Alimentary Pharmacology and Therapeutics
Anaemia in inflammatory bowel disease: a population-based 10-year follow-up M. L. Høivik*,†, W. Reinisch‡, M. Cvancarova*,§, B. Moum*,† & the IBSEN study group
*Department of Gastroenterology, Oslo University Hospital, Ullev al, Oslo, Norway. † Faculty of Medicine, University of Oslo, Oslo, Norway. ‡ Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University Vienna, Vienna, Austria. § Department of Biostatistics, Oslo University Hospital, Oslo, Norway.
Correspondence to: Dr M. L. Høivik, Department of Gastroenterology, Oslo University Hospital, Ullev al, Pb 4956 Nydalen, 0424 Oslo, Norway. E-mail: [email protected]
Publication data Submitted 21 August 2013 First decision 2 September 2013 Resubmitted 9 October 2013 Accepted 9 October 2013 EV Pub Online 31 October 2013
SUMMARY Background The point prevalence estimates of anaemia in patients with inflammatory bowel disease (IBD) range between 6% and 74%. The variation is probably due to differences in the definition of anaemia and the study populations. Aim To retrospectively determine the prevalence of anaemia at diagnosis and at the 1-, 5- and 10-year follow-ups in patients with IBD from a prospectively followed, population-based inception cohort (the IBSEN Study). To compare the prevalence of anaemia after a 10-year disease course with the prevalence of anaemia in the background population, and to assess clinical factors associated with anaemia at diagnosis and during follow-up. Methods Newly diagnosed IBD patients were included in a population-based, prospective cohort. Follow-up was performed at 1, 5 and 10 years. All visits included clinical examinations and blood samples. Anaemia was defined according to the WHO. Results A total of 756 patients (UC, n = 519 and CD, n = 237) were included; 48.8% of CD and 20.2% of UC patients were anaemic at diagnosis (P < 0.001). The proportion of patients with anaemia decreased during the disease course in all patients, except in women with CD. After 10 years of disease, the relative risk for anaemia was increased in all groups, except for women with UC. The variables associated with anaemia were generally unchanged during the disease course, and elevated CRP was the strongest predictor of risk. Conclusions Anaemia was more common in CD than in UC. The prevalence of anaemia decreased during the disease course. Women with CD were at high risk for anaemia. Elevated CRP was independently associated with anaemia. Aliment Pharmacol Ther 2014; 39: 69–76
ª 2013 John Wiley & Sons Ltd doi:10.1111/apt.12541
69
M. L. Høivik et al. INTRODUCTION Inflammatory bowel disease (IBD), which includes Crohn’s disease (CD) and ulcerative colitis (UC), is a group of chronic inflammatory conditions affecting the gastrointestinal tract. Intestinal manifestations, such as diarrhoea, abdominal pain and bleeding, are important in the management and treatment of these diseases. However, IBD is often complicated by manifestations that may be less apparent to the physician and the patient, such as malnutrition and anaemia.1 Anaemia in IBD is associated with a reduced quality of life and necessitates adequate monitoring and treatment of the underlying, often multifactorial, causes.2, 3 Iron deficiency and anaemia of chronic disease are the main causes of anaemia in IBD.4, 5 However, vitamin deficiencies and drug-induced bone marrow suppression can also contribute. It has been suggested that anaemia is probably too common to be specifically recognised as a complication of IBD.6, 7 However, the reported prevalence of anaemia in IBD varies substantially depending on the definition of anaemia and the patient population considered (hospitalised patients vs. out-patients). Gasche reported that one-third of patients with IBD are anaemic at any given time.8 Systematic reviews have reported point prevalence estimates of anaemia ranging from 6% to 74%.1, 6, 9 Gisbert et al. showed that the weighted mean prevalence of anaemia calculated from 22 studies was 17% [95% confidence interval (CI) 16–18%].7 However, when the results were stratified by out-patients and hospitalised patients, the weighted mean prevalence was 16% and 68% respectively. In two recent papers, the prevalence of anaemia was reported to be 19% in an unselected out-patient population and 6% in a population-based cohort.10, 11 To our knowledge, there are no estimates of the prevalence of anaemia in population-based inception cohorts or any reports on the course of anaemia from diagnosis to the chronic phase of IBD. The main aim of this study was to retrospectively determine the prevalence of anaemia at diagnosis and at the 1-, 5- and 10-year follow-ups in patients with IBD from a prospectively followed, population-based inception cohort. Furthermore, this study compared the prevalence of anaemia in patients after a 10-year disease course with the prevalence of anaemia in the background population and assessed the clinical factors that were associated with anaemia at diagnosis and during follow-up.
70
METHODS Study design and population From 1 January 1990 to 31 December 1993, all newly diagnosed cases of IBD or possible IBD in four well-defined areas in south-eastern Norway (the counties of Oslo, Østfold, Telemark and Aust-Agder) were registered prospectively; 843 patients were originally included in this inception cohort. The cohort was followed comprehensively for 10 years, with scheduled follow-up visits at 1, 5 and 10 years (1 year) after the diagnosis. The organisation of the cohort, the diagnostic criteria and the clinical follow-up protocol are described elsewhere.12–15 Data collection The follow-up visits consisted of a structured interview, a review of hospital records, a clinical examination, laboratory tests [including measurement of haemoglobin (Hb) and C-reactive protein (CRP)] and, when indicated, an ileocolonoscopy and/or a small-bowel enema. Definition of variables Hb levels 25 years of age. * The observed number of patients with anaemia in the study population. † The expected number of patients was estimated using data from the background population, which were only available for people >25 years of age.18 Aliment Pharmacol Ther 2014; 39: 69-76 ª 2013 John Wiley & Sons Ltd
73
M. L. Høivik et al. (from the first 5 years after diagnosis to the second 5-year period). In addition, inflammation and disease activity appeared to decrease. Less inflammation results in less blood loss, decreased inhibition of hepcidin and increased iron absorption from the intestine. Moreover, a shorter duration between the start of a relapse and successful treatment may contribute, as both patients and their doctors recognise symptoms and consequently initiate efficient treatment earlier. A general improvement in IBD treatment over these 10 years might also be a factor. However, very few of our patients received anti-tumour necrosis factor therapy, and relatively few patients received immunomodulators. Consequently, we cannot evaluate the impact of these medications in this study. After 5 years, there was only a minor increase in the absolute risk of anaemia for the patient groups compared with the expected risk for the background population.18 However, we did find a significantly increased RR of anaemia in CD patients and in men with UC compared with the background population, even after 10 years of disease. This finding was most pronounced in the youngest CD patients. The treatment goal in each patient should be the maintenance of normal Hb levels.21 However, from a population perspective, we might not expect prevalence numbers that are lower than the prevalence found in the general population. The fact that the RR of anaemia in women with UC after 10 years was not increased could therefore be interpreted as adequate follow-up and successful treatment of this group. Moreover, at each time point, previously non-anaemic patients became anaemic. Thus, a normal Hb measurement does not imply that continued surveillance is unnecessary for any subgroup of patients. Women with CD appeared to be at particular risk of anaemia over the long-term disease course. Data from the IBSEN cohort did not indicate that women have a more serious disease course than men.20 In contrast, a recent German study that presented data from a large cohort of IBD out-patients suggested that women received less immunosuppressive treatment than men and had more active disease.22 This finding could partly explain a gender difference in CD patients, but would also imply a similar difference in UC patients, which we did not find. Interestingly, in the IBSEN study, it was this subgroup of women with CD who reported the lowest health-related quality of life and who also had the highest risk of being work disabled after 10 years of disease.23, 24 However, these publications did not explore the potential association between anaemia and these factors, hence conclusions cannot be drawn. 74
CRP, an objective biomarker of inflammation, was the most consistent variable associated with anaemia. This result supports the importance of inflammation in the pathophysiology of anaemia.25 The use of GCS can also be considered as a marker of inflammatory activity, which partly explains the association of GCS use with anaemia. Disease location was associated with anaemia in UC patients at diagnosis. More extensive disease was associated with a higher the risk of anaemia; this result is probably due to more bleeding and an increased inflammatory load. Anaemia at previous visits was also associated with anaemia at follow-up visits. This finding could be due to a more severe course of disease in the affected individuals. Smoking was associated with a lower risk of anaemia at the time of diagnosis. It is known that smokers can develop compensatory polycythaemia caused by the carbon monoxide in cigarette smoke, which could explain this finding.26
Limitations We have only studied anaemia defined by Hb levels since we had no data to differentiate between different causes of anaemia (e.g. iron-deficiency anaemia). Therefore, we can only comment on anaemia in general and not on subtypes. However, according to a recent study by Bager et al., most anaemia in IBD patients is caused by iron deficiency and anaemia of chronic disease, while folic acid and vitamin B12 deficiencies are of minor importance.10 In our study, 25% of UC patients and 65% of CD patients had elevated CRP levels at diagnosis, and CRP was independently associated with anaemia. Therefore, anaemia of chronic disease was most likely to have contributed to the reduced Hb levels in our patients. We did not have information on iron substitution in these patients, which represents another limitation of this study. During the IBSEN study period (1990–2004), iron substitution products were limited to oral preparations or low-dosage intravenous preparations that were administered repeatedly over several weeks. Whether the more frequent use of intravenous (iv) iron preparations over the 10-year observation period contributed to the declining prevalence of anaemia in our cohort therefore remains unknown.27 There were few anaemic patients, especially at the 10-year follow-up visit. This limitation in the data did restrict both the stratified analyses and the multiple regression analysis. Aliment Pharmacol Ther 2014; 39: 69-76 ª 2013 John Wiley & Sons Ltd
Anaemia in IBD CONCLUSIONS Anaemia is more common in CD patients than in UC patients, and the prevalence of anaemia decreases during the disease course. Furthermore, women with CD are at high risk for anaemia, even after 10 years of disease. The variables associated with anaemia were generally unchanged during the disease course, with increased CRP levels and the use of corticosteroids being the strongest predictors of risk. Our findings underline that anaemia in IBD is largely correlated with inflammatory activity. Close monitoring and adequate treatment of anaemia and its causes could prevent this systemic manifestation and the associated reduction in quality of life. AUTHORSHIP Guarantor of the article: Marte Lie Høivik. Author contributions: BM and the IBSEN study Group: acquisition of data. MLH and MC: statistical analysis. MLH: Drafting of manuscript. All authors contributed to the study concept and design, interpretation of data, critical revision of the manuscript for important intellectual content and approved the final version of the manuscript.
ACKNOWLEDGEMENTS Declaration of personal interests: W. Reinisch reports personal fees from Pharmacosmos, outside the submitted work. We thank all members of the IBSEN Study Group and especially Morten Vatn, Akershus University Hospital; Inger Camilla Solberg, Øyvind Palm, Jørgen Jahnsen and Idar Lygren, Oslo University Hospital; Njaal Stray, Diakonhjemmet Hospital; Jostein Sauar, Øystein Kjellevold, Tomm Bernklev, Telemark Hospital; Stein Dahler, Blefjell Hospital; Finn Strøm, Lovisenberg Hospital; Ole Høie, Sørlandet Sykehus, Magne Henriksen, Østfold Hospital. Declaration of funding interests: None. SUPPORTING INFORMATION Additional Supporting Information may be found in the online version of this article: Table S1. Data completeness and prevalence of anaemia. Table S2. Logistic regression analysis with anaemia as the dependent variable. Table S3. Sensitivity analysis.
REFERENCES 1. Kulnigg S, Gasche C. Systematic review: managing anaemia in Crohn’s disease. Aliment Pharmacol Ther 2006; 24: 1507–23. 2. Pizzi LT, Weston CM, Goldfarb NI, et al. Impact of chronic conditions on quality of life in patients with inflammatory bowel disease. Inflamm Bowel Dis 2006; 12: 47–52. 3. Wells CW, Lewis S, Barton JR, Corbett S. Effects of changes in hemoglobin level on quality of life and cognitive function in inflammatory bowel disease patients. Inflamm Bowel Dis 2006; 12: 123–30. 4. Reinisch W, Staun M, Bhandari S, Munoz M. State of the iron: how to diagnose and efficiently treat iron deficiency anemia in inflammatory bowel disease. J Crohns Colitis 2013; 7: 429–40. 5. Gomollon F, Gisbert JP. Anemia and inflammatory bowel diseases. World J Gastroenterol 2009; 15: 4659–65. 6. Gasche C, Lomer MC, Cavill I, Weiss G. Iron, anaemia, and inflammatory bowel diseases. Gut 2004; 53: 1190–7. 7. Gisbert JP, Gomollon F. Common misconceptions in the diagnosis and management of anemia in Aliment Pharmacol Ther 2014; 39: 69-76 ª 2013 John Wiley & Sons Ltd
8.
9.
10.
11.
12.
inflammatory bowel disease. Am J Gastroenterol 2008; 103: 1299–307. Gasche C. Anemia in IBD: the overlooked villain. Inflamm Bowel Dis 2000; 6: 142–50. Wilson A, Reyes E, Ofman J. Prevalence and outcomes of anemia in inflammatory bowel disease: a systematic review of the literature. Am J Med 2004; 116: Suppl.–49S. Bager P, Befrits R, Wikman O, et al. The prevalence of anemia and iron deficiency in IBD outpatients in Scandinavia. Scand J Gastroenterol 2011; 46: 304–9. Rejler M, Tholstrup J, Andersson-Gare B, Spangeus A. Low prevalence of anemia in inflammatory bowel disease: a population-based study in Sweden. Scand J Gastroenterol 2012; 47: 937–42. Moum B, Vatn MH, Ekbom A, et al. Incidence of ulcerative colitis and indeterminate colitis in four counties of 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: 362–6.
13. Moum B, Ekbom A, Vatn MH, et al. Inflammatory bowel disease: reevaluation of the diagnosis in a prospective population based study in south eastern Norway. Gut 1997; 40: 328–32. 14. Henriksen M, Jahnsen J, Lygren I, et al. Ulcerative colitis and clinical course: results of a 5-year population-based follow-up study (the IBSEN study). Inflamm Bowel Dis 2006; 12: 543–50. 15. Solberg IC, Lygren I, Jahnsen J, et al. Clinical course during the first 10 years of ulcerative colitis: results from a population-based inception cohort (IBSEN Study). Scand J Gastroenterol 2009; 44: 431–40. 16. World Health Organization. Iron Deficiency Anemia Assessment, Prevention and Control A guide for programme managers. Report; 2011. Report No.: WHO/NHP/01.3. 17. Gasche C, Scholmerich J, Brynskov J, et al. A simple classification of Crohn’s disease: report of the Working Party for the World Congresses of Gastroenterology, Vienna 1998. Inflamm Bowel Dis 2000; 6: 8–15. 18. Skjelbakken T, Langbakk B, Dahl IM, Lochen ML, Tromso S. Haemoglobin 75
M. L. Høivik et al. and anaemia in a gender perspective: the Tromso Study. Eur J Haematol 2005; 74: 381–8. 19. Altman DG, Machin D, Bryant T, et al. Statistics with confidence. 2nd ed. London: Wiley, 2000. 20. Solberg IC, Vatn MH, Hoie O, et al. Clinical course in Crohn’s disease: results of a Norwegian populationbased ten-year follow-up study. Clin Gastroenterol Hepatol 2007; 5: 1430–8. 21. Van Assche G, Dignass A, Reinisch W, et al. The second European evidencebased Consensus on the diagnosis and management of Crohn’s disease: Special situations. J Crohns Colitis 2010; 4: 63– 101.
76
22. Blumenstein I, Herrmann E, Filmann N, et al. Female patients suffering from inflammatory bowel diseases are treated less frequently with immunosuppressive medication and have a higher disease activity: a subgroup analysis of a large multi-centre, prospective, internet-based study. J Crohns Colitis 2011; 5: 203–10. 23. Høivik ML, Bernklev T, Solberg IC, et al. Patients with Crohn’s disease experience reduced general health and vitality in the chronic stage: Ten-year results from the IBSEN study. J Crohns Colitis 2012; 6: 441–53. 24. Høivik ML, Moum B, Solberg IC, et al. Work disability in inflammatory bowel disease patients 10 years after disease
onset: results from the IBSEN Study. Gut 2013; 62: 368–75. 25. Weiss G, Gasche C. Pathogenesis and treatment of anemia in inflammatory bowel disease. Haematologica 2010; 95: 175–8. 26. Leifert JA. Anaemia and cigarette smoking. Int J Lab Hematol 2008; 30: 177–84. 27. Reinisch W, Chowers Y, Danese S, et al. The management of iron deficiency in inflammatory bowel disease – an online tool developed by the RAND/UCLA appropriateness method. Aliment Pharmacol Ther 2013; 38: 1109–18.
Aliment Pharmacol Ther 2014; 39: 69-76 ª 2013 John Wiley & Sons Ltd
Anaemia in inflammatory bowel disease: a population-based 10-year follow-up M. L. Høivik*,†, W. Reinisch‡, M. Cvancarova*,§, B. Moum*,† & the IBSEN study group
*Department of Gastroenterology, Oslo University Hospital, Ullev al, Oslo, Norway. † Faculty of Medicine, University of Oslo, Oslo, Norway. ‡ Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University Vienna, Vienna, Austria. § Department of Biostatistics, Oslo University Hospital, Oslo, Norway.
Correspondence to: Dr M. L. Høivik, Department of Gastroenterology, Oslo University Hospital, Ullev al, Pb 4956 Nydalen, 0424 Oslo, Norway. E-mail: [email protected]
Publication data Submitted 21 August 2013 First decision 2 September 2013 Resubmitted 9 October 2013 Accepted 9 October 2013 EV Pub Online 31 October 2013
SUMMARY Background The point prevalence estimates of anaemia in patients with inflammatory bowel disease (IBD) range between 6% and 74%. The variation is probably due to differences in the definition of anaemia and the study populations. Aim To retrospectively determine the prevalence of anaemia at diagnosis and at the 1-, 5- and 10-year follow-ups in patients with IBD from a prospectively followed, population-based inception cohort (the IBSEN Study). To compare the prevalence of anaemia after a 10-year disease course with the prevalence of anaemia in the background population, and to assess clinical factors associated with anaemia at diagnosis and during follow-up. Methods Newly diagnosed IBD patients were included in a population-based, prospective cohort. Follow-up was performed at 1, 5 and 10 years. All visits included clinical examinations and blood samples. Anaemia was defined according to the WHO. Results A total of 756 patients (UC, n = 519 and CD, n = 237) were included; 48.8% of CD and 20.2% of UC patients were anaemic at diagnosis (P < 0.001). The proportion of patients with anaemia decreased during the disease course in all patients, except in women with CD. After 10 years of disease, the relative risk for anaemia was increased in all groups, except for women with UC. The variables associated with anaemia were generally unchanged during the disease course, and elevated CRP was the strongest predictor of risk. Conclusions Anaemia was more common in CD than in UC. The prevalence of anaemia decreased during the disease course. Women with CD were at high risk for anaemia. Elevated CRP was independently associated with anaemia. Aliment Pharmacol Ther 2014; 39: 69–76
ª 2013 John Wiley & Sons Ltd doi:10.1111/apt.12541
69
M. L. Høivik et al. INTRODUCTION Inflammatory bowel disease (IBD), which includes Crohn’s disease (CD) and ulcerative colitis (UC), is a group of chronic inflammatory conditions affecting the gastrointestinal tract. Intestinal manifestations, such as diarrhoea, abdominal pain and bleeding, are important in the management and treatment of these diseases. However, IBD is often complicated by manifestations that may be less apparent to the physician and the patient, such as malnutrition and anaemia.1 Anaemia in IBD is associated with a reduced quality of life and necessitates adequate monitoring and treatment of the underlying, often multifactorial, causes.2, 3 Iron deficiency and anaemia of chronic disease are the main causes of anaemia in IBD.4, 5 However, vitamin deficiencies and drug-induced bone marrow suppression can also contribute. It has been suggested that anaemia is probably too common to be specifically recognised as a complication of IBD.6, 7 However, the reported prevalence of anaemia in IBD varies substantially depending on the definition of anaemia and the patient population considered (hospitalised patients vs. out-patients). Gasche reported that one-third of patients with IBD are anaemic at any given time.8 Systematic reviews have reported point prevalence estimates of anaemia ranging from 6% to 74%.1, 6, 9 Gisbert et al. showed that the weighted mean prevalence of anaemia calculated from 22 studies was 17% [95% confidence interval (CI) 16–18%].7 However, when the results were stratified by out-patients and hospitalised patients, the weighted mean prevalence was 16% and 68% respectively. In two recent papers, the prevalence of anaemia was reported to be 19% in an unselected out-patient population and 6% in a population-based cohort.10, 11 To our knowledge, there are no estimates of the prevalence of anaemia in population-based inception cohorts or any reports on the course of anaemia from diagnosis to the chronic phase of IBD. The main aim of this study was to retrospectively determine the prevalence of anaemia at diagnosis and at the 1-, 5- and 10-year follow-ups in patients with IBD from a prospectively followed, population-based inception cohort. Furthermore, this study compared the prevalence of anaemia in patients after a 10-year disease course with the prevalence of anaemia in the background population and assessed the clinical factors that were associated with anaemia at diagnosis and during follow-up.
70
METHODS Study design and population From 1 January 1990 to 31 December 1993, all newly diagnosed cases of IBD or possible IBD in four well-defined areas in south-eastern Norway (the counties of Oslo, Østfold, Telemark and Aust-Agder) were registered prospectively; 843 patients were originally included in this inception cohort. The cohort was followed comprehensively for 10 years, with scheduled follow-up visits at 1, 5 and 10 years (1 year) after the diagnosis. The organisation of the cohort, the diagnostic criteria and the clinical follow-up protocol are described elsewhere.12–15 Data collection The follow-up visits consisted of a structured interview, a review of hospital records, a clinical examination, laboratory tests [including measurement of haemoglobin (Hb) and C-reactive protein (CRP)] and, when indicated, an ileocolonoscopy and/or a small-bowel enema. Definition of variables Hb levels 25 years of age. * The observed number of patients with anaemia in the study population. † The expected number of patients was estimated using data from the background population, which were only available for people >25 years of age.18 Aliment Pharmacol Ther 2014; 39: 69-76 ª 2013 John Wiley & Sons Ltd
73
M. L. Høivik et al. (from the first 5 years after diagnosis to the second 5-year period). In addition, inflammation and disease activity appeared to decrease. Less inflammation results in less blood loss, decreased inhibition of hepcidin and increased iron absorption from the intestine. Moreover, a shorter duration between the start of a relapse and successful treatment may contribute, as both patients and their doctors recognise symptoms and consequently initiate efficient treatment earlier. A general improvement in IBD treatment over these 10 years might also be a factor. However, very few of our patients received anti-tumour necrosis factor therapy, and relatively few patients received immunomodulators. Consequently, we cannot evaluate the impact of these medications in this study. After 5 years, there was only a minor increase in the absolute risk of anaemia for the patient groups compared with the expected risk for the background population.18 However, we did find a significantly increased RR of anaemia in CD patients and in men with UC compared with the background population, even after 10 years of disease. This finding was most pronounced in the youngest CD patients. The treatment goal in each patient should be the maintenance of normal Hb levels.21 However, from a population perspective, we might not expect prevalence numbers that are lower than the prevalence found in the general population. The fact that the RR of anaemia in women with UC after 10 years was not increased could therefore be interpreted as adequate follow-up and successful treatment of this group. Moreover, at each time point, previously non-anaemic patients became anaemic. Thus, a normal Hb measurement does not imply that continued surveillance is unnecessary for any subgroup of patients. Women with CD appeared to be at particular risk of anaemia over the long-term disease course. Data from the IBSEN cohort did not indicate that women have a more serious disease course than men.20 In contrast, a recent German study that presented data from a large cohort of IBD out-patients suggested that women received less immunosuppressive treatment than men and had more active disease.22 This finding could partly explain a gender difference in CD patients, but would also imply a similar difference in UC patients, which we did not find. Interestingly, in the IBSEN study, it was this subgroup of women with CD who reported the lowest health-related quality of life and who also had the highest risk of being work disabled after 10 years of disease.23, 24 However, these publications did not explore the potential association between anaemia and these factors, hence conclusions cannot be drawn. 74
CRP, an objective biomarker of inflammation, was the most consistent variable associated with anaemia. This result supports the importance of inflammation in the pathophysiology of anaemia.25 The use of GCS can also be considered as a marker of inflammatory activity, which partly explains the association of GCS use with anaemia. Disease location was associated with anaemia in UC patients at diagnosis. More extensive disease was associated with a higher the risk of anaemia; this result is probably due to more bleeding and an increased inflammatory load. Anaemia at previous visits was also associated with anaemia at follow-up visits. This finding could be due to a more severe course of disease in the affected individuals. Smoking was associated with a lower risk of anaemia at the time of diagnosis. It is known that smokers can develop compensatory polycythaemia caused by the carbon monoxide in cigarette smoke, which could explain this finding.26
Limitations We have only studied anaemia defined by Hb levels since we had no data to differentiate between different causes of anaemia (e.g. iron-deficiency anaemia). Therefore, we can only comment on anaemia in general and not on subtypes. However, according to a recent study by Bager et al., most anaemia in IBD patients is caused by iron deficiency and anaemia of chronic disease, while folic acid and vitamin B12 deficiencies are of minor importance.10 In our study, 25% of UC patients and 65% of CD patients had elevated CRP levels at diagnosis, and CRP was independently associated with anaemia. Therefore, anaemia of chronic disease was most likely to have contributed to the reduced Hb levels in our patients. We did not have information on iron substitution in these patients, which represents another limitation of this study. During the IBSEN study period (1990–2004), iron substitution products were limited to oral preparations or low-dosage intravenous preparations that were administered repeatedly over several weeks. Whether the more frequent use of intravenous (iv) iron preparations over the 10-year observation period contributed to the declining prevalence of anaemia in our cohort therefore remains unknown.27 There were few anaemic patients, especially at the 10-year follow-up visit. This limitation in the data did restrict both the stratified analyses and the multiple regression analysis. Aliment Pharmacol Ther 2014; 39: 69-76 ª 2013 John Wiley & Sons Ltd
Anaemia in IBD CONCLUSIONS Anaemia is more common in CD patients than in UC patients, and the prevalence of anaemia decreases during the disease course. Furthermore, women with CD are at high risk for anaemia, even after 10 years of disease. The variables associated with anaemia were generally unchanged during the disease course, with increased CRP levels and the use of corticosteroids being the strongest predictors of risk. Our findings underline that anaemia in IBD is largely correlated with inflammatory activity. Close monitoring and adequate treatment of anaemia and its causes could prevent this systemic manifestation and the associated reduction in quality of life. AUTHORSHIP Guarantor of the article: Marte Lie Høivik. Author contributions: BM and the IBSEN study Group: acquisition of data. MLH and MC: statistical analysis. MLH: Drafting of manuscript. All authors contributed to the study concept and design, interpretation of data, critical revision of the manuscript for important intellectual content and approved the final version of the manuscript.
ACKNOWLEDGEMENTS Declaration of personal interests: W. Reinisch reports personal fees from Pharmacosmos, outside the submitted work. We thank all members of the IBSEN Study Group and especially Morten Vatn, Akershus University Hospital; Inger Camilla Solberg, Øyvind Palm, Jørgen Jahnsen and Idar Lygren, Oslo University Hospital; Njaal Stray, Diakonhjemmet Hospital; Jostein Sauar, Øystein Kjellevold, Tomm Bernklev, Telemark Hospital; Stein Dahler, Blefjell Hospital; Finn Strøm, Lovisenberg Hospital; Ole Høie, Sørlandet Sykehus, Magne Henriksen, Østfold Hospital. Declaration of funding interests: None. SUPPORTING INFORMATION Additional Supporting Information may be found in the online version of this article: Table S1. Data completeness and prevalence of anaemia. Table S2. Logistic regression analysis with anaemia as the dependent variable. Table S3. Sensitivity analysis.
REFERENCES 1. Kulnigg S, Gasche C. Systematic review: managing anaemia in Crohn’s disease. Aliment Pharmacol Ther 2006; 24: 1507–23. 2. Pizzi LT, Weston CM, Goldfarb NI, et al. Impact of chronic conditions on quality of life in patients with inflammatory bowel disease. Inflamm Bowel Dis 2006; 12: 47–52. 3. Wells CW, Lewis S, Barton JR, Corbett S. Effects of changes in hemoglobin level on quality of life and cognitive function in inflammatory bowel disease patients. Inflamm Bowel Dis 2006; 12: 123–30. 4. Reinisch W, Staun M, Bhandari S, Munoz M. State of the iron: how to diagnose and efficiently treat iron deficiency anemia in inflammatory bowel disease. J Crohns Colitis 2013; 7: 429–40. 5. Gomollon F, Gisbert JP. Anemia and inflammatory bowel diseases. World J Gastroenterol 2009; 15: 4659–65. 6. Gasche C, Lomer MC, Cavill I, Weiss G. Iron, anaemia, and inflammatory bowel diseases. Gut 2004; 53: 1190–7. 7. Gisbert JP, Gomollon F. Common misconceptions in the diagnosis and management of anemia in Aliment Pharmacol Ther 2014; 39: 69-76 ª 2013 John Wiley & Sons Ltd
8.
9.
10.
11.
12.
inflammatory bowel disease. Am J Gastroenterol 2008; 103: 1299–307. Gasche C. Anemia in IBD: the overlooked villain. Inflamm Bowel Dis 2000; 6: 142–50. Wilson A, Reyes E, Ofman J. Prevalence and outcomes of anemia in inflammatory bowel disease: a systematic review of the literature. Am J Med 2004; 116: Suppl.–49S. Bager P, Befrits R, Wikman O, et al. The prevalence of anemia and iron deficiency in IBD outpatients in Scandinavia. Scand J Gastroenterol 2011; 46: 304–9. Rejler M, Tholstrup J, Andersson-Gare B, Spangeus A. Low prevalence of anemia in inflammatory bowel disease: a population-based study in Sweden. Scand J Gastroenterol 2012; 47: 937–42. Moum B, Vatn MH, Ekbom A, et al. Incidence of ulcerative colitis and indeterminate colitis in four counties of 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: 362–6.
13. Moum B, Ekbom A, Vatn MH, et al. Inflammatory bowel disease: reevaluation of the diagnosis in a prospective population based study in south eastern Norway. Gut 1997; 40: 328–32. 14. Henriksen M, Jahnsen J, Lygren I, et al. Ulcerative colitis and clinical course: results of a 5-year population-based follow-up study (the IBSEN study). Inflamm Bowel Dis 2006; 12: 543–50. 15. Solberg IC, Lygren I, Jahnsen J, et al. Clinical course during the first 10 years of ulcerative colitis: results from a population-based inception cohort (IBSEN Study). Scand J Gastroenterol 2009; 44: 431–40. 16. World Health Organization. Iron Deficiency Anemia Assessment, Prevention and Control A guide for programme managers. Report; 2011. Report No.: WHO/NHP/01.3. 17. Gasche C, Scholmerich J, Brynskov J, et al. A simple classification of Crohn’s disease: report of the Working Party for the World Congresses of Gastroenterology, Vienna 1998. Inflamm Bowel Dis 2000; 6: 8–15. 18. Skjelbakken T, Langbakk B, Dahl IM, Lochen ML, Tromso S. Haemoglobin 75
M. L. Høivik et al. and anaemia in a gender perspective: the Tromso Study. Eur J Haematol 2005; 74: 381–8. 19. Altman DG, Machin D, Bryant T, et al. Statistics with confidence. 2nd ed. London: Wiley, 2000. 20. Solberg IC, Vatn MH, Hoie O, et al. Clinical course in Crohn’s disease: results of a Norwegian populationbased ten-year follow-up study. Clin Gastroenterol Hepatol 2007; 5: 1430–8. 21. Van Assche G, Dignass A, Reinisch W, et al. The second European evidencebased Consensus on the diagnosis and management of Crohn’s disease: Special situations. J Crohns Colitis 2010; 4: 63– 101.
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