- Email: [email protected]
Therapeutic goals in IBD
Crohn’s Disease: Achieving Patients’ Benefits / Digestive and Liver Disease Supplements 2 (2008) 3–26
7
SESSION II – Updates on clinical treatment
Therapeutic goals in IBD M. Campieri, F. Rizzello, P. Gionchetti IBD Unit, University of Bologna, Italy
Traditionally, the therapeutic short-term end-point in the treatment of Crohn’s disease (CD) is the induction of remission, defined as control of symptoms and normalization of quality of life. The long-term end-points are the prevention of relapse, complications and surgery. In the everyday work, clinicians assess these endpoints using a global medical judgment rather than numerical activity indices, which are often complex and time-consuming. On the contrary, clinical trials assess the effectiveness of a treatment based of the reduction of a specific activity index, that should be objective, reproducible and express the disease in its complexity. We know that CD is a polyhedral disease formed by numerous variables. A global measurement of its activity comprising clinical, endoscopic, pathological and biochemical features is not available and, probably, it is unobtainable. Crohn’s disease activity index (CDAI) is the clinical numerical index traditionally and widely used in the clinical trials and a lot of different drugs were judged only on the basis of this index. CDAI was developed and validated before the beginning of the National Cooperative Crohn’s Disease Study, the first big multicenter controlled study on CD, to share the assessment of disease activity. The investigators identified 18 potential predictive variables that, prospectively collected, best predicted the investigators’ overall rating for each patient. At multivariate regression analysis, 8 variables were identified for CDAI. CDAI scores range from 0 to approximately 600. Originally, the investigators identified, as reasonable compromise, 150 as the cut-off between remission and activity and 450 as the limit between mild-moderate activity and severe activity. But, is CDAI expression of all variables forming CD? No. CDAI has some limitations: there is an interobserver variability, it poorly correlates with endoscopic severity, it is complex to obtain, requiring a 7 days diary which precludes the use in clinical practice, it’s not accurate in patients with fistulizing and stenosing disease without predictive value, shows limitations in patients with fibrous strictures, who are psychologically disturbed, who had previous extensive resections or with stoma. However, it remains the most widely used in clinical trials and the gold standard in guidelines. Subsequently,
most other indexes were proposed in order to solve the above limitations, introducing more serological markers of inflammation or reducing the time of observation. All these indexes were compared with CDAI, showing a good correlation, but none outlasting it. In the 1980s was introduced a disease activity measurement from a patients’ point of view, evaluating their quality of life. Goyatt and Irving introduced the Inflammatory Bowel Disease Questionnaire (IBDQ), a specific instrument to assess quality of life in patients with IBD. This 32-item questionnaire explores four dimensions: bowel function, emotional status, systemic symptoms and social function, scores ranging from 32 to 224, with higher scores indicating better quality of life. This index, in the last decade introduced in the clinical trials as secondary endpoint, correlates relatively good with CDAI. This is not surprising because CDAI explores a lot of items of IBDQ such as bowel function (number of daily movement), emotional status (general well being), and systemic symptoms (abdominal pain, extraintestinal manifestations). So, IBDQ is an interesting point of view but adds only limited information to clinical data provided by CDAI. On the other side, the introduction of biological therapies on IBD proposed the mucosal healing as co-primary endpoint with clinical remission. It is well known that the first-line therapy in active CD, systemic corticosteroids, induces mucosal healing and clinical remission only in 27% of patients while 65% of patients presented a clinical remission without any influence of the treatment on mucosal lesions. Established that steroid treatment was unable to induce mucosal healing, the French group of GETAID, that wrote the history of CD treatment, tried to answer the question if mucosal healing modified the disease outcome. Landi and colleagues followed for up to 18 months a group of patients previously treated with a high dose of steroids for active CD. At the end of the study, no difference was observed in the relapse rate between patients who obtained mucosal healing or not (22% in both groups). D’Haens and colleagues demonstrated that azathioprine is able to induce mucosal healing in a large group of patients after 1 to 3 years of treatment. Unfortunately, we don’t have data about the modification of long-term outcome of the
8
Crohn’s Disease: Achieving Patients’ Benefits / Digestive and Liver Disease Supplements 2 (2008), 3–26
disease and, if the aim is to avoid complications related to the severity of lesions, a median of 24 months is probably too long to achieve this. The final message of these studies was that mucosal healing is not necessary for the clinical outcome of the patients. Biological treatment, instead, is able to obtain mucosal healing in a short period and this group of patients requires less hospitalization and surgery. Interestingly, both ACCENT 1 and ACT 1 and 2 studies demonstrated a higher percentage of endoscopic remission than clinical remission defined as CDAI < 150 (such as 46% vs 28% in Rutgeerts’ study). This discrepancy could be explained by the persistence of symptoms related to a Irritable Bowel Syndrome (IBS) rather than the activity of disease. But this leaves many questions about what we are measuring with CDAI at the beginning of the study. Is a mucosal healing induced by biological treatment different from mucosal healing induced by corticosteroids? A partial answer to this question is that biological treatment is able to induce not only mucosal healing but also histological remission not demonstrated in steroid-treated patients. The influence of mucosal lesions on the patient’s longterm outcome was demonstrated by Rutgeerts and colleagues with the study on post-operative relapse. The early relapse of mucosal lesions after a surgical induced remission strongly correlates with a poor clinical outcome and the major effort to do after surgery is to prevent it.
If we choose an absolute objective outcome, such as the necessity of surgery, mucosal healing induced without biologicals is able to avoid surgery, modifying the long-term outcome of the patients. In conclusion, the best measure of disease activity remains today a need unfulfilled and we need to continue this sort of search of the Holy Grail. In the same time, we need to have other data about the natural history of the disease and long-term outcome in patients with different treatments. Clinical parameters are important but not enough to satisfy the future expectations and hopes of the patients, requiring a therapeutic long-term project. Essential references [1] Sostegni R, Daperno M, Scaglione N, Lavagna A, Rocca R, Pera A. et al. Review artiche: Crohn’s disease: monitoring disease activity. Aliment Pharmacol Ther 2003;17(Suppl 2):11–7. [2] Best WR, Becktel JM, Singleton JW, Kern F Jr. Development of a Crohn’s dsiease activity index. NCCDS. Gastroenterology 1976;70:439–44. [3] Guyatt G, Mitchell A, Irvine EJ, Singer J, Williams N, Goodacre R et al. A new measure of health status for clinical trial in inflammatory bowel disease. Gastroenterology 1989;96:804–10. [4] Landi B, Anh TN, Cortot A, Soule JC, Rene E, Gendre JP et al. Endoscopic monitoring of Crohn’s disease treatment: a prospective, randomized clinical trial. The GETAIDs study. Gastroenterology 1992;102:1647–53. [5] Froslie KF, Jahnsen J, Moum BA Vatn MH; IBSEN Group. Mucosal healing in inflammatory bowel disease: results from a Norwey population-based cohort. Gastroenterology 2007;133:412–22.
7
SESSION II – Updates on clinical treatment
Therapeutic goals in IBD M. Campieri, F. Rizzello, P. Gionchetti IBD Unit, University of Bologna, Italy
Traditionally, the therapeutic short-term end-point in the treatment of Crohn’s disease (CD) is the induction of remission, defined as control of symptoms and normalization of quality of life. The long-term end-points are the prevention of relapse, complications and surgery. In the everyday work, clinicians assess these endpoints using a global medical judgment rather than numerical activity indices, which are often complex and time-consuming. On the contrary, clinical trials assess the effectiveness of a treatment based of the reduction of a specific activity index, that should be objective, reproducible and express the disease in its complexity. We know that CD is a polyhedral disease formed by numerous variables. A global measurement of its activity comprising clinical, endoscopic, pathological and biochemical features is not available and, probably, it is unobtainable. Crohn’s disease activity index (CDAI) is the clinical numerical index traditionally and widely used in the clinical trials and a lot of different drugs were judged only on the basis of this index. CDAI was developed and validated before the beginning of the National Cooperative Crohn’s Disease Study, the first big multicenter controlled study on CD, to share the assessment of disease activity. The investigators identified 18 potential predictive variables that, prospectively collected, best predicted the investigators’ overall rating for each patient. At multivariate regression analysis, 8 variables were identified for CDAI. CDAI scores range from 0 to approximately 600. Originally, the investigators identified, as reasonable compromise, 150 as the cut-off between remission and activity and 450 as the limit between mild-moderate activity and severe activity. But, is CDAI expression of all variables forming CD? No. CDAI has some limitations: there is an interobserver variability, it poorly correlates with endoscopic severity, it is complex to obtain, requiring a 7 days diary which precludes the use in clinical practice, it’s not accurate in patients with fistulizing and stenosing disease without predictive value, shows limitations in patients with fibrous strictures, who are psychologically disturbed, who had previous extensive resections or with stoma. However, it remains the most widely used in clinical trials and the gold standard in guidelines. Subsequently,
most other indexes were proposed in order to solve the above limitations, introducing more serological markers of inflammation or reducing the time of observation. All these indexes were compared with CDAI, showing a good correlation, but none outlasting it. In the 1980s was introduced a disease activity measurement from a patients’ point of view, evaluating their quality of life. Goyatt and Irving introduced the Inflammatory Bowel Disease Questionnaire (IBDQ), a specific instrument to assess quality of life in patients with IBD. This 32-item questionnaire explores four dimensions: bowel function, emotional status, systemic symptoms and social function, scores ranging from 32 to 224, with higher scores indicating better quality of life. This index, in the last decade introduced in the clinical trials as secondary endpoint, correlates relatively good with CDAI. This is not surprising because CDAI explores a lot of items of IBDQ such as bowel function (number of daily movement), emotional status (general well being), and systemic symptoms (abdominal pain, extraintestinal manifestations). So, IBDQ is an interesting point of view but adds only limited information to clinical data provided by CDAI. On the other side, the introduction of biological therapies on IBD proposed the mucosal healing as co-primary endpoint with clinical remission. It is well known that the first-line therapy in active CD, systemic corticosteroids, induces mucosal healing and clinical remission only in 27% of patients while 65% of patients presented a clinical remission without any influence of the treatment on mucosal lesions. Established that steroid treatment was unable to induce mucosal healing, the French group of GETAID, that wrote the history of CD treatment, tried to answer the question if mucosal healing modified the disease outcome. Landi and colleagues followed for up to 18 months a group of patients previously treated with a high dose of steroids for active CD. At the end of the study, no difference was observed in the relapse rate between patients who obtained mucosal healing or not (22% in both groups). D’Haens and colleagues demonstrated that azathioprine is able to induce mucosal healing in a large group of patients after 1 to 3 years of treatment. Unfortunately, we don’t have data about the modification of long-term outcome of the
8
Crohn’s Disease: Achieving Patients’ Benefits / Digestive and Liver Disease Supplements 2 (2008), 3–26
disease and, if the aim is to avoid complications related to the severity of lesions, a median of 24 months is probably too long to achieve this. The final message of these studies was that mucosal healing is not necessary for the clinical outcome of the patients. Biological treatment, instead, is able to obtain mucosal healing in a short period and this group of patients requires less hospitalization and surgery. Interestingly, both ACCENT 1 and ACT 1 and 2 studies demonstrated a higher percentage of endoscopic remission than clinical remission defined as CDAI < 150 (such as 46% vs 28% in Rutgeerts’ study). This discrepancy could be explained by the persistence of symptoms related to a Irritable Bowel Syndrome (IBS) rather than the activity of disease. But this leaves many questions about what we are measuring with CDAI at the beginning of the study. Is a mucosal healing induced by biological treatment different from mucosal healing induced by corticosteroids? A partial answer to this question is that biological treatment is able to induce not only mucosal healing but also histological remission not demonstrated in steroid-treated patients. The influence of mucosal lesions on the patient’s longterm outcome was demonstrated by Rutgeerts and colleagues with the study on post-operative relapse. The early relapse of mucosal lesions after a surgical induced remission strongly correlates with a poor clinical outcome and the major effort to do after surgery is to prevent it.
If we choose an absolute objective outcome, such as the necessity of surgery, mucosal healing induced without biologicals is able to avoid surgery, modifying the long-term outcome of the patients. In conclusion, the best measure of disease activity remains today a need unfulfilled and we need to continue this sort of search of the Holy Grail. In the same time, we need to have other data about the natural history of the disease and long-term outcome in patients with different treatments. Clinical parameters are important but not enough to satisfy the future expectations and hopes of the patients, requiring a therapeutic long-term project. Essential references [1] Sostegni R, Daperno M, Scaglione N, Lavagna A, Rocca R, Pera A. et al. Review artiche: Crohn’s disease: monitoring disease activity. Aliment Pharmacol Ther 2003;17(Suppl 2):11–7. [2] Best WR, Becktel JM, Singleton JW, Kern F Jr. Development of a Crohn’s dsiease activity index. NCCDS. Gastroenterology 1976;70:439–44. [3] Guyatt G, Mitchell A, Irvine EJ, Singer J, Williams N, Goodacre R et al. A new measure of health status for clinical trial in inflammatory bowel disease. Gastroenterology 1989;96:804–10. [4] Landi B, Anh TN, Cortot A, Soule JC, Rene E, Gendre JP et al. Endoscopic monitoring of Crohn’s disease treatment: a prospective, randomized clinical trial. The GETAIDs study. Gastroenterology 1992;102:1647–53. [5] Froslie KF, Jahnsen J, Moum BA Vatn MH; IBSEN Group. Mucosal healing in inflammatory bowel disease: results from a Norwey population-based cohort. Gastroenterology 2007;133:412–22.