Preventing Collateral Damage in Crohn’s Disease: The Lémann Index

Abstract

Crohn’s disease [CD] is a chronic progressive and destructive condition. Half of all CD patients will develop bowel damage at 10 years. As in rheumatic diseases, preventing the organ damage consequent to CD complications [fistula, abscess, and/or stricture] is emerging as a new therapeutic goal for these patients in clinical practice. This might be the only way to alter disease course, as surgery is often required for disease complications. Similar to the joint damage in rheumatoid arthritis, bowel damage has also emerged as a new endpoint in disease-modification trials such as the REACT trial. Recently, the Lemann Index [LI] has been developed to measure CD-related bowel damage, and to assess damage progression over time, in order to evaluate the impact of therapeutic strategies in terms of preventing bowel damage. While validation is pending, recent reports suggested that bowel damage is reversible by anti-tumour necrosis factor [TNF] therapy. The Lémann index may play a key role in CD management, and should be implemented in all upcoming disease-modification trials in CD.

1. Introduction

Crohn’s disease [CD] is a chronic progressive and destructive inflammatory bowel disease [IBD]. Gut inflammation is generally transmural, involving the small intestine and/or the colon. The chronic inflammatory pattern of the disease, which activates tissue-repairing mechanisms, can lead to irreversible and destructive bowel complications such as strictures, fistulas, or consequent abscesses,¹ often requiring surgery.² Moreover, perianal involvement of the disease can also cause structural and functional damage at that level. The organ damage consequent to CD complications and surgery is likely to progress during the course of the disease³ and, in some cases, can lead to disability.^4,5 Data from population-based cohorts show that up to 30% of patients have evidence of bowel damage at baseline, and half of the patients require surgery during 20 years since diagnosis, because of the presence of bowel damage. The risk of postoperative recurrence and consequent bowel damage after the first surgery is around 50% in the following 10 years, eventually leading to further surgical bowel resection^6,7

There is increasing evidence that the ultimate goal for the management of CD should go beyond remission of symptoms, to include mucosal healing.^8,9,10,11 Notably, the need for surgery has not changed in the past 30 years.¹² As surgery is not a cure for CD,¹³ current therapeutic strategies aim at preventing disease complications.¹⁴ These disease-modification-trials represent the next step in the field of CD clinical trials.

Thus, defining and assessing bowel damage using the Lémann Index represent key goals for therapeutic interventions in CD.

2. Lessons from Rheumatoid Arthritis

The concept of damage in immune-mediated disease has been clearly developed in rheumatology, particularly in rheumatoid arthritis [RA].¹⁵ Progressive joint damage [from erosions and space-narrowing to complete joint destruction] derived from chronic inflammation is a definite and easy-to-assess outcome that is independent of clinical activity.^{16,17,18,19,20,21,22,23,24,25} In particular, joint erosions and space narrowing [JSN] are the clearest signs of joint damage in RA.²⁵ These variables have been included in a simple damage score, the modified Sharp’s score. By combining and scoring the presence of erosions and JSN in 16 and 15 areas in the hands, respectively, and from 12 and 6 areas in the feet, respectively, rheumatologists can assess joint damage at each time point and its progression.¹⁵ The range of this score goes from 0 [no damage] to 448 [complete destruction].^15,26 Similar data are available in ankylosing spondylitis [AS], where findings like subchondral inflammation, and chronic changes, such as erosions and subchondral fatty marrow deposition, are prognostic for disease progression and spinal damage in the long term.¹⁹ Several trials show that treating early RA not only to achieve clinical remission, but also to block joint damage progression, is associated with reduced need for joint replacement.^{27,28,29,30,31,32,33} However, the impact of medications in reducing inflammation and preventing damage is less clear in AS than in RA.²⁴

3. The Need to Define Bowel Damage in Crohn’s Disease

The concept of bowel damage is not new in CD. Disease complications were first described by Crohn et al. in 1932, reporting 14 cases of regional ileitis requiring surgery for complicated disease.³⁴

Usually, a change in disease behaviour according to the Montreal³⁵ or Vienna classification³⁶ from non-stricturing, non-penetrating to stricturing or penetrating behaviour is considered disease progression.³⁷ Based on this outcome measure, longitudinal cohort studies show that from 30% up to 60% of subjects develop bowel damage in the long term.^38,39,40,41

Cosnes et al. showed that CD usually starts with a non-stricturing, non-penetrating pattern that evolves to stricturing and/or penetrating during the disease course. However in the same study, up to 20% of patients had stricturing or penetrating complications at onset.³⁸ Similar data were found by Thia et al. ⁶ in a prospective cohort of 306 patients with newly diagnosed CD, where 18.6% had stricturing or penetrating disease at diagnosis, but a further 66 subjects [26%] developed complications in the first 90 days following diagnosis. More recent data show that up to 50% of patients with newly diagnosed CD already have bowel damage at the time of diagnosis.⁴²

Interestingly, Cosnes et al. evaluated the post-surgical handicap index that was based on location and extent of resection at surgery, thus evaluating the impact of structural damage on the consequent functional damage,⁴³ finding a positive correlation between intestinal resection and functional impairment, defined as diarrhoea and malnutrition. More recently, Peyrin-Biroulet et al. ³⁷ defined bowel damage as the presence of any fistula [including perianal fistulas], abscess, or stricture, defined as wall thickening and luminal narrowing with prestenotic dilatation with a diameter greater than the normal diameter of the small bowel or colon, assessed with imaging techniques such as computerised tomography [CT] or magnetic resonance imaging [MRI].

However, there has not been an international, validated index capable of measuring bowel damage in CD. Based on these results, the International Program to develop New Indexes in Crohn’s disease [IPNIC] group has recently included bowel surgery, disease extent, and presence of stricturing or penetrating disease to develop a quantitative index of bowel damage, the Lémann Index.^44,45

4. Quantifying Bowel Damage: the Lémann Index

The assessment of bowel damage needs a complex and integrated evaluation of the entire gastrointestinal tract. Endoscopy is able to assess inflammatory lesions and complications, such as strictures,^46,47 but it does not allow for evaluation of CD transmural involvement. Imaging techniques, such as CT and MRI, allow for evaluation of the bowel wall and extra-intestinal involvement [including fistulas and abscesses], as well as perianal disease.^{3,15,48,49,50,51} In particular, MRI shows 85% accuracy for disease complications and bowel damage when compared with surgical findings, and is highly reproducible [κ value 80%].⁵² More recently, there is increasing evidence that MRI can help discriminate inflammatory from fibrotic strictures, adding more information on CD-related irreversible structural damage.^53,54 However, studies evaluating the role of MRI in assessing long-term damage progression are lacking.

Since 2007, the IPNIC group, including 28 gastroenterologists from 15 countries, one surgeon, two radiologists, and one biostatistician, has been working on the development of the Crohn’s Disease Digestive Damage Score [CD₃S], called the Lémann Index.⁵⁵ They aim to build up a score able to measure cumulative digestive tissue damage, based on a comprehensive assessment of structural bowel damage, including stricturing lesions, penetrating lesions [fistulas and abscesses], and surgical resection or previous surgical procedures, such as stricturoplasty or intestinal diversion, and applicable to different CD settings, such as early or advanced disease, patients with or without history of surgery, or with different CD locations and extension. To build up the index, the entire gastrointestinal tract was divided into four organs [upper tract, small bowel, colon/rectum, and anus] and each organ was divided into different segments, scoring structuring/penetrating on a 4-degree scale [0–3], according to the severity of lesions [Table 1]. Subjects were stratified in each centre according to their present CD location and disease duration [< 2 years, 2–10 years, and 10 years] The study was conducted from August 2008 to December 2010, including 138 patients stratified for disease location [24, 115, 92, and 59 with upper tract, small bowel, colon/rectum, and anus CD location, respectively], and for disease duration [< 2 years since diagnosis, from 2 to 10 years, and > 10 years].⁴⁵ For each patient, bowel damage was scored globally on a linear visual analogue scale [VAS] and by single organ, by recording and scoring the presence of any stricturing or penetrating lesions and previous surgical procedures, according to their severity. The multivariate analysis defined coefficients both for severity [from grade 0 to grade 3] and location [upper tract, small bowel, colon, and anus]. Good correlation between the Lémann Index and the investigator-based damage assessment was found [0.85, 0.98, 0.90, 0.82 for upper tract, small bowel, colon/rectum, and anus, respectively], with 0.84 overall agreement.⁴⁵ Further validation and sensitivity-to-change assessment on the IPNIC cohort are planned in the near future.

Table 1.

Reversible and non-reversible parameters included in the Lémann Index.

Parameters	Reversible?
Stricturing lesions
No stricturing lesions	NA
Bowel wall thickening < 3 cm	Yes/No
Bowel wall thickening >3cm without upper dilatation	Yes/No
Frank stricture with upper dilatation	Yes/No
Penetrating lesions
No penetrating lesions	NA
Superficial ulcerations	Yes
Deep transmural ulceration	Yes
Phlegmon or any type of fistula	Yes/No
Surgical history
None	NA
By-pass diversion or stricturoplasty	No
Resection	No
Perianal lesions
None	NA
Simple fistula	Yes
Multiple fistulas or any type of abscess	Yes
Extensive anal and perianal suppuration, horseshoe abscess, or fistula[s] involving or extending above the elevator plate	Yes

NA, not applicable.

5. Responsiveness to Change of the Lémann Index

There have been a number of studies conducted recently assessing whether the Lémann Index is sensitive to changes over time, and to determine the utility of changes in the Lémann Index in CD patients^{56,57,58,59,60} [Table 2]. Gilletta et al. evaluated a retrospective cohort of 221 CD subjects, finding that > 50% of patients had substantial bowel damage [defined as a Lémann Index > 2.0] after 2–10 years since diagnosis. Elevated Lémann Index at first evaluation, as well as duration of clinical activity and intestinal resection, were associated with bowel damage over time⁵⁶ although intestinal resection is a part of the Lémann Index, so the validity of resection as a predictor of bowel damage, rather than part of it, needs to be clarified by further studies. Duveau et al. retrospectively assessed the variation in the Lémann score in 30 CD subjects,⁵⁷ finding that the Lémann Index increased in more than one-third of patients during a median follow-up period of 23 months. Moreover, the increase in the Lémann Index was significantly related to disease duration, suggesting that re-evaluations should be appropriately spaced, but no clear recommendation on the right time interval to assess bowel damage by the Lémann Index was indicated.

Table 2.

Summary of clinical studies based on the Lémann Index calculation.

Study reference	Study design	Study population	Primary outcome	Main results
Gilletta et al. 56	Retrospective cohort analysis	221 CD subjects up to 10 years FU	LI cut-off for damage	1.LI > 2.0 is associated with bowel damage 2.High LI at baseline, chronically active disease, intestinal resection were associated with BD progression over time
Duveau et al. 57	Retrospective cohort analysis	30 CD subjects	LI evolution over time [median time 23 months]	1/3 of subjects have BD progression over time
Fiorino et al. 58	Prospective cohort	30 CD subjects starting anti- TNF [median FU 32.5 months]	Efficacy of anti-TNF on BD progression	1.Anti-TNFs block BD in 83% of subjects. 2.BD progression is associated with higher risk for surgery 3.Cut-off for BD: 4.8 4.Cut-off for BD progression: > 0.3
Bodini et al. 59	Retrospective cohort analysis	88 CD subjects treated with anti-TNF, IMM, or 5-ASA Median FU 26 months	Efficacy of different therapies on LI reduction	Anti-TNFs were more effective than IMM and 5-ASA to reduce the LI overtime
Fiorino et al. 60	Retrospective cohort analysis	39 CD subjects followed up after surgical resection Median FU [29 months]	1.Correlation between Rutgeerts’ score and LI 2.Prognostic value of the LI in the postoperative setting	The LI does not correlate with the Rutgeerts’ score LI progression is associated to POR

CD, Crohn’s disease; FU, follow-up; TNF: tumour necrosis factor; BD, bowel damage; LI, Lémann Index; IMM, immunomodulators; 5-ASA, 5-aminosalycilic acid; POR: postoperative recurrence.

Fiorino et al. ⁵⁸ prospectively evaluated 30 subjects who achieved clinical remission with anti-TNF and were followed up prospectively for a median time of 32.5 months. They found that a Lémann Index of 4.8 was the cut-off value for bowel damage, and that an increase > 0.3 in the Lémann Index was associated with bowel damage progression. Anti-TNF therapy was effective in stopping bowel damage progression in 83% of subjects. Bowel damage progression assessed by the Lémann Index was found to be predictive for major surgery in the follow-up period (hazard ratio [HR] 0.19, p = 0.005).⁵⁸ These findings are similar to those from a retrospective observational cohort study by Bodini et al. that compared the reduction in the Lémann Index in subjects treated with anti-TNF, azathioprine, and 5-aminosalicylic acid [5-ASA] compounds. They found that anti-TNF therapy was associated with a significantly higher reduction in the Lémann Index than 5-ASA compounds or immunosuppressants.⁵⁹ In another retrospective study on CD subjects undergoing bowel resection,⁶⁰ the assessment of endoscopic recurrence by the Rutgeerts’ score and bowel damage by the Lémann Index within 12 months of surgery was found to predict clinical recurrence [HR 0.03, p < 0.0001]. Bowel damage as assessed by the Lémann Index seemed to be independent from endoscopic disease activity as assessed by the Rutgeerts’ score [ρ = 0.26, p = 0.09]. The relationship between the Lémann Index and disease activity over time is summarised in Figure 1.

Figure 1.

Changes in the Lémann Index over time compared with activity indexes for Crohn’s disease [CD] (clinical, endoscopic, and magnetic resonance imaging [MRI]-based scores). Independently from disease activity, the ‘residual’ damage after a disease flare remains stable over time and increases after surgery.

6. Bowel Damage as a New Endpoint in Disease-modification Trials

Accumulating evidence indicates that we need to look beyond symptoms in Crohn’s disease.¹⁰ In this regard, deep remission [clinical and endoscopic remission] has emerged as a new therapeutic goal in both clinical trials⁹ and clinical practice¹¹ in Crohn’s disease. Disease-modification trials comparing different therapeutic strategies in early CD patients failed to show significant advantages in using early immunosuppression compared with step-up conventional strategy.^14,61,62,63 In particular, the REACT trial did not find any significant difference in terms of clinical remission, but CD patients treated with early combined immunosuppression [ECI] had significant lower risks for hospitalisation and surgery at Month 24 compared with the conventional therapeutic approach.¹⁴ In this study, the Lémann Index was not used to assess bowel damage progression in the study groups, as it was developed after the start of the enrolment. Similar data were found in the Step-Up Top-Down trial [SUTD] which showed no significant differences in clinical remission at Week 104 in early CD patients although disease complications, such as perianal fistulas, and the need for surgery, were higher in the step-up group compared with the top-down approach.⁶³ Similarly, Baert et al. found that mucosal healing at Year 2, achieved by a top-down approach [infliximab + azathioprine] was associated with a significantly lower rate of new or active perianal fistulas compared with subjects achieving mucosal healing by the conventional step-up approach with steroids [p = 0.0089].⁶¹ Moreover, the results from the RAPID trial did not show significant differences in terms of clinical remission and intestinal surgery at Year 3, but there was a significantly lower rate of perianal surgery in subjects treated early with azathioprine than those treated with conventional therapy.⁶²

It is possible that the use of the Lémann Index in those trials would have led to different results, with a different impact of the early therapeutic approach on bowel damage progression in this setting of patients, and might have provided more clear evidence on bowel damage progression as a primary outcome for disease-modification trials.

7. The Lémann Index for Clinicians: Practical Aspects and Perspectives

The possibility of measuring bowel damage opens up new perspectives for clinicians in the management of CD. The Lémann Index may be accurate for assessing bowel damage at a definite time-point [Figure 2]. This may allow the clinician to identify CD patients that are still within the therapeutic window of opportunity⁸ and thus most likely to benefit from effective therapeutic strategies to avoid progression to complications and surgery. Moreover, integration of the Lémann Index in the evaluation of efficacy of medications may be crucial for the accurate assessment of the impact of therapeutic strategies in the management of CD. Recent data suggest that if the Lémann Index does not increase during follow-up, the risk of progression and of negative outcomes is significantly reduced.⁴²

Figure 2.

Evolution of bowel damage over time assessed by magnetic resonance imaging [MRI] in a male patient with 20-cm long stricturing ileal Crohn’s disease at diagnosis. a, between arrows, Lémann Index 0.6, then developed a fistula between ileum and rectum. b, within the circle, Lémann Index 1.6, underwent surgical resection [Lémann Index 8.3 after surgery], and had further anastomotic recurrence. c, within surgery, Lémann Index 9.0. The Lémann Index was able to assess the severity of damage and its progression over time.

Assessment using the Lémann index may guide the clinician in optimising therapeutic strategies in case of an increase in the score. However, it is important to remember that the validity of Lémann Index for non-progression as a target in CD still needs to be confirmed by large long-term controlled trials. Moreover, there have been some issues raised from the preliminary data on the use of the Lémann Index in clinical practice.

First, structural bowel damage should be irreversible by definition, whereas the Lémann Index has been shown to be reduced by effective therapies. The presence of parameters of inflammation in the score calculation is the main reason for such discrepancy. As examples, ulcers are definitively related to active inflammation and are clearly reversible damage, bowel wall thickening is also a parameter of disease activity,⁶⁴ and strictures can be a result of inflammation or fibrosis and can be reversible under effective therapy⁶⁵ [Table 1]. Fiorino et al. found that the Lémann Index can significantly change after treatments for acute inflammation, but it remains stable in the maintenance phase, suggesting that ‘residual bowel damage’ as a baseline measurement for disease progression over time should actually be the starting point of disease progression. There is no clear indication on what the right time to assess ‘residual damage’ is, but previous studies based on resolution of inflammation assessed by MRI would suggest at minimum 26 weeks from baseline.⁶⁶ Moreover, this may suggest the need for refinement by including only non-reversible parameters,⁶⁷ although the concomitance between inflammation and structural damage due to repair processes can be a major limitation. This is the main reason why the Lémann Index would differ from the modified Sharp Score, since the parameters for RA are more clearly independent from active inflammation and are definitively irreversible.

Second, there are no clear cut-offs to discriminate the presence of bowel damage and clinically meaningful changes over time. Gilletta et al. found that a Lémann Index > 2.0 was related to the presence of bowel damage, although this value was based on patients undergoing surgery for complications.⁵⁶ Fiorino et al. propose a cut-off of 4.8, based on a blinded independent clinical evaluation by a gastroenterologist.⁵⁸ Because there is no objective definition for bowel damage, the proposed cut-offs could be considered valid, but not validated, and need confirmation.

Finally, the Lémann Index remains complex to calculate, since it requires the combination of disease history, endoscopy, imaging, and clinical evaluation, and it is difficult to use in clinical practice, especially for non-trained physicians.

In conclusion, the Lémann Index has the potential to be a powerful tool for measuring the real impact of therapeutic strategies on long-term outcomes in CD, in particular in terms of prevention of bowel damage progression. Further studies are needed to clarify the cut-offs for bowel damage and to confirm the sensitivity-to-changes and the validity of changes assessed by the Lémann Index as a therapeutic target.

Achieving deep remission in CD in order to prevent the development of bowel damage, with the final aim of reducing the need for surgery and changing patients’ lives, may be the ultimate therapeutic goals in CD.

Funding

None.

Conflict of Interest

The authors declare no relevant conflict of interest