J Clin Gastroenterol
Volume 49, Number 2, February 2015
in perianal fistulas in Crohn’s disease patients naive to anti-TNF therapy,” by Castan˜o-Milla et al,1 recently published in this journal. In this retrospective multicenter analysis, the authors found 54% of remission after 6 months of induction therapy with adalimumab (ADA) and 41% after 12 months, in a population of patients with perianal fistulas caused by Crohn’s disease (CD), naive to antiTNF therapy. They also found good correlation between clinical remission and radiologic improvement described in magnetic resonance imaging tests, performed at 6 and 12 months after ADA initiation in a significant number of patients. In this study, the authors also found by logistic regression analysis that complex fistulas were the only predictor of poorer response to ADA (hazard ratio = 0.083; 95% confidence interval, 0.0009-0.764; P = 0.028). Although subanalysis from the pivotal trials with ADA demonstrated the superiority of this agent in remission of perianal fistulas in CD as compared with placebo, these information were only assessed as secondary endpoints of the studies.2 Realworld data published recently also demonstrated the benefits of ADA in the management of perianal fistulizing CD, in some case series.3,4 The study by Castan˜o-Milla and colleagues brought significant evidence of radiologic improvement in perianal fistulous tracks with ADA. Although this is a well-conducted study, an important limitation must be taken in consideration. The authors did not make it clear if all patients were previously submitted to examination under anesthesia before ADA induction regimen. It is known from other case series with infliximab that combined therapy with anti-TNF agents and examination under anesthesia, with seton placement and curettage of the fistulous tracks, can lead to better remission rates as compared with medical therapy in isolation.5 Therefore, the interesting results described in this important Spanish study could be even improved if combined therapy could be used before ADA initiation, with the addition of this medical-surgical strategy. This study, even if retrospective, brings real-world data to an important question regarding the effectiveness of ADA in perianal fistulizing CD.
Significant controversy exists regarding the real benefits of this agent in this subpopulation of patients, mainly due to the lack of a prospective randomized placebo-controlled trial, as performed for infliximab, which allowed fistulizing CD to be one indication in the label of this biological agent.6 The same indication does not exist in the label of ADA, and in some countries reimbursement for fistulizing CD can be a difficult issue for that reason. Therefore, clinical data that prove the efficacy of ADA, as the results of this interesting Spanish multicenter case series, can help us to answer this important question, and put ADA as an important tool in the management of perianal fistulizing CD.
Paulo G. Kotze, MD* Antonino Spinelli, MD, PhDw *Colorectal Surgery Unit, Cajuru University Hospital, Catholic University of Parana´ (PUCPR), Curitiba, Parana´, Brazil wIBD Section, Colorectal Surgery Unit Department of Surgery, Istituto Clinico Humanitas, Milano, Italy
REFERENCES 1. Castan˜o-Milla C, Chaparro M, Saro C, et al. Adalimumab for perianal fistulizing Crohn’s disease: real world data adds important information for clinical practice. J Clin Gastroenterol. 2015;49: 34–40. 2. 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. 3. Fortea-Ormaechea JI, Gonza´lez-Lama Y, Casis B, et al. Adalimumab is effective in long-term real life clinical practice in both luminal and perianal Crohn’s disease. The Madrid experience. Gastroenterol Hepatol. 2011;34:443–448. 4. Echarri A, Castro J, Barreiro M, et al. Evaluation of adalimumab therapy in multidisciplinary strategy for perianal Crohn’s disease patients with infliximab failure. J Crohns Colitis. 2010;4: 654–660. 5. Gaertner WB, Decanini A, Mellgren A, et al. Does infliximab infusions impact results of operative treatment for Crohn’s perianal fistulas? Dis Colon Rectum. 2007;50:1754–1760. 6. Sands BE, Anderson FH, Bernstein CN, et al. Infliximab maintenance therapy for fistulizing Crohn’s disease. N Engl J Med. 2004;350:876–885.
Letters to the Editor
Combined Fibrosis Indices More Than 1 Way to Skin a Cat To the Editor: We read with interest the comments by Sertoglu et al1 emphasizing the need to evaluate combined fibrosis indices in patients with low levels of hepatitis B virus (HBV) DNA. Although the value of these combined markers has been clearly elucidated in patients with chronic HBV,2 they have not been explicitly studied in the low-replicative form of the disease. Although appended analyses to better identify significant fibrosis are required, the scope of our original study was limited to defining the predictors in the simplicity of the routinely available individual factors.3 Hence, in our view, the inclusion of combined indices would have created redundancy, and as such was beyond the scope of the prevailing mandate. In addition, Sertoglu and colleagues express concern regarding the manner of performing multivariate analysis. They advocate that parameters included in the multivariate model should only be those that are significant at a univariate level and not correlating with each other. We undoubtedly concur that only parameters significant at the univariate level ought to be included (which formed the basis of our evaluation); however, we take exception to the view that there must be an additional step of conducting a correlation analysis before inclusion of variables in the multivariate model. To the best of our knowledge, we remain unaware of this step’s necessity, usefulness, or legitimacy, having clearly checked the issue of multicollinearity (evaluating the SEs of coefficients) and interaction of variables included in the multivariate analysis model.4 Faisal M. Sanai, SBG, MD*w Khalid Alswat, MRCPw Waleed Al-Hamoudi, MDw Shaffi A. Shaikh, PhDz Ayman A. Abdo, FRCPCw *Department of Medicine Division of Gastroenterology King Abdulaziz Medical City Jeddah The authors declare that they have nothing to disclose.
Copyright
r
2014 Wolters Kluwer Health, Inc. All rights reserved.
www.jcge.com |
175
J Clin Gastroenterol
Letters to the Editor
wLiver Disease Research Center zDepartment of Family & Community Medicine, College of Medicine, King Saud University, Riyadh, Saudi Arabia
REFERENCES 1. Sertoglu E, Kayadibi H, Uyanik M. Importance of combined fibrosis indices
176 | www.jcge.com
in chronic hepatitis B patients with low viremia. J Clin Gastroenterol. 2015;49: 170–171. 2. Teshale E, Lu M, Rupp LB, et al. APRI and FIB-4 are good predictors of the stage of liver fibrosis in chronic hepatitis B: the Chronic Hepatitis Cohort Study (CHeCS). J Viral Hepat. 2014;21: 917–920.
Copyright
r
Volume 49, Number 2, February 2015
3. Abdo AA, Bzeizi KI, Babatin MA, et al. Predictors of significant fibrosis in chronic hepatitis B patients with low viremia. J Clin Gastroenterol. 2014;48: e50–e56. 4. Hosmer DW, Lemeshow S. In: Shewhart WA, Wilks SS, eds. Applied Logistic Regression. 2nd ed. New York: Wiley Inter-Science; 2000:47–90.
2014 Wolters Kluwer Health, Inc. All rights reserved.
Volume 49, Number 2, February 2015
in perianal fistulas in Crohn’s disease patients naive to anti-TNF therapy,” by Castan˜o-Milla et al,1 recently published in this journal. In this retrospective multicenter analysis, the authors found 54% of remission after 6 months of induction therapy with adalimumab (ADA) and 41% after 12 months, in a population of patients with perianal fistulas caused by Crohn’s disease (CD), naive to antiTNF therapy. They also found good correlation between clinical remission and radiologic improvement described in magnetic resonance imaging tests, performed at 6 and 12 months after ADA initiation in a significant number of patients. In this study, the authors also found by logistic regression analysis that complex fistulas were the only predictor of poorer response to ADA (hazard ratio = 0.083; 95% confidence interval, 0.0009-0.764; P = 0.028). Although subanalysis from the pivotal trials with ADA demonstrated the superiority of this agent in remission of perianal fistulas in CD as compared with placebo, these information were only assessed as secondary endpoints of the studies.2 Realworld data published recently also demonstrated the benefits of ADA in the management of perianal fistulizing CD, in some case series.3,4 The study by Castan˜o-Milla and colleagues brought significant evidence of radiologic improvement in perianal fistulous tracks with ADA. Although this is a well-conducted study, an important limitation must be taken in consideration. The authors did not make it clear if all patients were previously submitted to examination under anesthesia before ADA induction regimen. It is known from other case series with infliximab that combined therapy with anti-TNF agents and examination under anesthesia, with seton placement and curettage of the fistulous tracks, can lead to better remission rates as compared with medical therapy in isolation.5 Therefore, the interesting results described in this important Spanish study could be even improved if combined therapy could be used before ADA initiation, with the addition of this medical-surgical strategy. This study, even if retrospective, brings real-world data to an important question regarding the effectiveness of ADA in perianal fistulizing CD.
Significant controversy exists regarding the real benefits of this agent in this subpopulation of patients, mainly due to the lack of a prospective randomized placebo-controlled trial, as performed for infliximab, which allowed fistulizing CD to be one indication in the label of this biological agent.6 The same indication does not exist in the label of ADA, and in some countries reimbursement for fistulizing CD can be a difficult issue for that reason. Therefore, clinical data that prove the efficacy of ADA, as the results of this interesting Spanish multicenter case series, can help us to answer this important question, and put ADA as an important tool in the management of perianal fistulizing CD.
Paulo G. Kotze, MD* Antonino Spinelli, MD, PhDw *Colorectal Surgery Unit, Cajuru University Hospital, Catholic University of Parana´ (PUCPR), Curitiba, Parana´, Brazil wIBD Section, Colorectal Surgery Unit Department of Surgery, Istituto Clinico Humanitas, Milano, Italy
REFERENCES 1. Castan˜o-Milla C, Chaparro M, Saro C, et al. Adalimumab for perianal fistulizing Crohn’s disease: real world data adds important information for clinical practice. J Clin Gastroenterol. 2015;49: 34–40. 2. 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. 3. Fortea-Ormaechea JI, Gonza´lez-Lama Y, Casis B, et al. Adalimumab is effective in long-term real life clinical practice in both luminal and perianal Crohn’s disease. The Madrid experience. Gastroenterol Hepatol. 2011;34:443–448. 4. Echarri A, Castro J, Barreiro M, et al. Evaluation of adalimumab therapy in multidisciplinary strategy for perianal Crohn’s disease patients with infliximab failure. J Crohns Colitis. 2010;4: 654–660. 5. Gaertner WB, Decanini A, Mellgren A, et al. Does infliximab infusions impact results of operative treatment for Crohn’s perianal fistulas? Dis Colon Rectum. 2007;50:1754–1760. 6. Sands BE, Anderson FH, Bernstein CN, et al. Infliximab maintenance therapy for fistulizing Crohn’s disease. N Engl J Med. 2004;350:876–885.
Letters to the Editor
Combined Fibrosis Indices More Than 1 Way to Skin a Cat To the Editor: We read with interest the comments by Sertoglu et al1 emphasizing the need to evaluate combined fibrosis indices in patients with low levels of hepatitis B virus (HBV) DNA. Although the value of these combined markers has been clearly elucidated in patients with chronic HBV,2 they have not been explicitly studied in the low-replicative form of the disease. Although appended analyses to better identify significant fibrosis are required, the scope of our original study was limited to defining the predictors in the simplicity of the routinely available individual factors.3 Hence, in our view, the inclusion of combined indices would have created redundancy, and as such was beyond the scope of the prevailing mandate. In addition, Sertoglu and colleagues express concern regarding the manner of performing multivariate analysis. They advocate that parameters included in the multivariate model should only be those that are significant at a univariate level and not correlating with each other. We undoubtedly concur that only parameters significant at the univariate level ought to be included (which formed the basis of our evaluation); however, we take exception to the view that there must be an additional step of conducting a correlation analysis before inclusion of variables in the multivariate model. To the best of our knowledge, we remain unaware of this step’s necessity, usefulness, or legitimacy, having clearly checked the issue of multicollinearity (evaluating the SEs of coefficients) and interaction of variables included in the multivariate analysis model.4 Faisal M. Sanai, SBG, MD*w Khalid Alswat, MRCPw Waleed Al-Hamoudi, MDw Shaffi A. Shaikh, PhDz Ayman A. Abdo, FRCPCw *Department of Medicine Division of Gastroenterology King Abdulaziz Medical City Jeddah The authors declare that they have nothing to disclose.
Copyright
r
2014 Wolters Kluwer Health, Inc. All rights reserved.
www.jcge.com |
175
J Clin Gastroenterol
Letters to the Editor
wLiver Disease Research Center zDepartment of Family & Community Medicine, College of Medicine, King Saud University, Riyadh, Saudi Arabia
REFERENCES 1. Sertoglu E, Kayadibi H, Uyanik M. Importance of combined fibrosis indices
176 | www.jcge.com
in chronic hepatitis B patients with low viremia. J Clin Gastroenterol. 2015;49: 170–171. 2. Teshale E, Lu M, Rupp LB, et al. APRI and FIB-4 are good predictors of the stage of liver fibrosis in chronic hepatitis B: the Chronic Hepatitis Cohort Study (CHeCS). J Viral Hepat. 2014;21: 917–920.
Copyright
r
Volume 49, Number 2, February 2015
3. Abdo AA, Bzeizi KI, Babatin MA, et al. Predictors of significant fibrosis in chronic hepatitis B patients with low viremia. J Clin Gastroenterol. 2014;48: e50–e56. 4. Hosmer DW, Lemeshow S. In: Shewhart WA, Wilks SS, eds. Applied Logistic Regression. 2nd ed. New York: Wiley Inter-Science; 2000:47–90.
2014 Wolters Kluwer Health, Inc. All rights reserved.
