in the Lémann Index as determined by magnetic resonance enterography, and almost half (48.7%) of the patients demonstrated postoperative endoscopic disease recurrence as quantified by the Rutgeerts' score (scores of 3 to 4). Postoperative bowel wall thickening on imaging was found to be significantly associated with endoscopic recurrence [odds ratio (OR), 25.5; 95% confidence interval (CI), 4.3-151; P=0.0004], and the majority (84%) of patients with early endoscopic recurrence demonstrated a significant increase in the Lémann Index (P=0.0007). However, bowel damage measured by the Lémann Index did not significantly correlate with the Rutgeerts' score. Subjects demonstrating either an increase in Lémann Index alone or an increase in Lémann Index combined with endoscopic recurrence (Rutgeerts' score of 3 to 4) within 12 months of surgery were significantly more likely to experience clinical relapse over the follow-up period (HR, 0.0; 95% CI, 0.04-0.87; P=0.03 and HR, 0.03; 95% CI, 0.000-0.0051; P<0.0001, respectively); the latter combination did not predict further disease complications.18 In this edition of the Journal of Clinical Gastroenterology, Bhagya Rao and colleagues report their prospective observational experience from a tertiary IBD center using the change in Lémann Index (delta Lémann Index, DLI) to risk-stratify an independent cohort of Crohn’s disease patients into patterns of disease-related bowel damage and to further characterize each group’s clinical trajectory over a 5-year period using an analysis of disease-related characteristics, treatment, health care utilization, and quality of life. They included 363 Crohn’s disease patients seen in clinic at least yearly with appropriate 5-year follow-up data. The investigators calculated DLI as the change between final and baseline Lémann Index scores (L2 to L1, or the difference in Lémann Index scores between final and initial clinical encounters), using numeric results to distinguish among 3 patient groups based on progression of Crohn’s disease-related damage: those with (1) no change in Lémann Index (DLI=0); (2) improvement (DLI<0); or (3) deterioration (DLI>0). Lémann Index scoring was based on both endoscopic and cross-sectional imaging (magnetic resonance imaging) findings in 73% of cases (n=265), and the remaining 27% was based on endoscopic evaluation alone. The median interval between L1 and L2 was 42 months (IQR, 32 to 52). The cohort was predominantly female (57%) with a median age of 43 years (IQR, 33 to 55) and median Crohn’s disease duration of 12 years (IQR, 3 to 19). Almost 70% of the cohort had Crohn's disease-related surgical exposure before study inclusion, with greater than half of the cohort having had 2 or more procedures. During the study period, almost 40% of patients required operative Crohn’s disease management, and roughly 15% of these patients required 2 or more surgeries. The Lémann Index appeared to increase with disease duration, and a wide range of calculated DLI was noted (−22 to 47, median 0). Several patients in this cohort (48.2%) demonstrated clinical deterioration over 5 years (DLI>0), with significantly higher health care utilization (outpatient IBD clinic, emergency department, and inpatient encounters), Crohn's disease-related surgical exposures, and annual use of medications including steroids, narcotics, and anti-TNF agents when compared across study groups. These patients with progressive disease trajectories (DLI>0) also showed a significantly higher prevalence of penetrating (30.9%) and perianal (29.1%) disease and significantly higher C-reactive protein levels compared with patients showing no change in Lémann Index scores (DLI=0), the group with DLI>5 demonstrated significantly higher mean 5-year Harvey Bradshaw Index scores (4.1 vs. 3.2, P=0.006) and significantly lower mean 5-year Short Inflammatory Bowel Disease Questionnaire scores (48.5 vs. 54, P=0.006). Multivariate logistic regression analysis found independent significant correlations of DLI with perianal disease (OR, 2.7; 95% CI, 0.07-5.3; P=0.044), steroid use (OR, 1.2; 95% CI, 0.3-2.1; P=0.007), new Crohn's disease-related surgeries (OR, 5.3; 95% CI, 2.1-8.5; P=0.001), and IBD clinic visits (OR, 0.23; 95% CI 0.05-0.41; P=0.013). Overall, the authors supported their hypothesis that DLI could be used to stratify patients into Crohn’s disease trajectories, with worsening scores (DLI>0) portending a more aggressive clinical course, warranting more frequent use of medications (including steroids, biologics, and narcotics) and need for Crohn's disease-related surgical interventions with greater health care utilization and lower disease-specific health-related quality-of-life scores over time.19 The findings from this study, in conjunction with previous results, demonstrate that the change in Lémann Index may be used to risk-stratify and prognosticate the course of Crohn’s disease, although further studies are required to better incorporate the instrument into practical models. The Lémann Index may facilitate primary outcome measurements for disease-modification trials and can potentially be utilized in clinical practice and postoperative settings to facilitate targeted management strategies. Limitations to this approach include perceptions of the metric as burdensome to calculate, particularly outside of clinical research settings. The timing for determining a baseline Lémann Index measurement is indeterminate, and the ideal interval for serial Lémann Index assessments has not yet been defined. Furthermore, an objective definition of bowel damage using the Lémann Index has not been clearly established and must be validated. In addition, some components of the Lémann Index may need to be redefined over time. It is important to consider that structural bowel damage as a component of the Lémann Index is not necessarily immutable and may be reversed in the presence of effective therapy, as in cases of bowel wall thickening, ulceration, inflammatory strictures, or even fistula. Early aggressive therapy with biologic and/or immunomodulator therapy in altering the course of progressive bowel damage and surgery in Crohn’s disease20 is an important management concept and is currently not routinely accounted for in Lémann Index calculations. Additional studies are required to elucidate these issues, including large-scale, longitudinal clinical trials, sensitivity-to-change analyses, and validation studies addressing the change in Lémann Index as a therapeutic target for nonprogression in Crohn’s disease. This study by Bhagya Rao et al19 provides a positive next step toward incorporating the Lémann Index into clinical research settings. As we move from episodic to longitudinal care strategies in IBD, the Lémann Index may prove useful for mapping disease trajectories, identifying patients at high risk for rapid progression of intestinal injury, and determining the impact of various therapeutic approaches on long-term outcomes in Crohn’s disease. Overall, as a comprehensive and quantitative metric, the DLI coupled with disease-modifying treatment models may help to minimize collateral damage and defer surgery in Crohn’s disease by outlining the disease course, substantiating treatment goals, and optimizing medical therapy. Further validation studies and demonstration of sensitivity-to-change analyses are needed to advance and more broadly implement the Lémann Index into research and clinical practice.

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