Letters to the Editor
We have 3 comments to make which will be developed below: (1) An important confirmatory study was not referenced; (2) It is unclear whether a U-shaped relationship with body mass index was sufficiently explored; and (3) The possibility to explore a dose–response relationship between degrees of obesity and risk of Crohn’s is present but was not taken. An important confirmatory study in addition to our own initial case–control study2 was reported last year from the Danish National Birth cohort.3 Surprisingly, this was not referenced in this article. Given the previous publication of a negative prospective study from the EPIC investigators in a much older population at baseline (median age at recruitment 53 years),4 it is important in assessing the likelihood that the association of obesity with developing Crohn’s disease is a true one. The report by Harpsoe et al describes the association of prepregnancy body mass index with a wide range of autoimmune diseases including Crohn’s disease in 75,008 women at baseline recruited from 1996 to 2002. The median age at recruitment was 30.2 years, and they were followed for a median of 11.4 years until December 2011. Evidence of a U-shaped relationship of baseline body mass index with Crohn’s disease (96 documented incident cases) but not ulcerative colitis was reported with a hazard ratio of 1.88 (1.02–3.47) for obese and 2.57 (1.30–5.06) for underweight versus normal weight women, respectively. This Ushaped relationship is in line with our own case–control study of weight at diagnosis. The 20 years of follow-up in NHSII was longer, but the mean age at recruitment was slightly older at around 35 years, with a median time to diagnosis of 9.7 years. The median time to diagnosis in the Danish National Birth Cohort is not stated but is likely to be substantially less than this given that the median time of follow-up was only 11.4 years. From the NHSII analysis, there is a suggestion that a U-shaped relationship is beginning to emerge in the data for updated body mass index which will have been within 2 years of diagnosis. Was this formally tested? This is more proximate to the date of diagnosis than the Danish
E18
Inflamm Bowel Dis Volume 21, Number 8, August 2015
National Birth Cohort which is in turn more proximate than NHSII baseline. A U-shaped relationship would support the idea that there may be two distinct etiologies underlying Montreal A2 and A3 Crohn’s disease, with one etiological pathway driving weight loss and obesity or the factors underlying it driving the other. The association with obesity at 18 years was stronger than the association at later ages with a hazard ratio of 2.48 (1.24–4.98) for the 9 obese subjects who later developed Crohn’s as opposed to 1.60 (1.07–2.39) for the 43 obese subjects at their most recent follow-up who developed Crohn’s. This is of interest but is not developed any further by the authors. It should be possible to analyze whether there is any graded dose response among these 43 obese subjects. As a minimum, it should be possible to add a further category of BMI .35 and also possibly BMI .40. The explanation for the stronger association with BMI at age 18 years may merely be because these subjects developed more severe obesity as they aged. A graded dose response would add greatly to the credibility of the association. In summary, it would be of interest if the NHSII investigators could confirm whether a U-shaped relationship exists in the data most proximate to incident Crohn’s cases and at successive data collection points back from this. This would give an idea for the length of the latent period for Crohn’s and shedding light on whether there may be distinct forms of Crohn’s disease with distinct etiologies. Second, the authors should explore whether there is a dose–response relationship particularly with the updated body mass index and also possibly the baseline BMI for the reasons given above. This would add further credibility to the association.
Michael Mendall, MA, MD* Derek Chan, MRCP† Devinder Kumar, PhD† *Department of Gastroenterology Croydon University Hospital and St George’s Medical School London, United Kingdom
†
Department of Surgery St George’s Medical School London, United Kingdom
REFERENCES 1. Khalilli HK, Anathakrishnan AN, Konijeti GG, et al. Measures of obesity and risk of Crohn’s disease and ulcerative colitis. Inflamm Bowel Dis. 2015;21:361–368. 2. Mendall MA, Gunarsekera AV, John BJ, et al. Is obesity a risk factor for Crohn’s disease? Dig Dis Sci. 2011;56:837. 3. Harsoe MC, Basit S, Andersson M, et al. Body mass index and risk of autoimmune diseases: a study within the Danish National Birth Cohort. Int J Epidemiol. 2014;43:843–855. 4. Chan SS, Luben R, Olsen A, et al. Body mass index and the risk of Crohn’s disease and ulcerative colitis: data from a European Prospective Cohort Study. Am J Gastroenterol. 2013;108:575–582.
Reply to Comments on Measures of Obesity and Risk of Crohn’s Disease and Ulcerative Colitis Reply: We appreciate the comments by Mendell et al regarding our study “Measures of Obesity and Risk of Crohn’s Disease and Ulcerative Colitis.” We are also pleased to review the results of the study by Harsoe et al,1 confirming our findings that obesity, as measured by body mass index (BMI), is associated with an increased risk of Crohn’s disease (CD). We did not initially reference this study because it was published after our article was initially submitted to Inflammatory Bowel Diseases.1,2 As stated in our Methods section, we did examine the possibility of a nonlinear association between obesity and risk of CD and UC using a previously reported nonparametric cubic spline method.3 This method allowed us to examine nonlinear associations including J- and U-shaped relationships between obesity of risk of CD. However, we did not find such associations between baseline BMI, updated BMI, BMI at age 18, and risk of CD. Nevertheless, as we collected environmental data Dr. Chan has served as a consultant for Bayer Healthcare, Pfizer Inc., and Pozen Inc. The authors have no other conflicts of interest to disclose. Copyright © 2015 Crohn’s & Colitis Foundation of America, Inc. DOI 10.1097/MIB.0000000000000485 Published online 24 June 2015.
| www.ibdjournal.org
Copyright © 2015 Crohn’s & Colitis Foundation of America, Inc. Unauthorized reproduction of this article is prohibited.
Inflamm Bowel Dis Volume 21, Number 8, August 2015
every 2 years, it is possible that the previously recognized U-shaped relationship is only observed with BMI information collected closer to the time of diagnosis. Regarding a dose relationship among participants with BMI $30 at baseline, age 18, or at least 2 years before diagnosis, we only had 1 case of CD with BMI .35; thus, we were not able to specifically assess for the presence of a dose relationship among obese participants.
Hamed Khalili, MD, MPH* Andrew T. Chan, MD, MPH*,† *Division of Gastroenterology Massachusetts General Hospital and Harvard Medical School Boston, Massachusetts † Channing Laboratory Department of Medicine Brigham and Women’s Hospital and Harvard Medical School Boston, Massachusetts
REFERENCES 1. Harpsoe MC, Basit S, Andersson M, et al. Body mass index and risk of autoimmune diseases: a study within the Danish National Birth Cohort. Int J Epidemiol. 2014;43:843–855. 2. Khalili H, Ananthakrishnan AN, Konijeti GG, et al. Measures of obesity and risk of Crohn’s disease and ulcerative colitis. Inflamm Bowel Dis. 2015;21:361–368. 3. Durrleman S, Simon R. Flexible regression models with cubic splines. Stat Med. 1989;8:551–561.
Body Fat Composition Predicts Infectious Complications After Bowel Resection in Crohn’s Disease To the Editor: We read with interest the article by Stidham et al1 regarding the fat accumulation and postoperative outcomes. In this study, the authors investigated whether body composition could be a predictor of The authors have no conflict of interest to disclose. Copyright © 2015 Crohn’s & Colitis Foundation of America, Inc. DOI 10.1097/MIB.0000000000000510 Published online 2 July 2015.
postoperative infectious complications in patients with Crohn’s disease (CD) undergoing intestinal resection. To our knowledge, this is the first study that evaluated the impact of fat composition on postoperative infectious complications in patients with CD using analytic morphomics. This study was well designed and conducted; however, there are several limitations from a clinical point of view on which we wish to add our consideration. First, risk factors such as CD-related surgical history, wound classification, and postoperative glucose value that are associated with infectious complications after surgery were not included in the analysis. Second, it is not presented in the article how many patients had CD-related abdominal surgical history that may affect the fat distribution on computed tomography. Third, for preoperative use of corticosteroids, it is interesting to know more information of the corticosteroids use such as how long it has been used and when it was stopped. This is important, considering the fact that corticosteroids use was demonstrated to be associated with fat accumulation and fat distribution. In addition, the correlations between corticosteroids use and fat composition and the level of C-reactive protein should also be evaluated because mesenteric fat is an important source of C-reactive protein in patients with CD.2 Fourth, the author demonstrated that subcutaneous-tovisceral fat ratio is an independent risk factor for postoperative infectious complications; however, the visceral-to-subcutaneous fat ratio was not assessed. It would be interesting to evaluate the predict value of visceralto-subcutaneous fat ratio on postoperative infectious complications because visceralto-subcutaneous fat ratio was found to be associated with complicated disease and level of C-reactive protein,3,4 and obesityassociated metabolic disorders correlate positively with visceral fat but not with subcutaneous fat. Finally, it should be noted that there is a difference between male and female patients in terms of body fat distribution.3–5 For example, a male patient with high fat volume in male group may have low rank in female group. It is more acceptable to rank the fat volume in male patients and female patients, respectively.
Letters to the Editor
The effect of body fat composition on postoperative outcome is very interesting. Although there are several limitations in the study, it provides a potential risk factor for postoperative adverse outcomes. Further prospective designed clinical trials are needed to confirm the predict value of body composition on postoperative sepsis complications.
Yi Li, MD, PhD*,† Weiming Zhu, MD* *Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China † Department of Colorectal Surgery, The Cleveland Clinic Foundation, Cleveland, Ohio
REFERENCES 1. Stidham RW, Waljee AK, Day NM, et al. Body fat composition assessment using analytic morphomics predicts infectious complications after bowel resection in Crohn’s disease. Inflamm Bowel Dis. 2015;21:1306–1313. 2. Peyrin-Biroulet L, Gonzalez F, Dubuquoy L, et al. Mesenteric fat as a source of C reactive protein and as a target for bacterial translocation in Crohn’s disease. Gut. 2012;61:78–85. 3. Li Y, Zhu W, Gong J, et al. Influence of exclusive enteral nutrition therapy on visceral fat in patients with Crohn’s disease. Inflamm Bowel Dis. 2014;20:1568–1574. 4. Erhayiem B, Dhingsa R, Hawkey CJ, et al. Ratio of visceral to subcutaneous fat area is a biomarker of complicated Crohn’s disease. Clin Gastroenterol Hepatol. 2011;9:684–687. 5. Li Y, Zhu W, Gong J, et al. Visceral fat area is associated with a high risk for early postoperative recurrence in Crohn’s disease. Colorectal Dis. 2015;17:225–234.
Reply to Body Fat Composition Predicts Infectious Complications After Bowel Resection in Crohn’s Disease Reply: We thank Drs. Li and Zhu for their thoughtful letter. Their correspondence The authors have no conflict of interest to disclose. Supported by Crohn’s and Colitis Foundation of America Career Development Award #3775 (to R.W.S.). Veterans Affairs HSR&D CDA-2 Career Development Award 1IK2HX000775 (to A.K.W.). Copyright © 2015 Crohn’s & Colitis Foundation of America, Inc. DOI 10.1097/MIB.0000000000000503 Published online 7 July 2015.
www.ibdjournal.org |
Copyright © 2015 Crohn’s & Colitis Foundation of America, Inc. Unauthorized reproduction of this article is prohibited.
E19
We have 3 comments to make which will be developed below: (1) An important confirmatory study was not referenced; (2) It is unclear whether a U-shaped relationship with body mass index was sufficiently explored; and (3) The possibility to explore a dose–response relationship between degrees of obesity and risk of Crohn’s is present but was not taken. An important confirmatory study in addition to our own initial case–control study2 was reported last year from the Danish National Birth cohort.3 Surprisingly, this was not referenced in this article. Given the previous publication of a negative prospective study from the EPIC investigators in a much older population at baseline (median age at recruitment 53 years),4 it is important in assessing the likelihood that the association of obesity with developing Crohn’s disease is a true one. The report by Harpsoe et al describes the association of prepregnancy body mass index with a wide range of autoimmune diseases including Crohn’s disease in 75,008 women at baseline recruited from 1996 to 2002. The median age at recruitment was 30.2 years, and they were followed for a median of 11.4 years until December 2011. Evidence of a U-shaped relationship of baseline body mass index with Crohn’s disease (96 documented incident cases) but not ulcerative colitis was reported with a hazard ratio of 1.88 (1.02–3.47) for obese and 2.57 (1.30–5.06) for underweight versus normal weight women, respectively. This Ushaped relationship is in line with our own case–control study of weight at diagnosis. The 20 years of follow-up in NHSII was longer, but the mean age at recruitment was slightly older at around 35 years, with a median time to diagnosis of 9.7 years. The median time to diagnosis in the Danish National Birth Cohort is not stated but is likely to be substantially less than this given that the median time of follow-up was only 11.4 years. From the NHSII analysis, there is a suggestion that a U-shaped relationship is beginning to emerge in the data for updated body mass index which will have been within 2 years of diagnosis. Was this formally tested? This is more proximate to the date of diagnosis than the Danish
E18
Inflamm Bowel Dis Volume 21, Number 8, August 2015
National Birth Cohort which is in turn more proximate than NHSII baseline. A U-shaped relationship would support the idea that there may be two distinct etiologies underlying Montreal A2 and A3 Crohn’s disease, with one etiological pathway driving weight loss and obesity or the factors underlying it driving the other. The association with obesity at 18 years was stronger than the association at later ages with a hazard ratio of 2.48 (1.24–4.98) for the 9 obese subjects who later developed Crohn’s as opposed to 1.60 (1.07–2.39) for the 43 obese subjects at their most recent follow-up who developed Crohn’s. This is of interest but is not developed any further by the authors. It should be possible to analyze whether there is any graded dose response among these 43 obese subjects. As a minimum, it should be possible to add a further category of BMI .35 and also possibly BMI .40. The explanation for the stronger association with BMI at age 18 years may merely be because these subjects developed more severe obesity as they aged. A graded dose response would add greatly to the credibility of the association. In summary, it would be of interest if the NHSII investigators could confirm whether a U-shaped relationship exists in the data most proximate to incident Crohn’s cases and at successive data collection points back from this. This would give an idea for the length of the latent period for Crohn’s and shedding light on whether there may be distinct forms of Crohn’s disease with distinct etiologies. Second, the authors should explore whether there is a dose–response relationship particularly with the updated body mass index and also possibly the baseline BMI for the reasons given above. This would add further credibility to the association.
Michael Mendall, MA, MD* Derek Chan, MRCP† Devinder Kumar, PhD† *Department of Gastroenterology Croydon University Hospital and St George’s Medical School London, United Kingdom
†
Department of Surgery St George’s Medical School London, United Kingdom
REFERENCES 1. Khalilli HK, Anathakrishnan AN, Konijeti GG, et al. Measures of obesity and risk of Crohn’s disease and ulcerative colitis. Inflamm Bowel Dis. 2015;21:361–368. 2. Mendall MA, Gunarsekera AV, John BJ, et al. Is obesity a risk factor for Crohn’s disease? Dig Dis Sci. 2011;56:837. 3. Harsoe MC, Basit S, Andersson M, et al. Body mass index and risk of autoimmune diseases: a study within the Danish National Birth Cohort. Int J Epidemiol. 2014;43:843–855. 4. Chan SS, Luben R, Olsen A, et al. Body mass index and the risk of Crohn’s disease and ulcerative colitis: data from a European Prospective Cohort Study. Am J Gastroenterol. 2013;108:575–582.
Reply to Comments on Measures of Obesity and Risk of Crohn’s Disease and Ulcerative Colitis Reply: We appreciate the comments by Mendell et al regarding our study “Measures of Obesity and Risk of Crohn’s Disease and Ulcerative Colitis.” We are also pleased to review the results of the study by Harsoe et al,1 confirming our findings that obesity, as measured by body mass index (BMI), is associated with an increased risk of Crohn’s disease (CD). We did not initially reference this study because it was published after our article was initially submitted to Inflammatory Bowel Diseases.1,2 As stated in our Methods section, we did examine the possibility of a nonlinear association between obesity and risk of CD and UC using a previously reported nonparametric cubic spline method.3 This method allowed us to examine nonlinear associations including J- and U-shaped relationships between obesity of risk of CD. However, we did not find such associations between baseline BMI, updated BMI, BMI at age 18, and risk of CD. Nevertheless, as we collected environmental data Dr. Chan has served as a consultant for Bayer Healthcare, Pfizer Inc., and Pozen Inc. The authors have no other conflicts of interest to disclose. Copyright © 2015 Crohn’s & Colitis Foundation of America, Inc. DOI 10.1097/MIB.0000000000000485 Published online 24 June 2015.
| www.ibdjournal.org
Copyright © 2015 Crohn’s & Colitis Foundation of America, Inc. Unauthorized reproduction of this article is prohibited.
Inflamm Bowel Dis Volume 21, Number 8, August 2015
every 2 years, it is possible that the previously recognized U-shaped relationship is only observed with BMI information collected closer to the time of diagnosis. Regarding a dose relationship among participants with BMI $30 at baseline, age 18, or at least 2 years before diagnosis, we only had 1 case of CD with BMI .35; thus, we were not able to specifically assess for the presence of a dose relationship among obese participants.
Hamed Khalili, MD, MPH* Andrew T. Chan, MD, MPH*,† *Division of Gastroenterology Massachusetts General Hospital and Harvard Medical School Boston, Massachusetts † Channing Laboratory Department of Medicine Brigham and Women’s Hospital and Harvard Medical School Boston, Massachusetts
REFERENCES 1. Harpsoe MC, Basit S, Andersson M, et al. Body mass index and risk of autoimmune diseases: a study within the Danish National Birth Cohort. Int J Epidemiol. 2014;43:843–855. 2. Khalili H, Ananthakrishnan AN, Konijeti GG, et al. Measures of obesity and risk of Crohn’s disease and ulcerative colitis. Inflamm Bowel Dis. 2015;21:361–368. 3. Durrleman S, Simon R. Flexible regression models with cubic splines. Stat Med. 1989;8:551–561.
Body Fat Composition Predicts Infectious Complications After Bowel Resection in Crohn’s Disease To the Editor: We read with interest the article by Stidham et al1 regarding the fat accumulation and postoperative outcomes. In this study, the authors investigated whether body composition could be a predictor of The authors have no conflict of interest to disclose. Copyright © 2015 Crohn’s & Colitis Foundation of America, Inc. DOI 10.1097/MIB.0000000000000510 Published online 2 July 2015.
postoperative infectious complications in patients with Crohn’s disease (CD) undergoing intestinal resection. To our knowledge, this is the first study that evaluated the impact of fat composition on postoperative infectious complications in patients with CD using analytic morphomics. This study was well designed and conducted; however, there are several limitations from a clinical point of view on which we wish to add our consideration. First, risk factors such as CD-related surgical history, wound classification, and postoperative glucose value that are associated with infectious complications after surgery were not included in the analysis. Second, it is not presented in the article how many patients had CD-related abdominal surgical history that may affect the fat distribution on computed tomography. Third, for preoperative use of corticosteroids, it is interesting to know more information of the corticosteroids use such as how long it has been used and when it was stopped. This is important, considering the fact that corticosteroids use was demonstrated to be associated with fat accumulation and fat distribution. In addition, the correlations between corticosteroids use and fat composition and the level of C-reactive protein should also be evaluated because mesenteric fat is an important source of C-reactive protein in patients with CD.2 Fourth, the author demonstrated that subcutaneous-tovisceral fat ratio is an independent risk factor for postoperative infectious complications; however, the visceral-to-subcutaneous fat ratio was not assessed. It would be interesting to evaluate the predict value of visceralto-subcutaneous fat ratio on postoperative infectious complications because visceralto-subcutaneous fat ratio was found to be associated with complicated disease and level of C-reactive protein,3,4 and obesityassociated metabolic disorders correlate positively with visceral fat but not with subcutaneous fat. Finally, it should be noted that there is a difference between male and female patients in terms of body fat distribution.3–5 For example, a male patient with high fat volume in male group may have low rank in female group. It is more acceptable to rank the fat volume in male patients and female patients, respectively.
Letters to the Editor
The effect of body fat composition on postoperative outcome is very interesting. Although there are several limitations in the study, it provides a potential risk factor for postoperative adverse outcomes. Further prospective designed clinical trials are needed to confirm the predict value of body composition on postoperative sepsis complications.
Yi Li, MD, PhD*,† Weiming Zhu, MD* *Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China † Department of Colorectal Surgery, The Cleveland Clinic Foundation, Cleveland, Ohio
REFERENCES 1. Stidham RW, Waljee AK, Day NM, et al. Body fat composition assessment using analytic morphomics predicts infectious complications after bowel resection in Crohn’s disease. Inflamm Bowel Dis. 2015;21:1306–1313. 2. Peyrin-Biroulet L, Gonzalez F, Dubuquoy L, et al. Mesenteric fat as a source of C reactive protein and as a target for bacterial translocation in Crohn’s disease. Gut. 2012;61:78–85. 3. Li Y, Zhu W, Gong J, et al. Influence of exclusive enteral nutrition therapy on visceral fat in patients with Crohn’s disease. Inflamm Bowel Dis. 2014;20:1568–1574. 4. Erhayiem B, Dhingsa R, Hawkey CJ, et al. Ratio of visceral to subcutaneous fat area is a biomarker of complicated Crohn’s disease. Clin Gastroenterol Hepatol. 2011;9:684–687. 5. Li Y, Zhu W, Gong J, et al. Visceral fat area is associated with a high risk for early postoperative recurrence in Crohn’s disease. Colorectal Dis. 2015;17:225–234.
Reply to Body Fat Composition Predicts Infectious Complications After Bowel Resection in Crohn’s Disease Reply: We thank Drs. Li and Zhu for their thoughtful letter. Their correspondence The authors have no conflict of interest to disclose. Supported by Crohn’s and Colitis Foundation of America Career Development Award #3775 (to R.W.S.). Veterans Affairs HSR&D CDA-2 Career Development Award 1IK2HX000775 (to A.K.W.). Copyright © 2015 Crohn’s & Colitis Foundation of America, Inc. DOI 10.1097/MIB.0000000000000503 Published online 7 July 2015.
www.ibdjournal.org |
Copyright © 2015 Crohn’s & Colitis Foundation of America, Inc. Unauthorized reproduction of this article is prohibited.
E19
