Mucosal Healing in Inflammatory Bowel Diseases
Mucosal Healing in Inflammatory Bowel Diseases
The major question is whether MH is associated with medium- or long-term outcomes. A growing body of data suggest a possible benefit. MH may lead to fewer hospitalizations and reduced surgery rates both in clinical trials and everyday clinical practice. Although imperfect as objective measurements, clinical factors are also associated with disease outcome. However, the relationship between clinical and endoscopic activity is poor in CD, with only a weak correlation (r = 0.32; p < 0.001) clinical (CDAI) and endoscopic indices (CDEIS). Furthermore, clinical improvement is not always associated with MH in CD. Therefore, the real question is whether the mucosal status offers an additional prognostic value over clinical predictors.
Severe endoscopic lesions clearly impact the long-term disease course. Allez et al. reported that risk of colectomy was independently associated with the presence of deep and extensive ulceration at index colonoscopy (RR: 5.4; 95% CI: 2.6–11.1) in CD patients. For patients with severe endoscopic lesions, the probability of colectomy was 31% at 1 year, 42% at 3 years and 62% at 8 years, whereas for those without such lesions, the probabilities were 6, 8 and 18% at the same intervals. Additional risk factors identified were a CDAI >288 (RR: 2.2; 95% CI: 1.1–4.5) and the absence of immunosuppressive therapy during follow-up (RR: 2.4; 95% CI: 1.2–5.0). Of note, a significant percentage of the studies (e.g., the study by Allez et al.) reporting on MH rates and the importance of MH was published before the early aggressive therapy with immunosuppressives and biological became standard of care. Therefore, caution should be applied when extrapolating conclusions to the current circumstances.
Similar findings were reported by the Leuven group in CD patients treated with anti-TNFs. In CD, complete MH was detected in 45.4% of the patients who responded to IFX and partial MH in 22.4%. MH was associated with the risk of surgery (14.1% for patients with, vs 38.4% of patients without MH; p < 0.0001) during long-term follow-up (median: 68.7 months as a median). Baert et al. reported that complete endoscopic remission in the step-up top-down trial predicts sustained corticosteroid-free clinical remission in early-stage CD patients. The risk of relapse was significantly lower in CD patients who achieved complete endoscopic healing, defined as a simple endoscopic score (SES-CD) of 0 after 2 years of therapy, irrespective of medication used (p = 0.036; OR: 4.3). Similarly, in the EXTEND trial patients with deep remission (CDAI <150 and MH) had lower rates of all-cause (0 vs 17%) and CD-related (9 vs 0%) hospitalizations by week 52.
Of note, MH rates were associated with disease duration. Finally, MH may be associated with the risk of relapse after therapy cessation. In the STORI trial, MH was one important factor predicting relapse after the cessation of IFX therapy in multivariate analysis (HR: 2.6; 95% CI: 1.3–5.3; p = 0.005). However, there were many independent predictors and hemoglobin level (<145 g/l) was identified as the variable with the highest HR (6.0; 95% CI: 2.2–16.5) with male gender, no prior surgery, previous steroid use and hs-CRP all having greater HRs compared with MH. Thus, its clinical importance as a sole marker is questionable. Also, in a previous study investigating relapse the after AZA cessation in 83 patients in clinical remission, lack of MH before discontinuation was not predictive of clinical relapse.
Similar examples are available also from the UC literature. In a post hoc analysis of the ACT trials, lower endoscopic Mayo subscore at week 8 predicted corticosteroid free symptomatic remission at weeks 30 and 54 (p < 0.0001) and lower risk for colectomy (p < 0.0001). However, these benefits were independent from the type of treatment. Results were similar in a recent, French, multicenter study evaluating refractory UC patients. Endoscopic reevaluation was performed between 6 and 52 weeks after the start of IFX therapy. According to the Mayo endoscopic subscore, patients were categorized into a MH group (0–1) and non-MH group (2–3). Colectomy-free survival rates at 12, 24 and 36 months were 100, 96 and 96% in patients with MH, and 80, 65 and 65% in patients without MH, respectively (p = 0.004). In a multivariate analysis, MH was the only factor associated with colectomy-free survival, with an OR of 18 (95% CI: 1.58–204.9). However, the predictive potential of MH in acute severe UC is more controversial. Kobayashi et al. reported that although MH was associated with the 1-year colectomy risk, it was not predictive of the long-term prognosis. Finally, data suggest that signs of mucosal inflammation may be associated the risk of colorectal cancer in longstanding colitis. In a case–control study, histological inflammation was the only independent factor associated with the risk of colorectal cancer (OR: 4.69; 95% CI: 2.10–10.5); p < 0.001) in patients with longstanding extensive UC, confirmed later also by Gupta et al.
Real-life experience is also accumulating. The significance of MH after 1 year of therapy was evaluated in the population-based IBSEN cohort. MH at this point was associated with the risk of colectomy during the observational period (p = 0.02) with a similar trend in patients with CD. The same study reported that MH was associated with decreased need for further steroid treatment (p = 0.02) and lower inflammatory status (p = 0.02) in CD after 5 years. The added benefit over clinical activity was, however, not analyzed. In addition, a significant proportion of UC patients lacking MH after 1 year underwent colectomy within the next 2–3 months suggesting continuously active disease.
What Is the Clinical Benefit of Mucosal Healing?
The major question is whether MH is associated with medium- or long-term outcomes. A growing body of data suggest a possible benefit. MH may lead to fewer hospitalizations and reduced surgery rates both in clinical trials and everyday clinical practice. Although imperfect as objective measurements, clinical factors are also associated with disease outcome. However, the relationship between clinical and endoscopic activity is poor in CD, with only a weak correlation (r = 0.32; p < 0.001) clinical (CDAI) and endoscopic indices (CDEIS). Furthermore, clinical improvement is not always associated with MH in CD. Therefore, the real question is whether the mucosal status offers an additional prognostic value over clinical predictors.
Severe endoscopic lesions clearly impact the long-term disease course. Allez et al. reported that risk of colectomy was independently associated with the presence of deep and extensive ulceration at index colonoscopy (RR: 5.4; 95% CI: 2.6–11.1) in CD patients. For patients with severe endoscopic lesions, the probability of colectomy was 31% at 1 year, 42% at 3 years and 62% at 8 years, whereas for those without such lesions, the probabilities were 6, 8 and 18% at the same intervals. Additional risk factors identified were a CDAI >288 (RR: 2.2; 95% CI: 1.1–4.5) and the absence of immunosuppressive therapy during follow-up (RR: 2.4; 95% CI: 1.2–5.0). Of note, a significant percentage of the studies (e.g., the study by Allez et al.) reporting on MH rates and the importance of MH was published before the early aggressive therapy with immunosuppressives and biological became standard of care. Therefore, caution should be applied when extrapolating conclusions to the current circumstances.
Similar findings were reported by the Leuven group in CD patients treated with anti-TNFs. In CD, complete MH was detected in 45.4% of the patients who responded to IFX and partial MH in 22.4%. MH was associated with the risk of surgery (14.1% for patients with, vs 38.4% of patients without MH; p < 0.0001) during long-term follow-up (median: 68.7 months as a median). Baert et al. reported that complete endoscopic remission in the step-up top-down trial predicts sustained corticosteroid-free clinical remission in early-stage CD patients. The risk of relapse was significantly lower in CD patients who achieved complete endoscopic healing, defined as a simple endoscopic score (SES-CD) of 0 after 2 years of therapy, irrespective of medication used (p = 0.036; OR: 4.3). Similarly, in the EXTEND trial patients with deep remission (CDAI <150 and MH) had lower rates of all-cause (0 vs 17%) and CD-related (9 vs 0%) hospitalizations by week 52.
Of note, MH rates were associated with disease duration. Finally, MH may be associated with the risk of relapse after therapy cessation. In the STORI trial, MH was one important factor predicting relapse after the cessation of IFX therapy in multivariate analysis (HR: 2.6; 95% CI: 1.3–5.3; p = 0.005). However, there were many independent predictors and hemoglobin level (<145 g/l) was identified as the variable with the highest HR (6.0; 95% CI: 2.2–16.5) with male gender, no prior surgery, previous steroid use and hs-CRP all having greater HRs compared with MH. Thus, its clinical importance as a sole marker is questionable. Also, in a previous study investigating relapse the after AZA cessation in 83 patients in clinical remission, lack of MH before discontinuation was not predictive of clinical relapse.
Similar examples are available also from the UC literature. In a post hoc analysis of the ACT trials, lower endoscopic Mayo subscore at week 8 predicted corticosteroid free symptomatic remission at weeks 30 and 54 (p < 0.0001) and lower risk for colectomy (p < 0.0001). However, these benefits were independent from the type of treatment. Results were similar in a recent, French, multicenter study evaluating refractory UC patients. Endoscopic reevaluation was performed between 6 and 52 weeks after the start of IFX therapy. According to the Mayo endoscopic subscore, patients were categorized into a MH group (0–1) and non-MH group (2–3). Colectomy-free survival rates at 12, 24 and 36 months were 100, 96 and 96% in patients with MH, and 80, 65 and 65% in patients without MH, respectively (p = 0.004). In a multivariate analysis, MH was the only factor associated with colectomy-free survival, with an OR of 18 (95% CI: 1.58–204.9). However, the predictive potential of MH in acute severe UC is more controversial. Kobayashi et al. reported that although MH was associated with the 1-year colectomy risk, it was not predictive of the long-term prognosis. Finally, data suggest that signs of mucosal inflammation may be associated the risk of colorectal cancer in longstanding colitis. In a case–control study, histological inflammation was the only independent factor associated with the risk of colorectal cancer (OR: 4.69; 95% CI: 2.10–10.5); p < 0.001) in patients with longstanding extensive UC, confirmed later also by Gupta et al.
Real-life experience is also accumulating. The significance of MH after 1 year of therapy was evaluated in the population-based IBSEN cohort. MH at this point was associated with the risk of colectomy during the observational period (p = 0.02) with a similar trend in patients with CD. The same study reported that MH was associated with decreased need for further steroid treatment (p = 0.02) and lower inflammatory status (p = 0.02) in CD after 5 years. The added benefit over clinical activity was, however, not analyzed. In addition, a significant proportion of UC patients lacking MH after 1 year underwent colectomy within the next 2–3 months suggesting continuously active disease.
Source...