Crohn s disease is a chronic idiopathic disease of the

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1 GASTROENTEROLOGY 1999;117:49 57 Clinical Course and Costs of Care for Crohn s Disease: Markov Model Analysis of a Population-Based Cohort MARC D. SILVERSTEIN,*,, EDWARD V. LOFTUS, Jr., WILLIAM J. SANDBORN, WILLIAM J. TREMAINE, BRIAN G. FEAGAN, PAUL J. NIETERT, W. SCOTT HARMSEN, # and ALAN R. ZINSMEISTER # Divisions of *Area General Internal Medicine and Gastroenterology and Sections of Clinical Epidemiology and # Biostatistics, Mayo Clinic, Rochester, Minnesota; Departments of Medicine and Epidemiology and Biostatistics, University of Western Ontario, London, Ontario, Canada; and Center for Health Care Research, Medical University of South Carolina, Charleston, South Carolina Background & Aims: Crohn s disease results in substantial morbidity and high use of health services. The aim of this study was to describe the lifetime clinical course and costs of Crohn s disease in a 24-year populationbased inception cohort of patients with Crohn s disease in Olmsted County, Minnesota. Methods: Disease states were defined by medical and surgical treatment. A Markov model analysis calculated time in each disease state and present value of excess lifetime costs in comparison with an age- and sex-matched cohort. Results: For a representative patient, projected lifetime costs were $39,906 per patient using median charges and $125,404 using mean charges. There were 29.1 years (63% of total) without medications. There were 12.7 years (27%) on aminosalicylate therapy, generating $11,467 (29%) in charges, and 3.2 years (7%) on corticosteroid or immunosuppressive therapy, generating $5147 (13%) in charges. Surgery generated $17,526 (44%) in charges. Conclusions: Most of the clinical course is spent in remission, either medical or surgical. Aminosalicylate therapy accounts for 29% of the costs of care. Surgery has the highest charges but the longest remissions. Treatment strategies that induce remission in mild disease and maintain remission with lower-cost maintenance therapy will have the largest effect on patient outcomes and costs. Crohn s disease is a chronic idiopathic disease of the gut characterized by transmural inflammation and ulceration. Crohn s disease causes symptoms of abdominal pain, diarrhea, and weight loss and may be complicated by bowel obstruction, enteric fistulas, abscess formation, or extraintestinal manifestations. Immunosuppressive drugs and surgical interventions may be required. Although Crohn s disease has a low incidence and in recent years a relatively low mortality rate, the chronic course results in relatively high prevalence, high morbidity, and high use of health services. The waxing and waning nature of Crohn s disease makes it difficult to analyze and describe prognoses and long-term outcomes. Several clinical classifications of Crohn s disease based on anatomic localization, disease behavior (inflammatory vs. fibrostenotic vs. fistulizing), and surgical history have been developed to predict the clinical course of disease. 1 3 More recently, Crohn s disease has been classified by response to corticosteroid treatment. 4 One method of describing the clinical course of diseases characterized by remissions and exacerbations is the Markov model. 5,6 This method defines discrete health states and uses clinical data to derive probabilities of patients disease activity changing from one state to another state. This method has been used previously to describe the course of patients with Crohn s disease. 7 We defined Crohn s disease states based on intensity of medical and surgical treatment. Previous definitions of Crohn s disease activity that were based on response to glucocorticoid treatment 4 were adapted, and definitions of disease activity and severity states for Crohn s disease based on intensity of other medical and surgical treatments were developed. These definitions were used to analyze the clinical course of patients in a communitybased inception cohort of Olmsted County, Minnesota, residents with Crohn s disease. Information on severity of Crohn s disease was obtained directly from the original medical records. Information on direct medical charges was obtained from providers of health care to all residents in the community and used to estimate the present value of projected lifetime direct medical costs for the care of patients with Crohn s disease. Materials and Methods Design A population-based retrospective cohort was studied for information on the clinical course and costs of care, and a Markov model analysis was used to calculate projected lifetime clinical course and costs of Crohn s disease by disease severity 1999 by the American Gastroenterological Association /99/$10.00

2 50 SILVERSTEIN ET AL. GASTROENTEROLOGY Vol. 117, No. 1 state. Analysis of the clinical course and projected lifetime direct medical costs was conducted from a payer s perspective. An 8-state Markov model was constructed, and a Markov cohort analysis was performed using Data 3.0 software (Treeage Software, Inc., Williamstown, MA) to calculate projected time in each Crohn s disease state and direct medical costs for each Crohn s disease state. The Markov model is represented as a decision tree and is shown in Figure 1. Setting Olmsted County, situated in southeastern Minnesota, comprised approximately 106,000 people in the 1990 U.S. Census. The resources of the Rochester Epidemiology Project 8,9 were used to identify permanent residents of Olmsted County who had Crohn s disease diagnosed between January 1, 1970, and December 31, The Mayo Clinic Institutional Review Board approved the study. Data Collection The complete (inpatient and outpatient) medical records of all potential cases identified through the diagnostic index were reviewed to confirm the diagnosis of Crohn s disease. Diagnostic criteria were identical to those used in previous studies of Crohn s disease in Olmsted County. 10,11 For all patients, date of birth, date of diagnosis, sex, start date and stop date for all medications for Crohn s disease, hospital admissions (for any cause), types and dates of all surgical procedures, date of last follow-up visit, and vital status at last follow-up were recorded. Information on all clinical services Figure 1. Decision tree representing Markov model of Crohn s disease treatment. Nodes with [ ] have same structure as the node labeled remission. was sorted in chronological order and reviewed by two physician investigators for classification of disease severity over time. For some courses of medical therapy, dates of initiation or cessation of treatment were incomplete, and dates were interpolated between visits with complete information. The two physician reviewers independently performed all such determinations based on available information, and discrepancies were resolved by discussion between the investigators and review of original records as needed. Thus, for each patient, a chronological course of Crohn s disease by severity state from date of diagnosis to date of last follow-up was constructed. Disease Severity States Disease severity states were defined by type of medical or surgical therapy and by the patients response to medical therapy. Patients receiving multiple therapies were assigned to the state associated with the most intensive therapy (in descending order of intensity): (1) surgery; (2) immune modifier or corticosteroid; (3) sulfasalazine, 5-aminosalicylate, antibiotics, or topical medications; and (4) no medication. Remission or no medication state. No medication for Crohn s disease (excluding antidiarrheals). Mild disease. Treatment with sulfasalazine, a 5-aminosalicylate (mesalamine or olsalazine), an antibiotic (metronidazole or ciprofloxacin), or topical therapy, including topical corticosteroids. Severe disease, drug-responsive. Treatment with oral corticosteroids or immunosuppressive medications (6-mercaptopurine, azathioprine, methotrexate, or cyclosporin A) with documented improvement. Severe disease, drug-dependent. Treatment with oral corticosteroids or immunosuppressive therapy lasting more than 6 months, with documented improvement. Severe disease, drug-refractory. Treatment with oral corticosteroids or immunosuppressive therapy with no documentation of clinical improvement within 2 months for corticosteroids or within 6 months for immunosuppressive medication. Patients receiving corticosteroids for more than 6 months who had evidence of continuing high activity as defined by stool pattern, abdominal pain, fever, or weight loss were classified as having drug-refractory severe disease. Surgery. Inpatient surgical procedures for Crohn s disease. The surgery state included the entire hospital admission and 6 weeks of posthospitalization convalescence. Minor surgical procedures performed in the outpatient setting were excluded. Postsurgical remission. No medication or treatment for Crohn s disease after a surgical procedure for Crohn s disease. Death. Death from any cause. Probability of Transitions Between Crohn s Disease States The probability of transitions between the Crohn s disease states was estimated using a transition intensity matrix assuming a Markov model for transitions among disease states.

3 July 1999 CLINICAL COURSE AND COSTS OF CROHN S DISEASE 51 The Markov model approach estimated the transition intensities by combining the hazards for the exponential waiting time distributions in each state and the probabilities of transitions from one state to another. The transition probability matrix was then estimated from the transition intensity matrix using a canonical decomposition of the intensity matrix. 12 State-wide vital statistics data were used to calculate agespecific 2-month probabilities of death. In the Markov cohort analysis of the clinical course and lifetime costs of Crohn s disease, the 2-month probabilities for transitions among disease states were thus proportionally adjusted to reflect the changing (age-specific) probabilities of death. Costs The direct medical cost of Crohn s disease was estimated from the difference in the direct medical charges for the Crohn s disease cohort and a control cohort consisting of 10 age- and sex-matched Olmsted County residents (without Crohn s disease) for each patient in the Crohn s disease cohort. Medical charges were used to estimate costs. 13 Information on charges was retrieved from the Olmsted County Utilization and Expenditure Database, which includes all charges for all medical and surgical hospital and ambulatory services from all Olmsted County providers of care. Medical charges were available only for the years and were used to estimate the charges per month by disease state for the Markov model. The charges for prescription medications were estimated from medical record documentation of drug prescribed, dose, dates of initiation and discontinuation of medication, and prevailing 1995 Olmsted County pharmacy charges for the most frequently prescribed brands of medications for Crohn s disease. Charges were adjusted to non-medicare dollars. All charges were adjusted by the Medical Price Index and expressed in 1995 U.S. dollars. The analysis of projected lifetime costs of medical services for Crohn s disease patients used a discount rate of 5% to adjust for the time value of money. Projected future lifetime charges are reported for a representative patient, using median ages and median charges for the cases and controls to reflect the projected life expectancy and costs for the most typical patients with Crohn s disease. We also report the overall results for the cohort, using mean ages and mean charges for the cases and controls to reflect the average projected life expectancy and costs for a person in the cohort and permit an estimation of the total projected future years of life and costs for the entire cohort. Sensitivity Analyses Analyses were performed to determine the impact of changes in the discount rate, the costs of aminosalicylate and immunosuppressive medications, and the hazard rate on projected life expectancy and lifetime costs. To assess the impact of an increased risk of death due to Crohn s disease on life expectancy, a proportional increase in the underlying hazard rate was calculated to produce estimates of relative survival of 96% at 10 years 14 or relative survival of 93.7% at 15 years 15 that had been previously reported from large cohort studies. Results Patients The inception cohort of Olmsted County, Minnesota, residents with a diagnosis of Crohn s disease from January 1, 1970, through December 31, 1993, consisted of 174 patients (78 male and 96 female). The median age at diagnosis was 28.1 years (mean age, 32.1 years) with an age range of years. The cohort was followed up through medical records for a total of 1957 person-years of observation. Median duration of follow-up was 10 years. The distribution of person-years of follow-up by disease treatment state is summarized in Table 1. The maximum likelihood estimates of the 2-month probabilities of transition between disease states are shown in Table 2. The charges per month for direct medical care services for the Olmsted County Crohn s disease cohort and ageand sex-matched cohort of Olmsted County residents without Crohn s disease are shown in Table 3 by disease activity state (for cases) and by charge category for both cases and controls. Several features are evident from these data. First, the charges are skewed, with mean charges often severalfold higher than the median charges, which is typical of studies of medical costs. Second, the medical charges were highest for Crohn s disease patients in the surgery state. Third, charges for physician services are the Table 1. Patient Days of Observation for Crohn s Disease State No. of patients ever in state Duration (days) Minimum 25th percentile Median 75th percentile Maximum Total person-years Remission Mild Severe Drug-responsive Drug-dependent Drug-refractory Surgery Postsurgery remission

4 52 SILVERSTEIN ET AL. GASTROENTEROLOGY Vol. 117, No. 1 Table 2. Maximum Likelihood Estimates of 2-Month Probabilities of Transition Between Disease States Subsequent state Postsurgery Initial state Remission Mild Drug-responsive Drug-dependent Drug-refractory Surgery remission Death Remission Mild Drug-responsive Drug-dependent Drug-refractory Surgery Postsurgery remission Death largest component of services for nonsurgical states. Fourth, Crohn s disease patients in the remission state or remission after surgery state (patients who are not receiving any medication for Crohn s disease) have charges for medical services that are substantially greater than those for age- and sex-matched controls. A summary of the direct medical care charges for services from providers of care for Crohn s disease patients by disease activity state is shown in Table 4. As expected, the charges were highest for surgery. The drug-dependent state charges are lower than the charges for the drugresponsive and drug-refractory states, most likely because of more intensive use of services early in patients with a high level of active disease. Clinical Course The Markov cohort analysis projected a future clinical course, or future life expectancy, of 46.4 years for a representative Crohn s disease patient aged 28.1 years at the time of diagnosis (Table 5). The projected future clinical course consisted of 11.1 years (23.9%) in medical remission (no medications) and 18.9 years (40.7%) in postsurgical remission (no medications). Thus, for a representative person with Crohn s disease, approximately 30.0 years (64% of future life expectancy) would not require any pharmacological therapy for Crohn s disease. Conversely, a representative patient in the Crohn s disease cohort could expect to be receiving an aminosalicylate or a similar class of medication for 12.7 years, or approximately 27% of future life expectancy. Disease severe enough to require corticosteroids or immunosuppressives lasted a total of 3.2 years, accounting for 6.9% of future life expectancy. The cohort analysis, based on the mean age at diagnosis of 32.1 years, projected a future life expectancy of 42.6 years, with similar distribution of future years by disease state. The overall clinical course of the entire Crohn s disease cohort is shown in Figure 2, which illustrates the distribution of the Crohn s disease cohort by disease state over time. The proportion of patients in medical remission rapidly decreases to approximately 30% by 5 years after diagnosis, and the proportion of patients with mild disease (on aminosalicylates) rapidly increases to approximately 35% by 5 years. At any given time, only a small proportion of the cohort requires surgery or is receiving corticosteroids or immunosuppressive medication. Although only a small proportion of patients requires Table 3. Number of Patients With Charges and Charges per Month for Crohn s Disease Patients by Disease State and for Age- and Sex-Matched Controls Controls Remission Mild Drug-responsive Drug-dependent Drug-refractory Surgery Remission postsurgery Category n Median Mean n Median Mean n Median Mean n Median Mean n Median Mean n Median Mean n Median Mean n Median Mean Physician visits Laboratory Radiology Endoscopy Room and board Surgery Surgical pathology Other Overall NOTE. These charges include hospital and ambulatory charges for Olmsted County residents with Crohn s disease and age- and sex-matched controls. Charges are expressed as median and mean charges per month in 1995 dollars, for persons using medical services, by category. These charges from Olmsted County Utilization and Expenditure Database do not include ambulatory pharmacy charges.

5 July 1999 CLINICAL COURSE AND COSTS OF CROHN S DISEASE 53 Table 4. Direct Medical Charges per Month by Crohn s Disease State State No. with charges in state surgery, the long duration of surgical remission results in a high proportion of patients in postsurgical remission, which progressively increases over the subsequent 20 years to approximately 40%. Projected Lifetime Costs of Crohn s Disease The projected lifetime direct medical cost of care for Crohn s disease, using an annual discount rate of 5%, was $39,906 in 1995 U.S. dollars. The projected direct medical care costs by disease treatment state are summarized in Table 5. As expected, the charges for health care services were highest for surgery state, $17,526, and these charges accounted for approximately 44% of projected direct medical costs of Crohn s disease. Mild disease, treated with aminosalicylates, accounts for $11,467, approximately 30% of projected direct medical care costs. Although the median costs per month for mild disease state are relatively low ($143), the long duration of aminosalicylate therapy, almost 13 years, results in high aggregate costs. Medication costs account for approximately 43% of the total monthly direct medical costs of the mild disease state. Proportions of costs by 2-month intervals contributed by cohort members in each disease state by year after diagnosis are shown in the area graph in Figure 3. The n Charges/mo (1995 U.S. $) Median Mean Maximum Remission ,380 Mild ,961 Severe Drug-responsive ,333 Drug-dependent Drug-refractory ,402 Surgery ,944 Postsurgery remission Overall surgery state and the aminosalicylate state contribute the largest proportion of projected lifetime costs for the Crohn s disease cohort throughout the future clinical course. The costs of the mild disease state result from the large number of patients receiving aminosalicylates and the high costs of aminosalicylates. The decrease in costs in all states over time is the result of discounting future costs at 5% per year to express the present value of these costs per state in 1995 dollars. Sensitivity Analyses Sensitivity analysis was performed to assess the impact of the discount rate on projected lifetime direct medical care costs (Figure 4). Our analysis for a representative Crohn s disease patient used a base case assumption of annual discount rate of 5%, and projected lifetime costs yields an estimate of $39,906. The present value of the direct medical care costs of Crohn s disease would be $100,085 with no discounting and $23,189 with a discount rate of 10%. For the cohort analysis using the mean ages and charges, and an annual discount rate of 5%, the projected lifetime costs would be $125,404. The direct medical care costs would be $289,856 with no discounting and $75,740 with a discount rate of 10%. Sensitivity analyses were also performed to evaluate the impact of changes in the projected lifetime costs resulting from changes in costs of aminosalicylates and in the costs of immunosuppressive medications. Each additional dollar increase in aminosalicylates increases the projected total lifetime costs by $61.02, whereas each additional dollar increase in immunosuppressive medication costs increases the projected total lifetime costs by $6.55. Thus the total projected lifetime costs of care of Crohn s disease are more sensitive to increases in the costs of aminosalicylates than to increases in the costs of immunosuppressive medications. A sensitivity analysis was also performed to estimate the impact of an increased risk of death in Crohn s disease. In our base case, we assumed no increased risk of death. We calculated the risk of death that would result in Table 5. Projected Lifetime Clinical Course and Direct Medical Costs for Crohn s Disease Using median age Using median charges Using mean age Using mean charges Disease state Course ( yr) % Costs (1995 $) % Course ( yr) % Costs (1995 $) % Remission , Mild , , Severe Drug-responsive Drug-dependent Drug-refractory Surgery , , Postsurgery remission Total , ,

6 54 SILVERSTEIN ET AL. GASTROENTEROLOGY Vol. 117, No. 1 Figure 2. Proportion of Crohn s disease patients in each treatment state by year since diagnosis of Crohn s disease. Figure 3. Discounted direct medical costs per 2-month interval of Crohn s disease treatment states by year since diagnosis of Crohn s disease (area graph indicating component costs of Crohn s disease).

7 July 1999 CLINICAL COURSE AND COSTS OF CROHN S DISEASE 55 Figure 4. Sensitivity analysis of relationship of direct medical care costs to annual discount rate. 10-year survival equal to 96% of expected survival in an age-matched cohort. For the typical patient (median age at onset and median charges), the increased relative hazard risk decreased life expectancy by 13.4 years and reduced lifetime costs by $4581. Thus an increased risk of death due to Crohn s disease has a greater impact on life expectancy than on lifetime direct medical care costs because future years of life are associated with lower costs as a result of discounting. Discussion Using data on the clinical course and direct medical charges of an actual population-based cohort of patients with Crohn s disease, we constructed a Markov model to estimate lifetime clinical course and costs of illness in a typical patient with Crohn s disease. Several important findings emerged. First, Crohn s disease is quiescent through much of its clinical course, as demonstrated by the fact that the majority (65%) of follow-up time is spent in states characterized by medical or surgical remission. Second, although surgery and immediate postoperative convalescence account for only 1% of the clinical course, they contribute 44% of lifetime costs. Third, medical treatments aimed at avoiding surgery may have significant impact on future costs of illness. On the other hand, surgery leads to a much more durable remission than that induced by medication, raising the possibility that treatment strategies that feature early surgery may be more favorable from an economic perspective than the continued use of expensive medications. Fourth, the use of medications for maintenance therapy results in substantial aggregate cost because of medication costs and long duration of use. Fifth, the projected lifetime cost of Crohn s disease is much more sensitive to the price of aminosalicylates than to the price of immunosuppressive medications. Sixth, an increased risk of death caused by Crohn s disease has a smaller impact on costs than on life expectancy because future years of life are associated with lower costs. Our study has several strengths. First, we studied a population-based inception cohort of Crohn s disease patients whose clinical course represents the full spectrum of disease. Second, the Markov model analysis used transition probabilities between disease states derived from the actual clinical course of the cohort and actual charges for medical services to the cohort. The Markov model provides estimates of the life expectancy and projected costs, expressed in 1995 dollars. The analysis permits evaluation of the impact of changes in discount rates and medication costs on the costs of care. Third, the sensitivity analysis and Markov model analysis provide estimates of the impact of increased risk of death caused by Crohn s disease on life expectancy and projected lifetime costs. Our study has some potential limitations. The size of the cohort is small. Although we studied a populationbased inception cohort, the clinical information for the classification of the course of disease was based on retrospective review of medical records. Our classification of Crohn s disease is based on therapy, which reflects

8 56 SILVERSTEIN ET AL. GASTROENTEROLOGY Vol. 117, No. 1 decisions made by the patients physicians. Treatment practices may have changed over the course of the study ( ). Therefore, the generalizability of our findings depends on similar decisions by physicians for care of patients elsewhere. We believe these disadvantages are more than offset by the compelling advantages: its population-based nature (unique in North America); the availability of all direct medical charges (again, unique in North America, and perhaps in the world); and the availability of the complete medical record. The last advantage allows for a level of detail of clinical course not possible in larger population-based studies. Although the length of follow-up can be viewed as a negative feature, we strongly believe this is one of the strengths of the study. The median follow-up after diagnosis was 10 years, and follow-up was as long as 26 years in some cases. This allows for a more accurate picture of the lifetime clinical course of the disease that cannot be obtained from other administrative data sets. There may also be concern that the clinical course and costs of Crohn s disease in patients treated at our tertiary care center may not be generalizable. We again emphasize that the study is of Olmsted County residents, many of whom received little or no medical care from the Mayo Clinic. In addition, most county residents seen at Mayo have a primary care physician (general internist or family practitioner) from whom they seek the bulk of their medical care. Before 1992, patients with inflammatory bowel disease who were referred to the Mayo Clinic were seen by any of approximately 50 staff gastroenterologists, many of whom had no special interest in inflammatory bowel disease. The Mayo Inflammatory Bowel Disease Clinic, where a small number of gastroenterologists with a primary interest in inflammatory bowel disease provide highly specialized care, was formed in Thus the vast majority of the experience of this cohort has not been so highly specialized that it cannot be generalized to Crohn s disease in other regions. Markov models have been used in other studies to describe the clinical course of patients with inflammatory bowel disease. 7,16 Munkholm et al. 7 used a Markov chain analysis to describe disease activity in an inception cohort of 373 patients with Crohn s disease in Copenhagen County. Crohn s disease activity varied markedly over time, but age, sex, extent of disease at diagnosis, and treatment in year of diagnosis did not predict the subsequent course of disease. The costs of Crohn s disease were not addressed in that study. There are only a few published comprehensive studies of cost of inflammatory bowel disease. 17,18 In the first study, medical cost algorithms were developed to model severity stages of Crohn s disease and ulcerative colitis, and average annual costs were estimated based on estimates of proportion of patients in each stage. The average annual cost of Crohn s disease was estimated to be $ In the second study, medical insurance claims for 4212 patients with an ICD-9 diagnosis of Crohn s disease were analyzed. The mean charges for Crohn s disease were $ These charges would be $11,781 in 1995 U.S. dollars. The annual charges for all direct medical services for our Crohn s disease cohort during the years 1987 through 1994, expressed in 1995 U.S. dollars, were $4308. Our lower estimates reflect charges from all providers of care for Crohn s disease patients in the population-based inception cohort who had any contact with an Olmsted County health care provider, not just those submitting a claim with an ICD-9 diagnosis of Crohn s disease. We believe our data more accurately reflect the population of patients with Crohn s disease, whereas previous reports reflect charges for a spectrum of Crohn s disease patients with more severe illness and greater use of health care services. The annual direct charges for all medical services of $4308 per Crohn s disease patient are quite similar to charges incurred by Olmsted County patients with rheumatoid arthritis, another chronic inflammatory disease ($3802). 19 A recent cross-sectional study estimated direct and indirect costs of inflammatory bowel disease in Sweden in Direct medical costs for approximately 40,000 patients with inflammatory bowel disease (Crohn s disease and ulcerative colitis) were $27.5 million (1994 U.S. dollars), or approximately $690 per patient. 20 Indirect costs were more than double this total because of sickness leave and early retirement, further emphasizing the morbidity of these illnesses. 20 Our analysis, which was conducted from the perspective of a third-party payer, was not designed to measure indirect costs. Measurement of indirect costs is an important component of the burden of a particular disease on society. However, the actual measurement of indirect costs is extremely difficult, no uniform methodology exists, and it was not possible to obtain indirect cost data from our respective cohort study. Direct medical costs were higher in our patients, but this may have been attributable to differences in the costs of medical care between the United States and Sweden. Our primary interest was in modeling the lifetime clinical course and costs of illness, so a longitudinal analysis was chosen. The longitudinal study allows for measurement of transitional probabilities between health states in a group of patients with long follow-up. A cross-sectional study of a larger group of patients may more accurately reflect the costs of illness in a particular

9 July 1999 CLINICAL COURSE AND COSTS OF CROHN S DISEASE 57 period, but it does not allow for accurate measurement of the natural history of disease. Our study has several implications for strategies to reduce the costs of Crohn s disease. For representative patients, a substantial portion of medical charges is related to aminosalicylate therapy. In view of a recent meta-analysis suggesting that the number of patients in remission needed to treat with aminosalicylates to prevent one relapse is 16, 21 further studies of the costeffectiveness of aminosalicylates may be required. The benefits of surgery (longer duration of remission than with medical therapy) need to be weighed against the risks of surgical complications, need for repeat surgeries, and ultimate short bowel syndrome. Our study suggests that the strategies that will have the largest effect on outcomes will be those that induce remission in patients with mild disease and maintain remission without medications or with lower-cost maintenance therapy. References 1. Sachar DB, Andrews HA, Farmer RG, Pallone F, Pena AS, Prantera C, Rutgeerts P. Proposed classification of patient subgroups in Crohn s disease. Gastroenterol Int 1992;5: Farmer RG, Whelan G, Fazio VW. Long-term follow-up of patients with Crohn s disease. Relationship between the clinical pattern and prognosis. Gastroenterology 1985;88: Greenstein AJ, Lachman P, Sachar DB, Springhorn J, Heimann T, Janowitz HD, Aufses AH Jr. Perforating and non-perforating indications for repeated operations in Crohn s disease: evidence for two clinical forms. Gut 1988;29: Munkholm P, Langholz E, Davidsen M, Binder V. Frequency of glucocorticoid resistance and dependency in Crohn s disease. Gut 1994;35: Beck JR, Pauker SG. The Markov process in medical prognosis. Med Dec Mak 1983;3: Silverstein MD, Albert DA, Hadler NM, Ropes MW. Prognosis in SLE: comparison of Markov model to life table analysis. J Clin Epidemiol 1988;41: Munkholm P, Langholz E, Davidsen M, Binder V. Disease activity courses in a regional cohort of Crohn s disease patients. Scand J Gastroenterol 1995;30: Melton LJ 3. History of the Rochester Epidemiology Project. Mayo Clin Proc 1996;71: Kurland LT, Molgaard CA. The patient record in epidemiology. Sci Am 1981;245: Gollop JH, Phillips SF, Melton LJ III, Zinsmeister AR. Epidemiologic aspects of Crohn s disease: a population based study in Olmsted County, Minnesota, Gut 1988;29: Loftus EV Jr, Silverstein MD, Sandborn WJ, Tremaine WJ, Harmsen WS, Zinsmeister AR. Crohn s disease in Olmsted County, Minnesota, : incidence, prevalence, and survival. Gastroenterology 1998;114: Klabfleisch JD, Lawless JF. The analysis of panel data under a Markov assumption. J Am Stat Assoc 1985;80: Finkler SA. The distinction between cost and charges. Ann Intern Med 1982;96: Ekbom A, Helmick CG, Zack M, Holmberg L, Adami HO. Survival and causes of death in patients with inflammatory bowel disease: a population-based study. Gastroenterology 1992;103: Persson PG, Bernell O, Leijonmarck CE, Farahmand BY, Hellers G, Ahlbom A. Survival and cause-specific mortality in inflammatory bowel disease: a population-based cohort study. Gastroenterology 1996;110: Langholz E, Munkholm P, Davidsen M, Binder V. Course of ulcerative colitis: analysis of changes in disease activity over years. Gastroenterology 1994;107: Hay AR, Hay JW. Inflammatory bowel disease: medical cost algorithms. J Clin Gastroenterol 1992;14: Hay JW, Hay AR. Inflammatory bowel disease: costs-of-illness. J Clin Gastroenterol 1992;14: Gabriel SE, Crowson CS, Campion ME, O Fallon WM. Direct medical costs unique to people with arthritis. J Rheumatol 1997;24: Blomqvist P, Ekbom A. Inflammatory bowel diseases: health care and costs in Sweden in Scand J Gastroenterol 1997;32: Camma C, Giunta M, Rosselli M, Cottone M. Mesalamine in the maintenance treatment of Crohn s disease: a meta-analysis adjusted for confounding variables. Gastroenterology 1997;113: Received May 7, Accepted March 26, Address requests for reprints to: Marc D. Silverstein, M.D., Center for Health Care Research, Medical University of South Carolina, P.O. Box 25055, 135 Rutledge Avenue, Charleston, South Carolina silverstein.marc@musc.edu; fax: (843) Sponsored in part by a grant from Schering-Plough, by grant number AR from the National Institutes of Health, and by the Mayo Foundation.