Journal of Crohn's and Colitis, 2015, 599–600 doi:10.1093/ecco-jcc/jjv082 Advanced Access publication May 8, 2015 Editorial
Editorial What is Disease Progression in Crohn’s Disease and how can it be Measured? Index < 5. Patients were followed up for up to 36 months, with yearly evaluations including endoscopy and/or MRI depending on disease location, and additional evaluations in case of clinical relapse. To determine the accuracy of the Lémann Index to assess damage, a gastroenterologist unaware of the Lémann Index score assessed damage based on all information available [clinical plus examinations]. Using this assessment as gold standard, the authors found that a Lémann index > 4.8 identified subjects with bowel damage, and that an increase in Lémann index > 0.3 identified damage progression.6 Fiorino et al. describe in their study that the Lémann Index is reversible in a population of patients responding to anti-TNF drugs. Up to 60% of patients had a reduction in the Lémann index score 1 year after starting anti-TNF therapy. The regression of the damage score in CD contrasts with the always-progressive increase of damage indices in rheumatoid arthritis or multiple sclerosis over time, because the type of lesions evaluated are non-reversible. In multiple sclerosis, the quantification of atrophy7 and measures derived from magnetisation transfer MRI8 are indicators of the most destructive aspects of the disease and progress over time. In rheumatoid arthritis joint space narrowing, erosion, or deformation, also do not regress.9 The possibility that the Lémann index score, as it is defined now, could decrease over time was anticipated. The only irreversible parameters of the index are related to the surgical domain: resection surgeries and strictureplasties. In the stricturing lesions domain, all parameters including wall thickening, contrast enhancement, stricture, and prestenotic dilatation, are potentially reversible. Similarly, in the penetrating lesions domain, superficial or deep ulcerations, fistula, and phlegmon are also potentially reversible. Should an index measuring damage in CD include only lesions that are non-reversible? Probably not. Significant stenosis causing pre-stenotic dilatation, or penetrating lesions are major damage lesions that should be captured in a damage index despite the possibility of regression. However, other components of the index such as ‘thickening < 3 mm’ [a contradictory term itself], segmental enhancement, or presence of ulcers are related to active inflammation and can rapidly and completely regress upon establishing an effective treatment such as anti-TNF therapy.10 Indeed, these variables [thickening, enhancement, ulcers] are components of the MaRIA score aimed at measuring severity of inflammation, not damage.11 The correlation observed in this study between the Lémann index and the MaRIA index supports the notion that some of the components now included in the Lémann index are more directly related to acute inflammation than to established
Copyright © 2015 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: [email protected]
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Downloaded from http://ecco-jcc.oxfordjournals.org/ by guest on January 21, 2016
To advance in the assessment of therapeutic interventions for diseases that progress slowly but that lead ultimately to permanent disability, such as multiple sclerosis, rheumatoid arthritis or Crohn’s disease [CD], it is essential to evaluate the disease-modifying effects of available treatments. It is also necessary to separate these long-term effects from the short-term effects on symptoms that these treatments may afford. This separation of improvement in symptoms from change in primary disease progression can be difficult. In clinical trials, the measure of the effects of a particular therapeutic intervention is commonly done using indices. The majority of indices that have been developed for assessment of CD are measures of the severity of inflammatory activity, including evaluations based on symptoms and biomarkers [Crohn’s Disease Activity Index [CDAI]],1 endoscopy [Crohn’s Endoscopic Index of Severity [CDEIS]],2 or radiology [Magnetic Resonance Index of Activity [MaRIA]].3 Nevertheless, these are not indices reflecting purely inflammatory activity; each of these indices may be influenced by irreversible damage in the absence of active inflammation; for example, CDAI may increase due to bile salt–induced diarrhoea after ileal resection, CDEIS may increase due to presence of scars or fixed stenotic lesions, and MaRIA may increase due to persistent fibrotic thickening of the bowel wall. This may be among the reasons contributing to higher remission and response rates in early CD with the use of anti-tumour necrosis factor [TNF] therapies.4 With the purpose of measuring digestive tract damage instead of inflammation severity in CD, and facilitate the assessment of disease progression over time, a group of investigators recently developed the Lémann index.5 This index is designed to measure the damage severity in all segments of the digestive tract, based on assessment of stricturing and penetrating lesions using MRI and endoscopy, together with the history of surgical interventions. A first proof of the ability of the Lémann index to measure damage progression was shown in the original publication, by demonstrating an increase of the Lémann Index with disease duration from a mean score of 6.3 for disease duration < 2 years to a mean score of 19.0 for a duration ≥ 10 years. An internal validation was provided using the bootstrap method. The article published in this issue of ECCOJCC by Dr Fiorino and collaborators6 is the first prospective study applying the Lémann Index to an independent cohort of patients, with sequential measurements over time. This is a prospective cohort study carried out at Humanitas Research Hospital in Milan, which enrolled 30 patients starting anti-TNF monotherapy and achieving clinical remission at the end of the induction phase, defined as a Harvey-Bradshaw
J. Panés
600
Julián Panés, MD, PhD, Department of Gastroenterology, Hospital Clínic de Barcelona, Villarroel 170, 08036 Barcelona, Spain. Tel.: +34 932275418; e-mail: [email protected]
Conflict of Interest None declared.
Acknowledgments The author’s work is largely supported by grants SAF2012/33560 from Ministerio de Economía y competitividad, Spain, and a grant from the Leona and Harry Helmsley Trust.
References 1. Best WR, Becktel JM, Singleton JW, Kern F Jr. Development of a Crohn’s disease activity index: National Cooperative Crohn’s Disease Study. Gastroenterology 1976;70:439–44. 2. 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 Therapeutiques des Affections Inflammatoires du Tube Digestif [GETAID]. Gut 1989;30:983–9. 3. Rimola J, Rodriguez S, Garcia-Bosch O, et al. Magnetic resonance for assessment of disease activity and severity in ileocolonic Crohn’s disease. Gut 2009;58:1113–20. 4. Schreiber S, Reinisch W, Colombel JF, et al. Subgroup analysis of the placebo-controlled CHARM trial: increased remission rates through 3 years for adalimumab-treated patients with early Crohn’s disease. J Crohn’s Colitis 2013;7:213–21. 5. Pariente B, Mary JY, Danese S, et al. Development of the Lemann index to assess digestive tract damage in patients with Crohn’s disease. Gastroenterology 2015;148:52–63 e3. 6. Fiorino G, Bonifacio C, Allocca M, et al. Bowel damage as assessed by the Lémann index is reversible on anti-TNF therapy for Crohn’s disease. J Crohn’s Colitis 2015:in press. 7. Giorgio A, Battaglini M, Smith SM, De Stefano N. Brain atrophy assessment in multiple sclerosis: importance and limitations. Neuroimaging Clin North Am 2008;18:675–86, xi. 8. Filippi M, Rocca MA. MR imaging of multiple sclerosis. Radiology 2011;259:659–81. 9. Guillemin F, Billot L, Boini S, Gerard N, Odegaard S, Kvien TK. Reproducibility and sensitivity to change of 5 methods for scoring hand radiographic damage in patients with rheumatoid arthritis. J Rheumatol 2005;32:778–86. 10. Ordas I, Rimola J, Rodriguez S, et al. Accuracy of magnetic resonance enterography in assessing response to therapy and mucosal healing in patients with Crohn’s disease. Gastroenterology 2014;146:374–82 e1. 11. Rimola J, Ordas I, Rodriguez S, et al. Magnetic resonance imaging for evaluation of Crohn’s disease: validation of parameters of severity and quantitative index of activity. Inflamm Bowel Dis 2011;17:1759–68. 12. Colombel JF, Sandborn WJ, Rutgeerts P, et al. Adalimumab for maintenance of clinical response and remission in patients with Crohn’s disease: the CHARM trial. Gastroenterology 2007;132:52–65. 13. Hanauer SB, Feagan BG, Lichtenstein GR, et al. Maintenance inf liximab for Crohn’s disease: the ACCENT I randomised trial. Lancet 2002;359:1541–9. 14. Filippi M, Preziosa P, Copetti M, et al. Gray matter damage predicts the accumulation of disability 13 years later in MS. Neurology 2013;81:1759–67.
Downloaded from http://ecco-jcc.oxfordjournals.org/ by guest on January 21, 2016
permanent damage. Some refinement in the definition of the components of the Lémann index may be necessary, as has been the case for the components and scoring systems of the Sharp index in rheumatoid arthritis over time.9 Fiorino et al. claim a potential efficacy of anti-TNF therapy to reduce damage, based on the observation of a reduction in the Lémann index in 60% of their patients.6 Considering the patient selection and characteristics of the study, this might be an overinterpretation of the observation. The population studied is a selection of patients achieving remission at the end of the induction period, which is a criterion even more stringent than the selection of responders in previous maintenance trials,12,13 and even more important, there is no control group. Therefore the interpretation of the value of anti-TNF therapy to alter disease progression should be taken with caution. A final interesting observation of the study from Milan shows that progression in damage score is associated with worse outcomes, including subsequent requirement of surgery.6 This is in line with observations in other disease areas. For example, in multiple sclerosis, grey matter damage predicts future disability and cognitive impairment,14 and in rheumatoid arthritis numerical assessment of the progression of radiological abnormalities has prognostic value.9 This observation, when validated, may lead to individualisation of treatment, increasing efficiency of therapeutic interventions in the population at highest risk for disease progression and disability.
Editorial What is Disease Progression in Crohn’s Disease and how can it be Measured? Index < 5. Patients were followed up for up to 36 months, with yearly evaluations including endoscopy and/or MRI depending on disease location, and additional evaluations in case of clinical relapse. To determine the accuracy of the Lémann Index to assess damage, a gastroenterologist unaware of the Lémann Index score assessed damage based on all information available [clinical plus examinations]. Using this assessment as gold standard, the authors found that a Lémann index > 4.8 identified subjects with bowel damage, and that an increase in Lémann index > 0.3 identified damage progression.6 Fiorino et al. describe in their study that the Lémann Index is reversible in a population of patients responding to anti-TNF drugs. Up to 60% of patients had a reduction in the Lémann index score 1 year after starting anti-TNF therapy. The regression of the damage score in CD contrasts with the always-progressive increase of damage indices in rheumatoid arthritis or multiple sclerosis over time, because the type of lesions evaluated are non-reversible. In multiple sclerosis, the quantification of atrophy7 and measures derived from magnetisation transfer MRI8 are indicators of the most destructive aspects of the disease and progress over time. In rheumatoid arthritis joint space narrowing, erosion, or deformation, also do not regress.9 The possibility that the Lémann index score, as it is defined now, could decrease over time was anticipated. The only irreversible parameters of the index are related to the surgical domain: resection surgeries and strictureplasties. In the stricturing lesions domain, all parameters including wall thickening, contrast enhancement, stricture, and prestenotic dilatation, are potentially reversible. Similarly, in the penetrating lesions domain, superficial or deep ulcerations, fistula, and phlegmon are also potentially reversible. Should an index measuring damage in CD include only lesions that are non-reversible? Probably not. Significant stenosis causing pre-stenotic dilatation, or penetrating lesions are major damage lesions that should be captured in a damage index despite the possibility of regression. However, other components of the index such as ‘thickening < 3 mm’ [a contradictory term itself], segmental enhancement, or presence of ulcers are related to active inflammation and can rapidly and completely regress upon establishing an effective treatment such as anti-TNF therapy.10 Indeed, these variables [thickening, enhancement, ulcers] are components of the MaRIA score aimed at measuring severity of inflammation, not damage.11 The correlation observed in this study between the Lémann index and the MaRIA index supports the notion that some of the components now included in the Lémann index are more directly related to acute inflammation than to established
Copyright © 2015 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: [email protected]
599
Downloaded from http://ecco-jcc.oxfordjournals.org/ by guest on January 21, 2016
To advance in the assessment of therapeutic interventions for diseases that progress slowly but that lead ultimately to permanent disability, such as multiple sclerosis, rheumatoid arthritis or Crohn’s disease [CD], it is essential to evaluate the disease-modifying effects of available treatments. It is also necessary to separate these long-term effects from the short-term effects on symptoms that these treatments may afford. This separation of improvement in symptoms from change in primary disease progression can be difficult. In clinical trials, the measure of the effects of a particular therapeutic intervention is commonly done using indices. The majority of indices that have been developed for assessment of CD are measures of the severity of inflammatory activity, including evaluations based on symptoms and biomarkers [Crohn’s Disease Activity Index [CDAI]],1 endoscopy [Crohn’s Endoscopic Index of Severity [CDEIS]],2 or radiology [Magnetic Resonance Index of Activity [MaRIA]].3 Nevertheless, these are not indices reflecting purely inflammatory activity; each of these indices may be influenced by irreversible damage in the absence of active inflammation; for example, CDAI may increase due to bile salt–induced diarrhoea after ileal resection, CDEIS may increase due to presence of scars or fixed stenotic lesions, and MaRIA may increase due to persistent fibrotic thickening of the bowel wall. This may be among the reasons contributing to higher remission and response rates in early CD with the use of anti-tumour necrosis factor [TNF] therapies.4 With the purpose of measuring digestive tract damage instead of inflammation severity in CD, and facilitate the assessment of disease progression over time, a group of investigators recently developed the Lémann index.5 This index is designed to measure the damage severity in all segments of the digestive tract, based on assessment of stricturing and penetrating lesions using MRI and endoscopy, together with the history of surgical interventions. A first proof of the ability of the Lémann index to measure damage progression was shown in the original publication, by demonstrating an increase of the Lémann Index with disease duration from a mean score of 6.3 for disease duration < 2 years to a mean score of 19.0 for a duration ≥ 10 years. An internal validation was provided using the bootstrap method. The article published in this issue of ECCOJCC by Dr Fiorino and collaborators6 is the first prospective study applying the Lémann Index to an independent cohort of patients, with sequential measurements over time. This is a prospective cohort study carried out at Humanitas Research Hospital in Milan, which enrolled 30 patients starting anti-TNF monotherapy and achieving clinical remission at the end of the induction phase, defined as a Harvey-Bradshaw
J. Panés
600
Julián Panés, MD, PhD, Department of Gastroenterology, Hospital Clínic de Barcelona, Villarroel 170, 08036 Barcelona, Spain. Tel.: +34 932275418; e-mail: [email protected]
Conflict of Interest None declared.
Acknowledgments The author’s work is largely supported by grants SAF2012/33560 from Ministerio de Economía y competitividad, Spain, and a grant from the Leona and Harry Helmsley Trust.
References 1. Best WR, Becktel JM, Singleton JW, Kern F Jr. Development of a Crohn’s disease activity index: National Cooperative Crohn’s Disease Study. Gastroenterology 1976;70:439–44. 2. 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 Therapeutiques des Affections Inflammatoires du Tube Digestif [GETAID]. Gut 1989;30:983–9. 3. Rimola J, Rodriguez S, Garcia-Bosch O, et al. Magnetic resonance for assessment of disease activity and severity in ileocolonic Crohn’s disease. Gut 2009;58:1113–20. 4. Schreiber S, Reinisch W, Colombel JF, et al. Subgroup analysis of the placebo-controlled CHARM trial: increased remission rates through 3 years for adalimumab-treated patients with early Crohn’s disease. J Crohn’s Colitis 2013;7:213–21. 5. Pariente B, Mary JY, Danese S, et al. Development of the Lemann index to assess digestive tract damage in patients with Crohn’s disease. Gastroenterology 2015;148:52–63 e3. 6. Fiorino G, Bonifacio C, Allocca M, et al. Bowel damage as assessed by the Lémann index is reversible on anti-TNF therapy for Crohn’s disease. J Crohn’s Colitis 2015:in press. 7. Giorgio A, Battaglini M, Smith SM, De Stefano N. Brain atrophy assessment in multiple sclerosis: importance and limitations. Neuroimaging Clin North Am 2008;18:675–86, xi. 8. Filippi M, Rocca MA. MR imaging of multiple sclerosis. Radiology 2011;259:659–81. 9. Guillemin F, Billot L, Boini S, Gerard N, Odegaard S, Kvien TK. Reproducibility and sensitivity to change of 5 methods for scoring hand radiographic damage in patients with rheumatoid arthritis. J Rheumatol 2005;32:778–86. 10. Ordas I, Rimola J, Rodriguez S, et al. Accuracy of magnetic resonance enterography in assessing response to therapy and mucosal healing in patients with Crohn’s disease. Gastroenterology 2014;146:374–82 e1. 11. Rimola J, Ordas I, Rodriguez S, et al. Magnetic resonance imaging for evaluation of Crohn’s disease: validation of parameters of severity and quantitative index of activity. Inflamm Bowel Dis 2011;17:1759–68. 12. Colombel JF, Sandborn WJ, Rutgeerts P, et al. Adalimumab for maintenance of clinical response and remission in patients with Crohn’s disease: the CHARM trial. Gastroenterology 2007;132:52–65. 13. Hanauer SB, Feagan BG, Lichtenstein GR, et al. Maintenance inf liximab for Crohn’s disease: the ACCENT I randomised trial. Lancet 2002;359:1541–9. 14. Filippi M, Preziosa P, Copetti M, et al. Gray matter damage predicts the accumulation of disability 13 years later in MS. Neurology 2013;81:1759–67.
Downloaded from http://ecco-jcc.oxfordjournals.org/ by guest on January 21, 2016
permanent damage. Some refinement in the definition of the components of the Lémann index may be necessary, as has been the case for the components and scoring systems of the Sharp index in rheumatoid arthritis over time.9 Fiorino et al. claim a potential efficacy of anti-TNF therapy to reduce damage, based on the observation of a reduction in the Lémann index in 60% of their patients.6 Considering the patient selection and characteristics of the study, this might be an overinterpretation of the observation. The population studied is a selection of patients achieving remission at the end of the induction period, which is a criterion even more stringent than the selection of responders in previous maintenance trials,12,13 and even more important, there is no control group. Therefore the interpretation of the value of anti-TNF therapy to alter disease progression should be taken with caution. A final interesting observation of the study from Milan shows that progression in damage score is associated with worse outcomes, including subsequent requirement of surgery.6 This is in line with observations in other disease areas. For example, in multiple sclerosis, grey matter damage predicts future disability and cognitive impairment,14 and in rheumatoid arthritis numerical assessment of the progression of radiological abnormalities has prognostic value.9 This observation, when validated, may lead to individualisation of treatment, increasing efficiency of therapeutic interventions in the population at highest risk for disease progression and disability.
