Hovde &, Moum BA. Epidemiology and clinical course of Crohn's disease: Results from observational studies. World J Gastroenterol 2012; 18(15): 1723-1731
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Øistein Hovde, MD, Gastroenterological Consultant, Department of Internal Medicine/Gastroenterology, Innlandet Hospital Trust, 2819 Gjøvik, Oppland, Norway. firstname.lastname@example.org
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World J Gastroenterol. Apr 21, 2012; 18(15): 1723-1731 Published online Apr 21, 2012. doi: 10.3748/wjg.v18.i15.1723
Epidemiology and clinical course of Crohn's disease: Results from observational studies
Øistein Hovde, Bjørn A Moum
Øistein Hovde, Department of Internal Medicine/Gastroenterology, Innlandet Hospital Trust, 2819 Gjøvik, Oppland, Norway
Bjørn A Moum, Department of Gastroenterology, Oslo University Hospital and University of Oslo, 0514 Oslo, Norway
Author contributions: Both authors contributed equally to the design, drafting of the article, and to the final approval/preparation.
Correspondence to: Øistein Hovde, MD, Gastroenterological Consultant, Department of Internal Medicine/Gastroenterology, Innlandet Hospital Trust, 2819 Gjøvik, Oppland, Norway. email@example.com
Telephone: +47-61157002 Fax: +47-61157439
Received: August 4, 2011 Revised: January 12, 2012 Accepted: January 19, 2012 Published online: April 21, 2012
The authors review the clinical outcome in patients with Crohn’s disease (CD) based on studies describing the natural course of the disease. Population-based studies have demonstrated that the incidence rates and prevalence rates for CD have increased since the mid-1970s. The authors search for English language articles from 1980 until 2011. Geographical variations, incidence, prevalence, smoking habits, sex, mortality and medications are investigated. An increasing incidence and prevalence of CD have been found over the last three decades. The disease seems to be most common in northern Europe and North America, but is probably increasing also in Asia and Africa. Smoking is associated with an increased risk of developing CD. Age < 40 at diagnosis, penetrating/stricturing complications, need for systemic steroids, and disease location in terminal ileum are factors associated with higher relapse rates. A slight predominance of women diagnosed with CD has been found. Ileocecal resection is the most commonly performed surgical procedure, and within the first five years after the diagnosis about one third of the patients have had intestinal surgery. Smoking is associated with a worse clinical course and with increased risk of flare-ups. In most studies the overall mortality is comparable to the background population. To date, the most effective treatment options in acute flares are glucocorticosteroids and tumor necrosis factor (TNF)-α- blockers. Azathioprine/methotrexate and TNF-α-blockers are effective in maintaining remission.
Citation: Hovde &, Moum BA. Epidemiology and clinical course of Crohn's disease: Results from observational studies. World J Gastroenterol 2012; 18(15): 1723-1731
The incidence rates for Crohn’s disease (CD) and ulcerative colitis (UC) in Western countries have increased since the mid-1970s. The same trend, although less pronounced, is also seen in the developing world[1-3]. The reported geographical variations in incidence may in part be due to differences in diagnostic tools and study design, and many of the epidemiological studies have been retrospective and hospital-based. CD is a disease with a broad spectrum of clinical manifestations, and the initial presentation is seldom a good predictor of the clinical course[5-7]. Patients with newly diagnosed CD often ask about expectations related to the course of the disease. To answer this question, information on the natural course of CD based on observational, population-based cohort studies is crucial. The “natural course” in CD might be different in 2011 compared to the situation for instance in the 1980s, and there are at least two reasons for this: we now have better tools to diagnose the condition in an earlier phase, and we have new therapeutic agents that hopefully will alter the course of the disease.
The primary aim of this article is to review the clinical outcome in patients with CD based on population-based studies conducted over the last thirty years, focusing predominantly on studies describing the natural clinical course in representative cohorts of patients with CD.
The factors investigated include incidence, prevalence, age, sex, smoking, geographical differences, surgical aspects, extra-intestinal manifestations, mortality, medication, clinical course with focus on relapse and surgery, the location and behavior of the disease, and finally, the need for sick leave/unemployment. A Medline search (1980 to 2011) for English language articles was conducted.
The MESH term “Crohn disease” was combined with free text search for “population based” and “clinical”. This search yielded sixty-seven articles. All potential relevant articles were evaluated.
EPIDEMIOLOGICAL ASPECTS OF CROHN'S DISEASE
Incidence, prevalence and time-trends
The incidence of CD differs depending on the region studied. The United Kingdom, North America and the northern part of Europe are the areas with the highest incidence[8-10]. A Danish study from 1997 found that the mean incidence rate for men per 100 000 person years increased from 3.3 in 1981-1984 to 4.1 in 1989-1992. For women in the same area and in the same time intervals, the incidence rate increased from 4.6 to 6.2. A peak incidence rate was found among 15-29-year-olds, with an incidence rate among men and women of 5.3 and 9.1, respectively. A recent study in which all new CD cases in Finland between 2000 and 2007 were included revealed an overall incidence rate of 9.2 per 100 000 inhabitants. The incidence rate in Olmsted County, Minnesota, United States was 5.7 cases per 100 000 person years between 1940 and 1993. During the study period, a marked increase in incidence was found: in 1940-1943 the incidence rate was 1.0, while the rate in 1984-1993 was 6.9. Traditionally, the incidence has been low in Asia and Africa. Studies from these areas suggest that the incidence of CD is increasing[2,13].
The prevalence of CD in Europe varies from less than 10 to about 150 per 100 000 inhabitants[9,14]. An adjusted prevalence of 133 per 100 000 was found in Minnesota, United States in 1991. One study from South Korea indicated prevalence of 11.2. From the existing data, one can conclude that the incidence and prevalence rates of CD have increased over last decades.
Sex and age at diagnosis and smoking
In a retrospective study from the United Kingdom on patients diagnosed with CD, the patient population was divided in three groups by year of diagnosis: 1986-1991, 1992-1997 and 1998-2003. Of a total of 341 subjects diagnosed with CD, 62% were females. In all time intervals, the median age at diagnosis was 30 years. In a prospective study from Denmark, all patients in Copenhagen County diagnosed with UC and CD from 2003 to 2005 were followed for 11.3 mo (median); 54% of the CD patients were females, and median age at diagnosis was 31 years. A retrospective study from Olmsted County, Minnesota, United States showed that 54% of the patients were females, and the median age at diagnosis was 29.5 years.
In Norway, the Inflammatory Bowel South-Eastern Norway (IBSEN) group, in a prospective study, has followed patients with inflammatory bowel disease (IBD) since the beginning of the 1990s. This study reported a slight predominance of women diagnosed with CD, with a male/female-ratio of 0.95. The median age at diagnosis was 30 years. In Finland, no significant difference between the genders was found. A population-based Canadian study found a female predominance: 58% of the patients were women. Cigarette smoking is associated with increased risk of developing CD. Smoking negatively influences the clinical course of CD and is also associated with the clinical recurrence of CD after surgical resection in CD patients. Cosnes et al found that smoking, particularly heavy smoking, markedly increased the risk of flare-ups of the disease.
Based on these studies, the conclusion is that there is a slight predominance of women diagnosed with CD, that the age at diagnosis is approximately 30, and that cigarette smoking is harmful in patients with CD.
The relationship between appendectomy and the risk of developing CD has been debated, and in 2009, a systematic review of the literature was performed. The authors found that the relative risk (RR) for having CD diagnosed following an appendectomy was significantly elevated. Within the first year after the surgery, the RR was 6.69 (95% CI: 5.42-8.25). An increase in the risk of developing CD also was found 1-4 years after the appendectomy, but thereafter the risk was not increased. Another study confirmed these results, but no increased risk of developing CD was found in patients who underwent appendectomy before the age of ten. It seems that there was an inverse relationship between appendectomy and the development of UC, at least in patients who underwent appendectomy before the age of 20.
The occurrence of CD seems to vary according to geographical location. A north-south axis has been found in both Europe and in the United States, with higher incidence and prevalence in the northern regions. In a study from 1996 on the incidence of IBD across Europe, incidence rates were found to be 80% higher in northern centers than in southern. A French study from 2006 also demonstrated a north-south gradient within France. Data from Columbia support the clinical experience that CD is rare in South America. Based on a prospective European population-based inception cohort of 380 CD patients, a difference in management was observed between northern and southern centers, indicating that CD patients in the north had a more severe disease course than did those in the south. One problem is that there are still huge differences in diagnostic facilities. South Asians who live in Europe are more likely to develop IBD than South Asians who do not. In some regions of the world, there are diagnostic challenges due to overlap with intestinal tuberculosis. In Brazil, Argentina, Puerto Rica and Panama, the prevalence of CD and UC together is between 20-100/100 000 inhabitants, but very few reports exist, and the ratio between CD and UC is uncertain. This is in marked contrast to the numbers from the United States and Canada, where the prevalence numbers vary between 320/100 000 and 511/100 000 inhabitants. The reasons for these differences are not fully elucidated.
Hispanics in the United States are less prone to develop IBD than the non-Hispanic population. It is known that the NOD2 gene on chromosome 16 is a marker for the susceptibility to CD. A recent study showed that 4.4% of Hispanics and 9.1% of the white population have NOD2. This indicates that there are real differences in incidence/prevalence between North and South America.
Clinical important risk factors
In many studies, risk factors predicting a disabling course of CD are described. The IBSEN group has described the relapse rates and need for surgery one, five, and ten years after the diagnosis. Age < 40 at diagnosis and the need for systemic steroids to treat the first flare-up were factors associated with higher relapse rates. Age < 40 at diagnosis, disease location in terminal ileum and penetrating/stricturing complications were associated with higher risk for surgery (Tables 1 and 2). Beaugerie et al also found that age < 40 at diagnosis of CD, presence of perianal disease, and initial requirement for steroids were independent factors predicting disabling disease during the first five years after the diagnosis. Henriksen et al did not find any association between CRP levels and a risk of surgery for the CD group as a whole, but a significant linear association between CRP levels and a risk of surgery was found with L1 localization (disease localization in terminal ileum).
Table 1 Cumulative rate (Cum %) of CD patients with relapsing disease during the first year and in the periods 1-5 and 5-10 years after diagnosis (Solberg et al, with permission).
Relapse during the 1st year
Relapse between 1-5 yr
Relapse between 5-10 yr
Variables at diagnosis
Total in each subgroup
A1 < 40 yr
A2 ≥ 40 yr
L1: Terminal ileum
L4: Upper GI
χ2 comparisons within each subgroup; CI: Confidence interval; GI: Gastrointestinal.
Table 2 Risk factors at diagnosis associated with surgery during follow-up analyzed by Cox regression (Solberg et al, with permission).
1Difficult to conclude because of an insufficient number of patients;
2data unknown in 6 cases. There were none in the operated group;
3data unknown in 2 cases; There was one in the operated group. Ref: Reference variable; HR: Hazard ratio; CI: Confidence interval.
Stenoses, fistulas and abscesses are the main reasons for bowel resection in patients with CD.
In a Danish study from 2003-2005, 12% of CD patients underwent bowel resection performed within one year after the diagnosis, and the median time from diagnosis to resection was one month (range 0-8 mo). The authors compared the results to what was seen in patients diagnosed with CD in the same area between 1962 and 1987. In the earlier period, as many as 35% of the CD patients underwent bowel resection performed within the first year of diagnosis. A shorter delay from the onset of symptoms to diagnosis and the introduction of more intensive immunosuppressive therapy might be among the explanations for this decreased risk of surgical resection.
The Montreal classification of CD includes the location (L) of the disease, where L1 is location in the terminal ileum, L2 is in the colon, L3 is an ileocolonic location, and L4 is an upper GI location. In one study, patients with L1 location at diagnosis had increased likelihood of intestinal surgery. Oral corticosteroid use within three months of diagnosis, stricturing disease and low age at diagnosis were also associated with increased likelihood of resection. In the IBSEN study, the cumulative probability of surgery was 13.6%, 27.0% and 37.9% at one, five, and ten years after diagnosis, respectively. In this cohort, L1 location was strongly associated with surgery compared to L2 and L3 locations (Table 1).
A United Kingdom study of changes in medical treatment and surgical resection rates from 1986 to 2003 found a marked reduction in the proportion of patients needing intestinal surgery. Within five years of diagnosis of CD, 59% of the patients diagnosed from 1986-1991 had intestinal surgery. In patients diagnosed between 1992-1997 and 1998-2003, 37% and 35%, respectively, had intestinal surgery within five years of diagnosis. In addition, there was a significant reduction in patients undergoing any surgical procedure (surgery for perianal disease or intestinal surgery) during an advanced stage of disease. Ileocecal resection was the most commonly performed procedure. The most striking reductions were seen in the numbers of ileocecal resections and in the numbers of panproctocolectomies.
A French retrospective study with 2573 CD patients divided the cohort in five groups according to the year of diagnosis (1978-1982, 1983-1987, 1988-1992, 1993-1997 and 1998-2002). The main outcome criterion was the time to first intestinal resection. The cumulative probability to receive immunosuppressants [azathioprine (AZA), methotrexate (MTX)] increased from 0 in the 1978-1982 cohort to 0.56 in the 1998-2002 cohort. Interestingly, in contrast to the study from the United Kingdom, one found that the year of diagnosis did not have any significant effect upon the need for surgery.
Extra-intestinal manifestations of CD include musculoskeletal, dermatologic, ocular, hepatobiliary, vascular and renal complications. About 25%-46% of the patients with CD will experience extra-intestinal manifestations[36,37]. Primary sclerosing cholangitis (PSC) is in many ways the most serious, and the most serious complication from this condition is cholangiocellular carcinoma (CCC); 7% to 15% of the patients with PSC eventually develop CCC[38,39], 60%-70% of the PSC patients are male, and the age at diagnosis is about 40 years. There is a close relationship between UC and PSC. The relationship between CD and PSC is less pronounced but marked. Studies form Sweden and Holland showed that 72% and 73%, respectively, of the PSC patients with IBD had UC, and 7% and 25%, respectively, of the PSC patients with IBD had CD[40,41].
In both studies, a certain proportion of patients with PSC did not have a diagnosis of IBD. To date, no medical treatment has been established to be effective. A hydrophilic dihydroxy bile acid, ursodeoxycholic acid, is used in the treatment of PSC, but the efficacy of the treatment is not well established. A recent study even concluded that serious adverse events were more common in the drug-treated group than in the placebo group.
Five-year follow up data from the IBSEN study showed that the cumulative occurrence of peripheral arthritis related to CD is 14%; 6% had ankylosing spondylitis; 1% had psoriatic arthritis; and 19% had undifferentiated spondyloarthropathy[43-45]. In Canada, one study following the patients from 1984 to 1997 showed that 6027 patients suffering from IBD had a 40% increased risk of fractures compared to the control group. The incidence rate ratio (IRR) for fracture at the hip was 1.59 (95% CI: 1.27-2.00, P < 0.001); the IRR for fracture of the spine was 1.74 (95% CI: 1.34 -2.24, P < 0.001); while the IRR for rib fracture was 1.25 (95% CI: 1.02-1.52, P = 0.03). No differences were found in the IRR between CD and UC patients. A study from Olmsted County, United States, showed that the relative risk for osteoporotic fractures in CD patients was 1.4 (95% CI: 0.7-2.7), and the risk ratio for thoracolumbar vertebral fracture was 2.2 (95% CI: 0.9-5.5).
During the decades from 1970 to 1990, population-based studies have shown a slightly decreased life expectancy in CD patients[48-50]. Because these studies are from the era before the introduction of the immunomodulating agents, the applicability might be of limited value.
A meta-analysis from 2007 identified 13 papers that reported standardized mortality ratios (SMR). Most of these papers included patients diagnosed in the 1950s to the 1970s, although four of them included patients diagnosed from 1980 to 1985. In this study, an age-adjusted mortality risk in CD patients was more than 50% greater than in the general population, but three of the studies actually reported an SMR below 1.0. A meta-analysis from 2010 also confirmed slightly increased mortality in CD patients (SMR 1.39, 95% CI: 1.30-1.50). In a recent report, a complete 10-year follow-up was achieved in 197 of 237 patients. Two deaths during follow-up were probably CD-related. Another study did not show any decrease in survival curves for the total group of 373 CD patients followed for five years compared to the background population, although a small subgroup of patients diagnosed at the age of 20-29 and a subgroup with extensive small bowel disease displayed slightly increased mortality. In the Netherlands, 1187 patients diagnosed with IBD during a 12-year period from 1991 were included. The mortality in CD, UC, and indeterminate colitis was comparable to the background population, but the disease-specific mortality risk was significantly increased for gastrointestinal causes in both CD and UC patients. Overall, a slight increase in mortality was found in CD patients. This is mainly caused by malignant diseases in the gastrointestinal tract and in the lungs.
CD is a chronic disorder that, at least so far, is not curable. The induction and maintenance of symptom improvement and, at best, the induction and maintenance of mucosal healing are the goals of treatment. Disease location, disease severity and complications should be taken into consideration when therapy is to be decided.
Even at high doses and prolonged administration, glucocorticosteroids (GCSs) induce endoscopic remission in less than one third of the patients with colonic CD. Use of GCSs has a favorable effect on the symptoms of Crohn´s disease of the small intestine but will not achieve a significant reduction in endoscopically observed inflammation.
A few decades ago, a large clinical trial showed that CD patients with colonic involvement were especially responsive to sulfasalazine, but a European multi-center double-blind study from the 1980s did not show any beneficial effects from sulfasalazine as compared to 6-methylprednisolone. Oral mesalamine has been, and still is, widely used in the treatment of CD. A meta-analysis of three large, double-blind, randomized studies in the treatment of active CD showed that mesalamine 4 g/d was better than placebo in reducing the Crohn’s Disease Activity Index, but the clinical significance was unclear. The recently published European evidence-based consensus on the diagnosis and management of CD concluded that active colonic CD may be treated with sulfasalazine if only mildly active, and that mesalazine should be considered no more effective than placebo in the treatment for active ileal or colonic CD.
The rationale for the use of antibiotics in the treatment of mild to moderate CD is the hypothesis that bacteria may cause or exacerbate CD. Metronidazole, 10 or 20 mg/kg per day, compared to placebo, did not show any difference in the ability to induce remission in patients with mild/moderate disease. Comparison of ciprofloxacin and mesalamine did not reveal any consistent pattern. About 50% in each group achieved clinical remission. A recent meta-analysis concludes that long-term treatment with nitroimidazoles or clofazimine appeared to be effective in CD patients.
A recent review on the effect of AZA or 6-mercaptopurine for the maintenance of remission in CD concluded that both AZA and 6-mercaptopurine had a positive effect on maintaining remission. The study reported weak evidence for a steroid-sparing effect of AZA. In a recent single-center study, the authors found that MTX is efficient as a second-line immunomodulator in chronic active CD. In steroid-dependent CD patients, complete remission and steroid withdrawal were seen in 77% of the cases after 22.9 mo of treatment. After six months, one, two, and three years on MTX, 95.3%, 89.5%, 70.6% and 62.8%, respectively, were in remission. However, a high proportion of the patients developed side-effects (79% and 39%, respectively), including hepatotoxicity and hair loss[66,67]. Side effects associated with the use of AZA and 6-mercaptupurine include leucopenia, thrombocytopenia, pancreatitis and an increased risk of developing lymphoma. The introduction of anti-tumor necrosis factor (TNF) agents has changed the treatment of refractory CD. Although the causes of CD are not known, many of the molecules involved in the disease process have been identified and can act as targets of biological treatment. TNF is a cytokine that promotes inflammatory responses in many diseases, including CD. Infliximab is effective in both luminal and fistulizing CD[69,70] and is highly effective and safe in children. The combination of infliximab and AZA is more effective in moderate-to-severe CD than infliximab alone. One problem is that, each year, about 10% of patients, for different reasons, drop out of treatment. Adalimumab is a human monoclonal antibody against TNF. It is administered subcutaneously and has proven effective in the treatment of luminal CD. Certolizumab pegol is approved in the United States for the treatment of CD. No trials exist that compare the three different anti-TNF agents, but it seems that infliximab, adalimumab and certolizumab pegol are comparable in efficacy. Anti-TNF agents definitely deserve to be considered as a treatment option for patients with CD; it is therefore widely discussed when patients should be introduced to these agents, and further studies are needed to establish this aspect of the approach to treatment.
In a review article, Vermeire et al summarized the therapies that have been shown to alter the natural history of CD. Mucosal healing, the need for hospitalizations/surgery together with decreased recurrence after surgery, are surrogate markers of changes in the natural course of the disease. Anti-TNF agents have shown the ability to induce mucosal healing and to reduce the need for surgery in randomized, placebo-controlled studies. It is not known, however, if they can reduce the risk of recurrence after surgery.
Markov models will show the probability of changes in state from one time-point to another. This model was used in a Danish study from 1995. One found that the disease activity course in CD is not dependent on age, sex, or localization of the disease. The United Kingdom study and the French study[16,31] showed conflicting results, at least in the proportion of patients requiring surgery. The IBSEN study showed that ten years after the diagnosis was made, the course was generally better than in earlier reports. The need for immunosuppressives and GCSs declined from the first five-year period to the second five-year period. The probability of surgery was 37.9%, and fewer patients than expected developed complicated disease behavior; however, the cumulative relapse rate was as high as 90% (Table 2). Because we have had the opportunity for biological treatment for some years now, we are looking forward to evaluating new epidemiological studies on the clinical course of the disease.
There are just a few reports on sick leave/unemployment in patients with CD. In 2006, Bernklev et al found that 24.6% of women with CD were on a disability pension (DP) five years after the diagnosis was established, which was a three-fold increase compared to the background population (8.8%). Five years after the diagnosis, 53% of the CD patients reported taking sick leave during the prior six months; 23% of the sick leaves were CD-related. A Dutch study from 2002 also concluded that CD patients had a significantly higher frequency of sick leave than the controls (odds ratio 1.7, 95% CI: 1.2-2.6). Both studies concluded that having CD is correlated to an increased unemployment rate. An earlier Danish study did not find any differences in the state of employment between CD patients nine years after the diagnosis compared to a control group, and as few as 3% were on DP.
Population-based studies have demonstrated that the incidence and prevalence of CD have increased over the last three decades. CD is most common in northern Europe and North America, and there is a slight predominance of women diagnosed with the disease. The majority of patients experience progression from inflammatory disease to the development of strictures and fistulas. Within the first five years of the disease, at least one third of the patients have had intestinal surgery, where ileocecal resection is the most commonly performed procedure. Appendectomy is associated with an increased risk of having CD diagnosed within the first four years after the surgery. A rising incidence and a slight female predominance is found in CD. The diagnosis is made when the patients are approximately thirty years old. Smoking is associated with an increased risk of developing CD, with a negative clinical course in patients with CD, and with increased risk of flare-ups of the disease in both operated and non-operated patients.
The overall mortality in most studies is comparable to the background population, although subgroups of CD patients seem to have slightly increased mortality. New therapeutic approaches are promising. To date, the most effective treatment options in acute disease are GCSs and TNF-α-blockers. TNF-α-blockers and AZA/MTX are effective in maintaining remission.
Peer reviewers: Alberto Tommasini, Institute of Child Health IRCCS Burlo Garofolo, 34137 Trieste, Italy; Charles Heise, Department of Surgery, University of Wisconsin, Madison, WI 53792, United States
S- Editor Xiong L L- Editor A E- Editor Xiong L
Baumgart DC, Bernstein CN, Abbas Z, Colombel JF, Day AS, D'Haens G, Dotan I, Goh KL, Hibi T, Kozarek RA. IBD Around the world: comparing the epidemiology, diagnosis, and treatment: proceedings of the World Digestive Health Day 2010--Inflammatory Bowel Disease Task Force meeting.Inflamm Bowel Dis. 2011;17:639-644.
Ahuja V, Tandon RK. Inflammatory bowel disease in the Asia-Pacific area: a comparison with developed countries and regional differences.J Dig Dis. 2010;11:134-147.
Michel P, St-Onge L, Lowe AM, Bigras-Poulin M, Brassard P. Geographical variation of Crohn's disease residual incidence in the Province of Quebec, Canada.Int J Health Geogr. 2010;9:22.
Moum B, Ekbom A. Epidemiology of inflammatory bowel disease--methodological considerations.Dig Liver Dis. 2002;34:364-369.
Bernell O, Lapidus A, Hellers G. Risk factors for surgery and postoperative recurrence in Crohn's disease.Ann Surg. 2000;231:38-45.
Munkholm P, Langholz E, Davidsen M, Binder V. Disease activity courses in a regional cohort of Crohn's disease patients.Scand J Gastroenterol. 1995;30:699-706.
Katz J. The course of inflammatory bowel disease.Med Clin North Am. 1994;78:1275-1280.
Vind I, Riis L, Jess T, Knudsen E, Pedersen N, Elkjaer M, Bak Andersen I, Wewer V, Nørregaard P, Moesgaard F. Increasing incidences of inflammatory bowel disease and decreasing surgery rates in Copenhagen City and County, 2003-2005: a population-based study from the Danish Crohn colitis database.Am J Gastroenterol. 2006;101:1274-1282.
Yapp TR, Stenson R, Thomas GA, Lawrie BW, Williams GT, Hawthorne AB. Crohn's disease incidence in Cardiff from 1930: an update for 1991-1995.Eur J Gastroenterol Hepatol. 2000;12:907-911.
Loftus EV, Silverstein MD, Sandborn WJ, Tremaine WJ, Harmsen WS, Zinsmeister AR. Crohn's disease in Olmsted County, Minnesota, 1940-1993: incidence, prevalence, and survival.Gastroenterology. 1998;114:1161-1168.
Fonager K, Sørensen HT, Olsen J. Change in incidence of Crohn's disease and ulcerative colitis in Denmark. A study based on the National Registry of Patients, 1981-1992.Int J Epidemiol. 1997;26:1003-1008.
Jussila A, Virta LJ, Kautiainen H, Rekiaro M, Nieminen U, Färkkilä MA. Increasing incidence of inflammatory bowel diseases between 2000 and 2007: A nationwide register study in Finland.Inflamm Bowel Dis. 2012;18:555-561.
Thia KT, Loftus EV, Sandborn WJ, Yang SK. An update on the epidemiology of inflammatory bowel disease in Asia.Am J Gastroenterol. 2008;103:3167-3182.
Gheorghe C, Pascu O, Gheorghe L, Iacob R, Dumitru E, Tantau M, Vadan R, Goldis A, Balan G, Iacob S. Epidemiology of inflammatory bowel disease in adults who refer to gastroenterology care in Romania: a multicentre study.Eur J Gastroenterol Hepatol. 2004;16:1153-1159.
Yang SK, Yun S, Kim JH, Park JY, Kim HY, Kim YH, Chang DK, Kim JS, Song IS, Park JB. Epidemiology of inflammatory bowel disease in the Songpa-Kangdong district, Seoul, Korea, 1986-2005: a KASID study.Inflamm Bowel Dis. 2008;14:542-549.
Ramadas AV, Gunesh S, Thomas GA, Williams GT, Hawthorne AB. Natural history of Crohn's disease in a population-based cohort from Cardiff (1986-2003): a study of changes in medical treatment and surgical resection rates.Gut. 2010;59:1200-1206.
Moum B, Vatn MH, Ekbom A, Aadland E, Fausa O, Lygren I, Stray N, Sauar J, Schulz T. Incidence of Crohn's disease in four counties in southeastern Norway, 1990-93. A prospective population-based study. The Inflammatory Bowel South-Eastern Norway (IBSEN) Study Group of Gastroenterologists.Scand J Gastroenterol. 1996;31:355-361.
Bernstein CN, Blanchard JF, Rawsthorne P, Wajda A. Epidemiology of Crohn's disease and ulcerative colitis in a central Canadian province: a population-based study.Am J Epidemiol. 1999;149:916-924.
Lindberg E, Tysk C, Andersson K, Järnerot G. Smoking and inflammatory bowel disease. A case control study.Gut. 1988;29:352-357.
Kane SV, Flicker M, Katz-Nelson F. Tobacco use is associated with accelerated clinical recurrence of Crohn's disease after surgically induced remission.J Clin Gastroenterol. 2005;39:32-35.
Cosnes J, Carbonnel F, Carrat F, Beaugerie L, Cattan S, Gendre J. Effects of current and former cigarette smoking on the clinical course of Crohn's disease.Aliment Pharmacol Ther. 1999;13:1403-1411.
Kaplan GG, Jackson T, Sands BE, Frisch M, Andersson RE, Korzenik J. The risk of developing Crohn's disease after an appendectomy: a meta-analysis.Am J Gastroenterol. 2008;103:2925-2931.
Kaplan GG, Pedersen BV, Andersson RE, Sands BE, Korzenik J, Frisch M. The risk of developing Crohn's disease after an appendectomy: a population-based cohort study in Sweden and Denmark.Gut. 2007;56:1387-1392.
Andersson RE, Olaison G, Tysk C, Ekbom A. Appendectomy and protection against ulcerative colitis.N Engl J Med. 2001;344:808-814.
Shivananda S, Lennard-Jones J, Logan R, Fear N, Price A, Carpenter L, van Blankenstein M. Incidence of inflammatory bowel disease across Europe: is there a difference between north and south? Results of the European Collaborative Study on Inflammatory Bowel Disease (EC-IBD).Gut. 1996;39:690-697.
Nerich V, Monnet E, Etienne A, Louafi S, Ramée C, Rican S, Weill A, Vallier N, Vanbockstael V, Auleley GR. Geographical variations of inflammatory bowel disease in France: a study based on national health insurance data.Inflamm Bowel Dis. 2006;12:218-226.
Vargas RD. Epidemiology of inflammatory bowel disease (IBD): Why are there differences between North America and Latin America?Rev Col Gastroenterol. 2010;25:103-104.
Wolters FL, Joling C, Russel MG, Sijbrandij J, De Bruin M, Odes S, Riis L, Munkholm P, Bodini P, Ryan B. Treatment inferred disease severity in Crohn's disease: evidence for a European gradient of disease course.Scand J Gastroenterol. 2007;42:333-344.
Kugathasan S, Loizides A, Babusukumar U, McGuire E, Wang T, Hooper P, Nebel J, Kofman G, Noel R, Broeckel U. Comparative phenotypic and CARD15 mutational analysis among African American, Hispanic, and White children with Crohn's disease.Inflamm Bowel Dis. 2005;11:631-638.
Solberg IC, Vatn MH, Høie O, Stray N, Sauar J, Jahnsen J, Moum B, Lygren I. Clinical course in Crohn's disease: results of a Norwegian population-based ten-year follow-up study.Clin Gastroenterol Hepatol. 2007;5:1430-1438.
Beaugerie L, Seksik P, Nion-Larmurier I, Gendre JP, Cosnes J. Predictors of Crohn's disease.Gastroenterology. 2006;130:650-656.
Henriksen M, Jahnsen J, Lygren I, Stray N, Sauar J, Vatn MH, Moum B. C-reactive protein: a predictive factor and marker of inflammation in inflammatory bowel disease. Results from a prospective population-based study.Gut. 2008;57:1518-1523.
Silverberg MS, Satsangi J, Ahmad T, Arnott ID, Bernstein CN, Brant SR, Caprilli R, Colombel JF, Gasche C, Geboes K. Toward an integrated clinical, molecular and serological classification of inflammatory bowel disease: Report of a Working Party of the 2005 Montreal World Congress of Gastroenterology.Can J Gastroenterol. 2005;19 Suppl A:5-36.
Cosnes J, Nion-Larmurier I, Beaugerie L, Afchain P, Tiret E, Gendre JP. Impact of the increasing use of immunosuppressants in Crohn's disease on the need for intestinal surgery.Gut. 2005;54:237-241.
Repiso A, Alcántara M, Muñoz-Rosas C, Rodríguez-Merlo R, Pérez-Grueso MJ, Carrobles JM, Martínez-Potenciano JL. Extraintestinal manifestations of Crohn's disease: prevalence and related factors.Rev Esp Enferm Dig. 2006;98:510-517.
Ephgrave K. Extra-intestinal manifestations of Crohn's disease.Surg Clin North Am. 2007;87:673-680.
Shorbagi A, Bayraktar Y. Primary sclerosing cholangitis--what is the difference between east and west?World J Gastroenterol. 2008;14:3974-3981.
Kaya M, de Groen PC, Angulo P, Nagorney DM, Gunderson LL, Gores GJ, Haddock MG, Lindor KD. Treatment of cholangiocarcinoma complicating primary sclerosing cholangitis: the Mayo Clinic experience.Am J Gastroenterol. 2001;96:1164-1169.
Chalasani N, Baluyut A, Ismail A, Zaman A, Sood G, Ghalib R, McCashland TM, Reddy KR, Zervos X, Anbari MA. Cholangiocarcinoma in patients with primary sclerosing cholangitis: a multicenter case-control study.Hepatology. 2000;31:7-11.
Broomé U, Olsson R, Lööf L, Bodemar G, Hultcrantz R, Danielsson A, Prytz H, Sandberg-Gertzén H, Wallerstedt S, Lindberg G. Natural history and prognostic factors in 305 Swedish patients with primary sclerosing cholangitis.Gut. 1996;38:610-615.
Ponsioen CY, Vrouenraets SM, Prawirodirdjo W, Rajaram R, Rauws EA, Mulder CJ, Reitsma JB, Heisterkamp SH, Tytgat GN. Natural history of primary sclerosing cholangitis and prognostic value of cholangiography in a Dutch population.Gut. 2002;51:562-566.
Lindor KD, Kowdley KV, Luketic VA, Harrison ME, McCashland T, Befeler AS, Harnois D, Jorgensen R, Petz J, Keach J. High-dose ursodeoxycholic acid for the treatment of primary sclerosing cholangitis.Hepatology. 2009;50:808-814.
Palm Ø, Moum B, Jahnsen J, Gran JT. The prevalence and incidence of peripheral arthritis in patients with inflammatory bowel disease, a prospective population-based study (the IBSEN study).Rheumatology (Oxford). 2001;40:1256-1261.
Palm O, Moum B, Jahnsen J, Gran JT. Fibromyalgia and chronic widespread pain in patients with inflammatory bowel disease: a cross sectional population survey.J Rheumatol. 2001;28:590-594.
Palm O, Moum B, Ongre A, Gran JT. Prevalence of ankylosing spondylitis and other spondyloarthropathies among patients with inflammatory bowel disease: a population study (the IBSEN study).J Rheumatol. 2002;29:511-515.
Bernstein CN, Blanchard JF, Leslie W, Wajda A, Yu BN. The incidence of fracture among patients with inflammatory bowel disease. A population-based cohort study.Ann Intern Med. 2000;133:795-799.
Loftus EV, Crowson CS, Sandborn WJ, Tremaine WJ, O'Fallon WM, Melton LJ. Long-term fracture risk in patients with Crohn's disease: a population-based study in Olmsted County, Minnesota.Gastroenterology. 2002;123:468-475.
Prior P, Gyde S, Cooke WT, Waterhouse JA, Allan RN. Mortality in Crohn's disease.Gastroenterology. 1981;80:307-312.
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;103:954-960.
Jess T, Winther KV, Munkholm P, Langholz E, Binder V. Mortality and causes of death in Crohn's disease: follow-up of a population-based cohort in Copenhagen County, Denmark.Gastroenterology. 2002;122:1808-1814.
Duricova D, Pedersen N, Elkjaer M, Gamborg M, Munkholm P, Jess T. Overall and cause-specific mortality in Crohn's disease: a meta-analysis of population-based studies.Inflamm Bowel Dis. 2010;16:347-353.
Munkholm P, Langholz E, Davidsen M, Binder V. Intestinal cancer risk and mortality in patients with Crohn's disease.Gastroenterology. 1993;105:1716-1723.
Romberg-Camps M, Kuiper E, Schouten L, Kester A, Hesselink-van de Kruijs M, Limonard C, Bos R, Goedhard J, Hameeteman W, Wolters F. Mortality in inflammatory bowel disease in the Netherlands 1991-2002: results of a population-based study: the IBD South-Limburg cohort.Inflamm Bowel Dis. 2010;16:1397-1410.
Lichtenstein GR, Hanauer SB, Sandborn WJ. Management of Crohn's disease in adults.Am J Gastroenterol. 2009;104:465-83; quiz 464, 484.
Rutgeerts P, Vermeire S, Van Assche G. Mucosal healing in inflammatory bowel disease: impossible ideal or therapeutic target?Gut. 2007;56:453-455.
Olaison G, Sjödahl R, Tagesson C. Glucocorticoid treatment in ileal Crohn's disease: relief of symptoms but not of endoscopically viewed inflammation.Gut. 1990;31:325-328.
Summers RW, Switz DM, Sessions JT, Becktel JM, Best WR, Kern F, Singleton JW. National Cooperative Crohn's Disease Study: results of drug treatment.Gastroenterology. 1979;77:847-869.
Malchow H, Ewe K, Brandes JW, Goebell H, Ehms H, Sommer H, Jesdinsky H. European Cooperative Crohn's Disease Study (ECCDS): results of drug treatment.Gastroenterology. 1984;86:249-266.
Hanauer SB, Strömberg U. Oral Pentasa in the treatment of active Crohn's disease: A meta-analysis of double-blind, placebo-controlled trials.Clin Gastroenterol Hepatol. 2004;2:379-388.
Dignass A, Van Assche G, Lindsay JO, Lémann M, Söderholm J, Colombel JF, Danese S, D'Hoore A, Gassull M, Gomollón F. The second European evidence-based Consensus on the diagnosis and management of Crohn's disease: Current management.J Crohns Colitis. 2010;4:28-62.
Sutherland L, Singleton J, Sessions J, Hanauer S, Krawitt E, Rankin G, Summers R, Mekhjian H, Greenberger N, Kelly M. Double blind, placebo controlled trial of metronidazole in Crohn's disease.Gut. 1991;32:1071-1075.
Colombel JF, Lémann M, Cassagnou M, Bouhnik Y, Duclos B, Dupas JL, Notteghem B, Mary JY. A controlled trial comparing ciprofloxacin with mesalazine for the treatment of active Crohn's disease. Groupe d'Etudes Thérapeutiques des Affections Inflammatoires Digestives (GETAID).Am J Gastroenterol. 1999;94:674-678.
Feller M, Huwiler K, Schoepfer A, Shang A, Furrer H, Egger M. Long-term antibiotic treatment for Crohn's disease: systematic review and meta-analysis of placebo-controlled trials.Clin Infect Dis. 2010;50:473-480.
Prefontaine E, Sutherland LR, MacDonald JK, Cepoiu M. Azathioprine or 6-mercaptopurine for maintenance of remission in Crohn's disease.Cochrane Database Systematic Reviews. 2009;1:CD000067.
Hausmann J, Zabel K, Herrmann E, Schröder O. Methotrexate for maintenance of remission in chronic active Crohn's disease: long-term single-center experience and meta-analysis of observational studies.Inflamm Bowel Dis. 2010;16:1195-1202.
Domènech E, Mañosa M, Navarro M, Masnou H, Garcia-Planella E, Zabana Y, Cabré E, Gassull MA. Long-term methotrexate for Crohn's disease: safety and efficacy in clinical practice.J Clin Gastroenterol. 2008;42:395-399.
Rutgeerts P, Vermeire S, Van Assche G. Biological therapies for inflammatory bowel diseases.Gastroenterology. 2009;136:1182-1197.
Hanauer SB, Feagan BG, Lichtenstein GR, Mayer LF, Schreiber S, Colombel JF, Rachmilewitz D, Wolf DC, Olson A, Bao W. Maintenance infliximab for Crohn's disease: the ACCENT I randomised trial.Lancet. 2002;359:1541-1549.
Hyams J, Crandall W, Kugathasan S, Griffiths A, Olson A, Johanns J, Liu G, Travers S, Heuschkel R, Markowitz J. Induction and maintenance infliximab therapy for the treatment of moderate-to-severe Crohn's disease in children.Gastroenterology. 2007;132:863-873; quiz 1165-1166.
Schnitzler F, Fidder H, Ferrante M, Noman M, Arijs I, Van Assche G, Hoffman I, Van Steen K, Vermeire S, Rutgeerts P. Long-term outcome of treatment with infliximab in 614 patients with Crohn's disease: results from a single-centre cohort.Gut. 2009;58:492-500.
Sandborn WJ, Hanauer SB, Rutgeerts P, Fedorak RN, Lukas M, MacIntosh DG, Panaccione R, Wolf D, Kent JD, Bittle B. Adalimumab for maintenance treatment of Crohn's disease: results of the CLASSIC II trial.Gut. 2007;56:1232-1239.
Vermeire S, van Assche G, Rutgeerts P. Review article: Altering the natural history of Crohn's disease--evidence for and against current therapies.Aliment Pharmacol Ther. 2007;25:3-12.
Bernklev T, Jahnsen J, Henriksen M, Lygren I, Aadland E, Sauar J, Schulz T, Stray N, Vatn M, Moum B. Relationship between sick leave, unemployment, disability, and health-related quality of life in patients with inflammatory bowel disease.Inflamm Bowel Dis. 2006;12:402-412.
Boonen A, Dagnelie PC, Feleus A, Hesselink MA, Muris JW, Stockbrügger RW, Russel MG. The impact of inflammatory bowel disease on labor force participation: results of a population sampled case-control study.Inflamm Bowel Dis. 2002;8:382-389.
Sørensen VZ, Olsen BG, Binder V. Life prospects and quality of life in patients with Crohn's disease.Gut. 1987;28:382-385.