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Cost utility of initial medical management for Crohn's disease perianal fistula
April 2 0 0 2
cells, 3-dimensional reconstructions show that nerve varicosities surround the ICC-IM cells. Both smooth muscles, as well as ICC-IMs, are equally exposed to neurotransmitter release from nerve varicosities. Moreover, it is not clear how ICC-IMs provide neurochemical information to the smooth muscle cells. The proposal that ICCs act to amplify nitric oxide production 8 has not been substantiated. If ICC-IM act by converting neurochemical signals into electrical signals, then a larger body of data showing nonelectrogenic smooth muscle responses remains unexplained. 4 Also, a more recent study argues against conventional gap junction coupling of ICC neurotransmission to LES smooth muscles in dogs. 9 The results of functional studies in W / W v mice lacking ICC-IM also do not establish the role of ICC-IM in neuromuscular transmission. The reported findings of abnormalities in these mice have been inconsistent, contradictory, and open to different interpretations. For example, Ward et al. 2 reported that inhibitory junction potentials (IJPs) are suppressed in W / W v mice, but their Figure (Figure 9) shows that IJP is increased in W / W v mouse with electrical stimulation at 1 Hz. Moreover, nitrergic IJP and cholinergic excitatory junction potential (EJP) are suppressed in W / W v mice, but the nonnitrergic IJP remains unchanged. 2,3 In our studies, neither nitrergic nor purinergic IJP in the pylorus was significantly depressed in W / W v mice. 1° It has also been reported that hyperpolarization to the nitric oxide donor sodium nitroprusside is suppressed, consistent with a role for ICC in nitrergic neurotransmission. 2.1° However, depolarization in W / W ~ mice due to acetylcholine is reportedly enhanced, an observation that is not consistent with the role of ICC in cholinergic excitatory neurotransmission. 3 Many of the observed findings in W / W v could be explained by abnormalities in smooth muscles themselves. For example, lack of hyperpolarization but normal relaxation of smooth muscle cells, 2,H abnormal pattern of contraction indicating abnormality of K + channels, 3 and inability to maintain tone may all be due to muscular abnormalities in W / W v mice. Moreover, increased compliance of gastric muscle in W / W v mutants that is more than that observed with atropine-treated wildtype mice, 3 and LES hypotension in these animals, 1 are difficult to ascribe solely to the deficiency of cholinergic excitatory neurotransmission if these mutants have simultaneous deficiencies of both cholinergic excitatory and nitrergic inhibitory neurotransmission. 3,5 ICC-IM has been recently suggested to be responsible for the secondary regenerative component of the slow waves which is missing in the stomachs of W / W v mutants. 12,I3 Because c-kit deficiency may affect the function and development of many types of cells, it is possible that c-kit deficiency may affect smooth muscle function and regenerative potential independent of producing deficiency of ICC-IM. W e believe that these observations are more consistent with myogenic abnormality in W / W v mice rather than deficiency of neural transmission. W e agree with Sanders et al. that further studies are needed not only to define the role of ICC-IM in neuromuscular transmission, but also to investigate the possible muscle abnormalities in W / W v mutant mice. DIGAVALLI V. SIVARAO H I R O S H I L. M A S H I M O H E M A N T S. THATTE RAJ K. GOYAL
Center for Swallowing and Motility Disorders Department of Veterans Affairs Medical Center West Roxbury, Massachusetts Harvard Medical School Boston, Massachusetts
CORRESPONDENCE
1187
1. Sivarao DV, Mashimo HL, Thatte HS, Goyal RK. Lower esophageal sphincter is achalasic in n N O S ( - / - ) and hypotensive in W/W(v) mutant mice. Gastroenterology 2 0 0 1 ; 1 2 1 : 3 4 - 4 2 . 2. Ward SM, Morris G, Reese L, Wang XY, Sanders KM. Interstitial cells of Cajal mediate enteric inhibitory neurotransmission in the lower esophageal and pyloric sphincters. Gastroenterology 1998; 115:314-329. 3. Ward SM, Beckett EA, Wang X, Baker F, Khoyi M, Sanders KM. Interstitial cells of Cajal mediate cholinergic neurotransmission from enteric motor neurons. J Neurosci 2 0 0 0 ; 2 0 : 1 3 9 3 - 1 4 0 3 . 4. Goyal RK, Sivarao DV. Functional anatomy and physiology of swallowing and esophageal motility. In: The Esophagus (3rd ed.), edited by D.O. Castell and J.E. Richter, Lippincott Williams & Wilkins, New York, NY, 1999. 5. Sanders KM. A case for interstitial cells of Cajal as pacemakers and mediators of neurotransmission to the gastrointestinal tract. Gastroenterology 1996;111:492-515. 6. Daniel EE, Posey-Daniel V. Neuromuscular structures in opossum esophagus; role of interstitial cells of Cajal. Am J Physiol 1984; 246:G305-G315. 7. Burnstock G. Structure of smooth muscle and its innervation. In: Bulbring E, Brading AF, Jones AW, Tomita T. Smooth muscle. Baltimore: Williams & Wilkins, 1 9 7 0 ; 1 - 6 9 . 8. Publicover NG, Hammond EM, Sanders KM. Amplification of nitric oxide signaling by interstitial cells isolated from canine colon. Proc Natl Acad Sci U S A 1993:1;90:2087-2091. 9. Daniel EE, Thomas J, Ramnarain M, Bowes TJ, Jury J. Do gap junctions couple interstitial cells of Cajal pacing and neurotransmission to gastrointestinal smooth muscle? Neurogastroenterol Mot 2 0 0 1 ; 1 3 : 2 9 7 - 3 0 7 . 10. He XD, Sang Q, Thatte H, Goyal RK. Inhibitory junction potential in pylorus of W/Wv mutant mouse. Gastroenterology 2000;118: A634. 11. Burns AJ, Lomax AB, Torihashi S, Sanders KM, Ward SM. Interstitial cells of Cajal mediate inhibitory neurotransmission in the stomach. Proc Natl Acad Sci U S A 1 9 9 6 ; 9 3 : 1 2 0 0 8 - 1 2 0 1 3 . 12. Dickens EJ, Edwards FR, Hirst GD. Selective knockout of intramuscular interstitial cells reveals their role in the generation of slow waves in mouse stomach. J Physiol 2001:15;531(Pt 3): 827-833. 13. He XD, Goyal RK. Effect of ion channel blockers on the slow waves activity in the antrum of WT and W/Wv mice. Gastroenterology 2001;120:A202.
Cost Utility of Initial Medical Management for Crohn's Disease Perianal Fistula Dear Sir: The recent cost utility analysis by Arseneau et al. 1 of the initial management of Crohn's disease fistulas was a very comprehensive study of an often challenging problem. However, one must exercise caution when interpreting their results, as serious questions regarding their study design jeopardize the validity of their findings and conclusions. In particular, the exclusion of surgical costs from the model, study selection, and validity of the patient population chosen to determine the utility scores, all need further justification. Studies of the cost of Crohn's disease have repeatedly shown that the overwhelming majority of costs associated with treatment of this disease are spent on surgery and hospitalization. Hay and Hay's model described 80% of costs coming from these 2 areas. 2 Hospitalized Crohn's patients in our University of Chicago study had 40% of costs and nearly 75% of charges due to surgery, 3 while the number was 61% in the Canadian hospitalization experience. 4 Patients with fistulizing Crohn's have been shown to have higher average annual
1188
CORRESPONDENCE
medical costs (predominately because of inpatient services) than those with luminal Crohn's. 5 Our group published preliminary data suggesting that infliximab decreases the utilization of health care resources in patients with Crohn's fistulas, with significant decreases in GI-related surgeries, emergency room visits, and endoscopies. 6 The exclusion of surgical cost data from the Arseneau study makes it difficult to apply their findings to the management of patients with Crohn's disease. Careful review of the 12 studies selected by Arseneau's group for their analysis reveals that only one is a study of the use of metronidazole v (the other was a preliminary publication of the same patientsS). Likewise, the "two" studies of the use of 6-mercaptopurine are also a duplication of a single initial population (reported in the placebo-controlled trial 9) with the latter addition of open-label pat i e n t s ) ° There is no study cited that clearly includes the "combination 6-mercaptopurine and azathioprine," which is the group that constitutes the comparator for the Arseneau study (only 2 patients were on "antimetabolites" in the metronidazole study by Bernstein et al. 8 and an unclear number of patients were on antibiotics in the 6-mercaptopurine (6-MP) study by Present et al.9). The theory put forth by the Arseneau group that one could sequentially piece together the data from metronidazole as the short-term response and 6-MP as the long-term response in determining the rates used for their analysis needs validation. It is also difficult to justify the practice of comparing unblinded, uncontrolled data from the metronidazole study 7 and the latter 6-MP study 9 with the double-blinded, placebo-controlled infliximab trial.~l Overestimation of benefit rates as high as 41% has been described in poorly concealed or unblinded studies) 2 Furthermore, the study populations are different, as the infliximab trial included only patients with fistulas refractory to other therapies. Fistula improvement rates with infliximab may have been even higher if "all comers" were included. Nearly one-half of the patients used to determine the utility scores of fistula improvement in the Arseneau study did not even have Crohn's fistulas! The authors conclude that since they did not show a difference in utility scores between Crohn's fistula patients and those without fistulas, or healthy controls, that it would be permissible to use the scores to represent the entire population. This surprising failure to show such a difference between these groups raises concerns over the validity of using utility analysis in these patients, the correlation of utility scores to other scales of clinical outcomes or quality of life in these patients, and the subsequent inclusion of this utility data in the Arseneau analysis. The quality of a complex utility analysis is only as good as the data that is put into the model. The exclusion of costs associated with surgeries, the inclusion of open-label experiences in the analysis, and questions surrounding the validity of the utility scores, raise too many legitimate concerns to currently accept the conclusions of the Arseneau group. As the authors admit, prospective studies comparing various fistula therapies would be more appropriate sources of data to use in future analyses. RUSSELL D. C O H E N
Department of Medicine Section of Gastroenterology Unil*rsity of Chicago Medical Center Chicago, Illinois 1. Arseneau KO, Cohn SM, Cominelli F, Connors AF, Jr. Cost-utility of initial medical management for Crohn's disease perianal fistulae. Gastroenterology 2 0 0 1 ; 1 2 0 : 1 6 4 0 - 1 6 5 6 .
GASTROENTEROLOGY Vol. 122, No. 4
2. Hay JW, Hay AR. Inflammatory bowel disease: costs-of-illness. J Clin Gastroenterol 1 9 9 2 ; 1 4 : 3 0 9 - 3 1 7 . 3. Cohen RD, Larson LR, Roth JR, Becker RV, Mummert MM. The cost of hospitalizations in Crohn's disease. Am J Gastroenterol 2000;95:524-530. 4. Bernstein CN, Papineau N, Zajaczkowski J, Rawsthorne P, Okrusko G, Blanchard JF. Direct hospital costs for patients with inflammatory bowel disease in a Canadian tertiary care university hospital [see comments]. Am J Gastroenterol 2 0 0 0 ; 9 5 : 6 7 7 683. 5. Feagan BG, Vreeland MG, Larson LR, Bala MV. Annual cost of care for Crohn's disease: a payor perspective. Am J Gastroenterol 2000;95:1955-1960. 6. Rubenstein JH, Chong RY, Cohen RD. Infliximab decreases resource utilization in patients with Crohn's disease (abstr). Am J Gastroenterol 2 0 0 0 ; 9 5 : 2 4 9 9 - 2 5 0 0 . 7. Brandt U, Bernstein LH, Boley SJ, Frank MS. Metronidazole therapy for perineal Crohn's disease: a follow-up study. Gastroenterology 1 9 8 2 ; 8 3 : 3 8 3 - 3 8 7 . 8. Bernstein LH, Frank MS, Brandt LI, Boley SJ. Healing of perineal Crohn's disease with metronidazole. Gastroenterology 1980;79: 599. 9. Present DH, Korelitz BI, Wisch N, Glass JL, Sachar DB, Pasternack BS. Treatment of Crohn's disease with 6-mercaptopurine. A long-term, randomized, double-blind study. N Engl J Med 1980; 302:981-987. 10. Korelitz BI, Present DH. Favorable effect of 6-mercaptopurine on fistulae of Crohn's disease. Dig Dis Sci 1 9 8 5 ; 3 0 : 5 8 - 6 4 . 11. Present DH, Rutgeerts P, Targan S, Hanauer SB, Mayer L, van Hogezand RA, Podolsky DK, Sands BE, Braakman T, DeWoody KL, Schaible TF, van Deventer 8J. Infliximab for the treatment of fistulas in patients with Crohn's disease. N Engl J Med 1999; 340:1398-1405. 12. Schulz KF, Chalmers I, Hayes RJ, Altman DG. Empirical evidence of bias. Dimensions of methodological quality associated with estimates of treatment effects in controlled trials. JAMA 1995; 273:408-412.
The author is a consultantfor Centocor. doi:10.1053/gast.2002.32782 Reply. W e appreciate the interest shown by Dr. Cohen with regard to our article. As the title clearly states, the intent of our paper was to compare specifically medical interventions for Crohn's disease perianal fistula. However, we recognize that surgery is an option for these patients. In fact, we originally included seton placement as an intervention in earlier versions of the model, but removed it from the analysis after careful consideration. It is well known that surgery is an uncommon treatment option for initial Crohn's perianal disease. In an analysis of the surgery rate among 116 fistulizing Crohn's patients at the University of Virginia, we used our hospital claims database to identify all cases that received conservative surgical therapy (fistulectomy, fistulotomy, or seton placement) during a 1-year period. W e found only 6 cases (5%). Since this number may include patients with long-standing fistula, we conclude that the true rate of surgery during the first year of treatment at our institution is less than 5%, making the inclusion of surgical data not relevant to our analysis. In his letter, Dr. Cohen refers to 3 cost analyses? 3 These studies assess the overall cost of Crohn's disease, but do not distinguish between costs for fistulizing vs. nonfistulizing Crohn's. W e caution Dr. Cohen to remember that Crohn's disease includes distinct clinical phenotypes, each of which may warrant unique patterns of care. Dr. Cohen later states that, "Patients with fistulizing Crohn's have been shown to have higher average annual medical costs (predominantly
cells, 3-dimensional reconstructions show that nerve varicosities surround the ICC-IM cells. Both smooth muscles, as well as ICC-IMs, are equally exposed to neurotransmitter release from nerve varicosities. Moreover, it is not clear how ICC-IMs provide neurochemical information to the smooth muscle cells. The proposal that ICCs act to amplify nitric oxide production 8 has not been substantiated. If ICC-IM act by converting neurochemical signals into electrical signals, then a larger body of data showing nonelectrogenic smooth muscle responses remains unexplained. 4 Also, a more recent study argues against conventional gap junction coupling of ICC neurotransmission to LES smooth muscles in dogs. 9 The results of functional studies in W / W v mice lacking ICC-IM also do not establish the role of ICC-IM in neuromuscular transmission. The reported findings of abnormalities in these mice have been inconsistent, contradictory, and open to different interpretations. For example, Ward et al. 2 reported that inhibitory junction potentials (IJPs) are suppressed in W / W v mice, but their Figure (Figure 9) shows that IJP is increased in W / W v mouse with electrical stimulation at 1 Hz. Moreover, nitrergic IJP and cholinergic excitatory junction potential (EJP) are suppressed in W / W v mice, but the nonnitrergic IJP remains unchanged. 2,3 In our studies, neither nitrergic nor purinergic IJP in the pylorus was significantly depressed in W / W v mice. 1° It has also been reported that hyperpolarization to the nitric oxide donor sodium nitroprusside is suppressed, consistent with a role for ICC in nitrergic neurotransmission. 2.1° However, depolarization in W / W ~ mice due to acetylcholine is reportedly enhanced, an observation that is not consistent with the role of ICC in cholinergic excitatory neurotransmission. 3 Many of the observed findings in W / W v could be explained by abnormalities in smooth muscles themselves. For example, lack of hyperpolarization but normal relaxation of smooth muscle cells, 2,H abnormal pattern of contraction indicating abnormality of K + channels, 3 and inability to maintain tone may all be due to muscular abnormalities in W / W v mice. Moreover, increased compliance of gastric muscle in W / W v mutants that is more than that observed with atropine-treated wildtype mice, 3 and LES hypotension in these animals, 1 are difficult to ascribe solely to the deficiency of cholinergic excitatory neurotransmission if these mutants have simultaneous deficiencies of both cholinergic excitatory and nitrergic inhibitory neurotransmission. 3,5 ICC-IM has been recently suggested to be responsible for the secondary regenerative component of the slow waves which is missing in the stomachs of W / W v mutants. 12,I3 Because c-kit deficiency may affect the function and development of many types of cells, it is possible that c-kit deficiency may affect smooth muscle function and regenerative potential independent of producing deficiency of ICC-IM. W e believe that these observations are more consistent with myogenic abnormality in W / W v mice rather than deficiency of neural transmission. W e agree with Sanders et al. that further studies are needed not only to define the role of ICC-IM in neuromuscular transmission, but also to investigate the possible muscle abnormalities in W / W v mutant mice. DIGAVALLI V. SIVARAO H I R O S H I L. M A S H I M O H E M A N T S. THATTE RAJ K. GOYAL
Center for Swallowing and Motility Disorders Department of Veterans Affairs Medical Center West Roxbury, Massachusetts Harvard Medical School Boston, Massachusetts
CORRESPONDENCE
1187
1. Sivarao DV, Mashimo HL, Thatte HS, Goyal RK. Lower esophageal sphincter is achalasic in n N O S ( - / - ) and hypotensive in W/W(v) mutant mice. Gastroenterology 2 0 0 1 ; 1 2 1 : 3 4 - 4 2 . 2. Ward SM, Morris G, Reese L, Wang XY, Sanders KM. Interstitial cells of Cajal mediate enteric inhibitory neurotransmission in the lower esophageal and pyloric sphincters. Gastroenterology 1998; 115:314-329. 3. Ward SM, Beckett EA, Wang X, Baker F, Khoyi M, Sanders KM. Interstitial cells of Cajal mediate cholinergic neurotransmission from enteric motor neurons. J Neurosci 2 0 0 0 ; 2 0 : 1 3 9 3 - 1 4 0 3 . 4. Goyal RK, Sivarao DV. Functional anatomy and physiology of swallowing and esophageal motility. In: The Esophagus (3rd ed.), edited by D.O. Castell and J.E. Richter, Lippincott Williams & Wilkins, New York, NY, 1999. 5. Sanders KM. A case for interstitial cells of Cajal as pacemakers and mediators of neurotransmission to the gastrointestinal tract. Gastroenterology 1996;111:492-515. 6. Daniel EE, Posey-Daniel V. Neuromuscular structures in opossum esophagus; role of interstitial cells of Cajal. Am J Physiol 1984; 246:G305-G315. 7. Burnstock G. Structure of smooth muscle and its innervation. In: Bulbring E, Brading AF, Jones AW, Tomita T. Smooth muscle. Baltimore: Williams & Wilkins, 1 9 7 0 ; 1 - 6 9 . 8. Publicover NG, Hammond EM, Sanders KM. Amplification of nitric oxide signaling by interstitial cells isolated from canine colon. Proc Natl Acad Sci U S A 1993:1;90:2087-2091. 9. Daniel EE, Thomas J, Ramnarain M, Bowes TJ, Jury J. Do gap junctions couple interstitial cells of Cajal pacing and neurotransmission to gastrointestinal smooth muscle? Neurogastroenterol Mot 2 0 0 1 ; 1 3 : 2 9 7 - 3 0 7 . 10. He XD, Sang Q, Thatte H, Goyal RK. Inhibitory junction potential in pylorus of W/Wv mutant mouse. Gastroenterology 2000;118: A634. 11. Burns AJ, Lomax AB, Torihashi S, Sanders KM, Ward SM. Interstitial cells of Cajal mediate inhibitory neurotransmission in the stomach. Proc Natl Acad Sci U S A 1 9 9 6 ; 9 3 : 1 2 0 0 8 - 1 2 0 1 3 . 12. Dickens EJ, Edwards FR, Hirst GD. Selective knockout of intramuscular interstitial cells reveals their role in the generation of slow waves in mouse stomach. J Physiol 2001:15;531(Pt 3): 827-833. 13. He XD, Goyal RK. Effect of ion channel blockers on the slow waves activity in the antrum of WT and W/Wv mice. Gastroenterology 2001;120:A202.
Cost Utility of Initial Medical Management for Crohn's Disease Perianal Fistula Dear Sir: The recent cost utility analysis by Arseneau et al. 1 of the initial management of Crohn's disease fistulas was a very comprehensive study of an often challenging problem. However, one must exercise caution when interpreting their results, as serious questions regarding their study design jeopardize the validity of their findings and conclusions. In particular, the exclusion of surgical costs from the model, study selection, and validity of the patient population chosen to determine the utility scores, all need further justification. Studies of the cost of Crohn's disease have repeatedly shown that the overwhelming majority of costs associated with treatment of this disease are spent on surgery and hospitalization. Hay and Hay's model described 80% of costs coming from these 2 areas. 2 Hospitalized Crohn's patients in our University of Chicago study had 40% of costs and nearly 75% of charges due to surgery, 3 while the number was 61% in the Canadian hospitalization experience. 4 Patients with fistulizing Crohn's have been shown to have higher average annual
1188
CORRESPONDENCE
medical costs (predominately because of inpatient services) than those with luminal Crohn's. 5 Our group published preliminary data suggesting that infliximab decreases the utilization of health care resources in patients with Crohn's fistulas, with significant decreases in GI-related surgeries, emergency room visits, and endoscopies. 6 The exclusion of surgical cost data from the Arseneau study makes it difficult to apply their findings to the management of patients with Crohn's disease. Careful review of the 12 studies selected by Arseneau's group for their analysis reveals that only one is a study of the use of metronidazole v (the other was a preliminary publication of the same patientsS). Likewise, the "two" studies of the use of 6-mercaptopurine are also a duplication of a single initial population (reported in the placebo-controlled trial 9) with the latter addition of open-label pat i e n t s ) ° There is no study cited that clearly includes the "combination 6-mercaptopurine and azathioprine," which is the group that constitutes the comparator for the Arseneau study (only 2 patients were on "antimetabolites" in the metronidazole study by Bernstein et al. 8 and an unclear number of patients were on antibiotics in the 6-mercaptopurine (6-MP) study by Present et al.9). The theory put forth by the Arseneau group that one could sequentially piece together the data from metronidazole as the short-term response and 6-MP as the long-term response in determining the rates used for their analysis needs validation. It is also difficult to justify the practice of comparing unblinded, uncontrolled data from the metronidazole study 7 and the latter 6-MP study 9 with the double-blinded, placebo-controlled infliximab trial.~l Overestimation of benefit rates as high as 41% has been described in poorly concealed or unblinded studies) 2 Furthermore, the study populations are different, as the infliximab trial included only patients with fistulas refractory to other therapies. Fistula improvement rates with infliximab may have been even higher if "all comers" were included. Nearly one-half of the patients used to determine the utility scores of fistula improvement in the Arseneau study did not even have Crohn's fistulas! The authors conclude that since they did not show a difference in utility scores between Crohn's fistula patients and those without fistulas, or healthy controls, that it would be permissible to use the scores to represent the entire population. This surprising failure to show such a difference between these groups raises concerns over the validity of using utility analysis in these patients, the correlation of utility scores to other scales of clinical outcomes or quality of life in these patients, and the subsequent inclusion of this utility data in the Arseneau analysis. The quality of a complex utility analysis is only as good as the data that is put into the model. The exclusion of costs associated with surgeries, the inclusion of open-label experiences in the analysis, and questions surrounding the validity of the utility scores, raise too many legitimate concerns to currently accept the conclusions of the Arseneau group. As the authors admit, prospective studies comparing various fistula therapies would be more appropriate sources of data to use in future analyses. RUSSELL D. C O H E N
Department of Medicine Section of Gastroenterology Unil*rsity of Chicago Medical Center Chicago, Illinois 1. Arseneau KO, Cohn SM, Cominelli F, Connors AF, Jr. Cost-utility of initial medical management for Crohn's disease perianal fistulae. Gastroenterology 2 0 0 1 ; 1 2 0 : 1 6 4 0 - 1 6 5 6 .
GASTROENTEROLOGY Vol. 122, No. 4
2. Hay JW, Hay AR. Inflammatory bowel disease: costs-of-illness. J Clin Gastroenterol 1 9 9 2 ; 1 4 : 3 0 9 - 3 1 7 . 3. Cohen RD, Larson LR, Roth JR, Becker RV, Mummert MM. The cost of hospitalizations in Crohn's disease. Am J Gastroenterol 2000;95:524-530. 4. Bernstein CN, Papineau N, Zajaczkowski J, Rawsthorne P, Okrusko G, Blanchard JF. Direct hospital costs for patients with inflammatory bowel disease in a Canadian tertiary care university hospital [see comments]. Am J Gastroenterol 2 0 0 0 ; 9 5 : 6 7 7 683. 5. Feagan BG, Vreeland MG, Larson LR, Bala MV. Annual cost of care for Crohn's disease: a payor perspective. Am J Gastroenterol 2000;95:1955-1960. 6. Rubenstein JH, Chong RY, Cohen RD. Infliximab decreases resource utilization in patients with Crohn's disease (abstr). Am J Gastroenterol 2 0 0 0 ; 9 5 : 2 4 9 9 - 2 5 0 0 . 7. Brandt U, Bernstein LH, Boley SJ, Frank MS. Metronidazole therapy for perineal Crohn's disease: a follow-up study. Gastroenterology 1 9 8 2 ; 8 3 : 3 8 3 - 3 8 7 . 8. Bernstein LH, Frank MS, Brandt LI, Boley SJ. Healing of perineal Crohn's disease with metronidazole. Gastroenterology 1980;79: 599. 9. Present DH, Korelitz BI, Wisch N, Glass JL, Sachar DB, Pasternack BS. Treatment of Crohn's disease with 6-mercaptopurine. A long-term, randomized, double-blind study. N Engl J Med 1980; 302:981-987. 10. Korelitz BI, Present DH. Favorable effect of 6-mercaptopurine on fistulae of Crohn's disease. Dig Dis Sci 1 9 8 5 ; 3 0 : 5 8 - 6 4 . 11. Present DH, Rutgeerts P, Targan S, Hanauer SB, Mayer L, van Hogezand RA, Podolsky DK, Sands BE, Braakman T, DeWoody KL, Schaible TF, van Deventer 8J. Infliximab for the treatment of fistulas in patients with Crohn's disease. N Engl J Med 1999; 340:1398-1405. 12. Schulz KF, Chalmers I, Hayes RJ, Altman DG. Empirical evidence of bias. Dimensions of methodological quality associated with estimates of treatment effects in controlled trials. JAMA 1995; 273:408-412.
The author is a consultantfor Centocor. doi:10.1053/gast.2002.32782 Reply. W e appreciate the interest shown by Dr. Cohen with regard to our article. As the title clearly states, the intent of our paper was to compare specifically medical interventions for Crohn's disease perianal fistula. However, we recognize that surgery is an option for these patients. In fact, we originally included seton placement as an intervention in earlier versions of the model, but removed it from the analysis after careful consideration. It is well known that surgery is an uncommon treatment option for initial Crohn's perianal disease. In an analysis of the surgery rate among 116 fistulizing Crohn's patients at the University of Virginia, we used our hospital claims database to identify all cases that received conservative surgical therapy (fistulectomy, fistulotomy, or seton placement) during a 1-year period. W e found only 6 cases (5%). Since this number may include patients with long-standing fistula, we conclude that the true rate of surgery during the first year of treatment at our institution is less than 5%, making the inclusion of surgical data not relevant to our analysis. In his letter, Dr. Cohen refers to 3 cost analyses? 3 These studies assess the overall cost of Crohn's disease, but do not distinguish between costs for fistulizing vs. nonfistulizing Crohn's. W e caution Dr. Cohen to remember that Crohn's disease includes distinct clinical phenotypes, each of which may warrant unique patterns of care. Dr. Cohen later states that, "Patients with fistulizing Crohn's have been shown to have higher average annual medical costs (predominantly