- Email: [email protected]
Inflammatory Bowel Disease Extending Its Reach
September 2005
EDITORIALS
1117
Inflammatory Bowel Disease Extending Its Reach See articles on pages 819 and 827.
s medical students and residents, we learned about the classic extraintestinal manifestations of inflammatory bowel disease (IBD): ankylosing spondylitis, peripheral arthritis, uveitis, pyoderma gangrenosum, erythema nodosum, and primary sclerosing cholangitis. In recent years, we have seen an extensive amount of literature emerge on less familiar extraintestinal complications of ulcerative colitis (UC) and Crohn’s disease; most notably osteoporosis and, to a lesser extent, thromboembolism. Two articles in this month’s GASTROENTEROLOGY remind us that the effects of IBD extend to every corner of the body, including the lung and the central nervous system.1,2 The 2 studies use roughly similar techniques—large databases, containing both patients with IBD and population controls, were searched for diagnoses of interest. A description of each database is necessary to understand the strengths and the limitations of these studies. During the past decade, Bernstein et al3 have created a population-based cohort of patients with IBD from Manitoba, Canada, using an administrative provincial health database and a validated algorithm based on codes from the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM). The algorithm was validated by medical record review of a sample of patients and resulted in greater than 90% accuracy for the diagnosis of IBD. These investigators have used this database and cohort to report on the descriptive epidemiology of Crohn’s disease and UC3; furthermore, they have contributed to the literature on a whole host of IBD-related outcomes, including the risk of classic extraintestinal manifestations,4 cancer,5 bone fractures,6 and venous thromboembolism.7 The University of Manitoba IBD cohort has grown over time to include more than 8000 patients.1 In the present study, the investigators searched their IBD database for ICD-9-CM codes for various immune-mediated diseases (eg, asthma, bronchitis, arthritis, thyroiditis, multiple sclerosis [MS], neuropathy, myasthenia gravis, chronic renal disease, psoriasis, and pericarditis) and calculated a period prevalence (1984 to 2003).1 A control group consisting of 10 Manitobans matched to each of the IBD cases on age, sex, postal code, and date of IBD diagnosis was identified, and a period prevalence for immune-mediated diseases in this cohort was similarly calculated. The ratio of auto-
A
immune disease prevalence in the 2 groups was then calculated.1 Gupta et al2 used the resources of the General Practice Research Database (GPRD) from the United Kingdom to investigate the association between IBD and immunemediated neurological disorders such as MS, optic neuritis (ON), and unspecified demyelinating disorders. The GPRD contains computerized medical records of general practitioners whose case panels in total comprise 6% of the entire British population; therefore, it serves as a proxy for a population-based study. Diagnostic codes in the GPRD are based on the Oxford Medical Indexing System (OXMIS). The investigators had previously shown by medical record review that their algorithm for identifying IBD by using OXMIS codes was reasonably accurate.8 The investigators have used this very large cohort of patients with IBD (n ⬎ 20,000) to investigate the relative and absolute risk of non-Hodgkin lymphoma, to study the influence of antibiotics on the risk of exacerbations of IBD, and to determine if exacerbations of IBD followed seasonal patterns.9 –11 Other investigators have used the GPRD to estimate mortality, fracture risk, and renal disease risk in patients with IBD.12–14 In the present study, they identified OXMIS codes for MS, demyelination, ON, and retrobulbar neuritis in both the IBD cohort and in a control cohort composed of 4 patients with GPRD matched to each of the IBD cases on year of birth, sex, and primary care practice.2 (Other investigators have shown that OXMIS codes for MS are accurate.15,16) The analysis was performed in 2 ways. The cross-sectional approach used an approach similar to Bernstein et al,1 in which the prevalence of the diagnoses of interest (either before or after IBD diagnosis) in the IBD cohort was compared to the prevalence in the control cohort. The cohort analysis compared the incidence of neurologic diagnoses after a diagnosis of IBD in the IBD cohort with the incidence of these diagnoses in the control cohort.2 What were the results? In the Manitoba study, the prevalence of immune-mediated disease in both the IBD cohort and the control cohort varied depending on the particular algorithm used to define the diagnosis of interest.1 Because the investigators did not undertake a medical record review to validate coding algorithms for these conditions, they wisely chose to present a range of prevalences defined at the high end by the least specific algorithm (at least 1 health contact with appropriate ICD-9-CM code) and at the low end by the most specific
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(at least 5 health contacts with ICD-9-CM code). For example, the prevalence of asthma ranged from 8% to 21% in the UC cases, 7% to 20% in the Crohn’s disease cases, and 5% to 16% in the controls. Fortunately, the prevalence ratios did not change significantly in most cases. Thus, for UC, the prevalence ratio for asthma ranged from 1.5 to 1.7, and for Crohn’s disease, the ratio for asthma ranged from 1.3 to 1.4. In other words, patients with UC were 50%–70% more likely than population-based controls to have asthma, whereas patients with Crohn’s disease were 30%– 40% more likely. Using the most rigorous algorithm, significant associations were observed between UC and the following conditions: asthma; bronchitis; arthritis; MS; and chronic renal disease, psoriasis, and pericarditis. For patients with Crohn’s disease, the prevalence of asthma, bronchitis, arthritis, psoriasis, and pericarditis were significantly higher than among controls. (MS was not significantly more prevalent among the Crohn’s disease cohort in this study.) Looking at the data in a different way, Manitobans with one of these immune-mediated conditions were more likely than those without to have been diagnosed with IBD, although minor differences in these associations were identified when stratified by IBD subtype or sex. In the GPRD study, the primary focus was on MS, ON, and demyelinating diseases.2 The cross-sectional analysis suggested that patients with Crohn’s disease were 54% more likely than community controls to have been diagnosed with MS, ON, or other demyelinating condition and patients with UC were 75% more likely. Patients with IBD who were treated with azathioprine or 6-mercaptopurine seemed less likely to develop these conditions than those not treated. The association between IBD and MS, ON, and demyelination appeared to be stronger among patients with UC who smoked than among non-smokers, whereas smoking did not appear to significantly influence neurologic risk among the patients with Crohn’s disease. In the cohort analysis, patients with UC were between 2 and 3 times more likely than controls to be diagnosed later with MS, ON, or demyelination. Patients with Crohn’s disease were about twice as likely as controls to be diagnosed later with one of these conditions, but this did not quite meet statistical significance. What do the results mean, and why should we care? These studies are packed with so much information that space precludes detailed commentary, but a few points should be made. The results of both studies lend credence to the emerging concept that patients with 1 immune-mediated condition are more likely than the general population to have another autoimmune disease.
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Although this had been recognized for more classic autoimmune conditions, these studies provide more definitive proof that the association holds true for UC and Crohn’s disease, too. Many immune-mediated conditions are thought, like IBD, to be polygenic, and it is likely that some of these conditions share susceptibility genes, both in the major histocompatibility region of chromosome 6 and in non–major histocompatibility areas.17 Secondly, the finding by Bernstein et al1 of a significant association between IBD and pulmonary diseases such as asthma and bronchitis highlights an underappreciated extraintestinal manifestation—pulmonary involvement. The lung is clearly a target organ in IBD, especially UC. A wide variety of pulmonary conditions have been reported in IBD, and this topic has been recently reviewed.18 Chronic bronchitis, bronchiectasis, bronchiolitis obliterans with organizing pneumonia, pulmonary vasculitis, and ␣-1 anti-trypsin deficiency have all been reported in association with UC. Pulmonary involvement with Crohn’s disease has been reported less commonly but ranges from colobronchial or esophagopulmonary fistula to tracheal involvement to bronchiolitis to granulomatous lung disease.19 Complicating the picture is the possibility of drug-induced lung disease—in the case of IBD, the most common offenders are mesalamine, sulfasalazine, and methotrexate. Pulmonary function testing in consecutive IBD patients yields abnormalities, usually diminution in forced expiratory volume or diffusing capacity, in approximately 50%.18 Many of these patients are seemingly without pulmonary symptoms, leading many clinicians (this author included) to not actively press patients with IBD for respiratory symptoms. However, the long-term consequences of untreated pulmonary involvement in IBD may be substantial. At least 3 studies of cause-specific mortality in population-based IBD cohorts have identified an increased risk of death due to pulmonary diseases.20 –22 One might expect this risk to be elevated in patients with Crohn’s disease, because they are more likely to be cigarette smokers, and decreased in UC patients, who tend to be nonsmokers. However, the exact opposite is found—the deaths due to respiratory disease are elevated in UC, not Crohn’s, ranging from 50% to 87% higher than expected in the background population.20 –22 As Bernstein et al1 point out in their conclusions, respiratory complaints in patients with IBD should be taken seriously, and probably should be investigated with pulmonary function testing at the very least. Finally, both studies detected an increased prevalence among IBD patients of immune-mediated neurologic disorders including MS, ON, and other demyelinating
September 2005
diseases.1,2 An association between IBD and MS has been investigated previously,23,24 but in these studies, the size of the cohorts investigated were not sufficiently large enough to produce robust results. One recent study of a referral-based cohort of patients with MS identified a higher-than-expected prevalence of IBD.25 In both of the present studies, the association between IBD and MS appears stronger with UC than with Crohn’s disease.1,2 The mechanism behind this association remains unclear, but presumably is due in part to shared susceptibility genes.17 The association between IBD and neurologic disorders remains underappreciated. Imaging studies of IBD patients without neurologic symptoms show white matter lesions in a substantial minority,26 and peripheral neuropathies of various types have been described in conjunction with IBD.27 In the latter case, there are reports of improvement with immunomodulatory therapy such as intravenous immunoglobulins.27 Awareness of the link between IBD and MS, ON, and demyelination is all the more important in the era of infliximab and other biologic agents. First, a number of case reports and small case series have noted that blockade of tumor necrosis factor ␣ with either etanercept or infliximab appeared to be associated with demyelinating disorders in patients with IBD or inflammatory arthritis.28 –34 Second, a randomized controlled trial of an anti–tumor necrosis factor ␣ agent, lenercept, for treatment of MS reported a higher rate of MS exacerbations in the group receiving active drug.35 For these reasons, the prescribing information for anti–tumor necrosis factor ␣ therapies now contains warnings about the risk of demyelinating diseases in patients receiving these agents. These drugs are contraindicated in patients with known demyelinating disorders. Our sensitivity for detecting neurologic complications of biologic therapies should be heightened by recent events associated with natalizumab (Tysabri; Elan Corporation, PLC, Dublin, Ireland; and Biogen Idec, Cambridge, MA), a monoclonal antibody directed against ␣4 integrin, a type of adhesion molecule. This agent had been approved by the Food and Drug Administration for the treatment of MS in 2004, and a development program for the treatment of Crohn’s disease was well underway. In early 2005, the drug was withdrawn from the market after progressive multifocal leukoencephalopathy (PML) was reported in 2 patients with MS who had received natalizumab in clinical trials.36,37 Initially, some believed this catastrophic complication may have been caused by combination therapy with natalizumab and interferon -1a (Avonex; Biogen Idec). However, Van Assche et al38 reinvestigated a patient with Crohn’s disease who had received natalizumab in a clinical trial
EDITORIALS
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and died in 2003 from what was thought to be an astrocytoma, and realized that the patient had actually died of PML. This patient had received multiple immunosuppressive agents in the past, but azathioprine had been discontinued 8 months before (and infliximab 20 months before) the development of neurologic symptoms. It is too early to fully understand the pathogenesis of PML in these patients. The disease typically occurs in profoundly immunosuppressed patients and is associated with reactivation of JC polyoma virus. Antibodies to this agent are found in the majority of adults. The virus causes an asymptomatic primary infection in childhood and remains latent in the kidneys and in lymphoid tissue. Presumably, inhibition of certain adhesion molecules led to reactivation of JC virus, and the increasing serum viral load after 3 infusions of natalizumab in the patient with Crohn’s disease reported by Van Assche et al38 would support this. The studies of the Manitoba and the GPRD IBD cohorts underline the propensity of our patients with IBD for developing autoimmune disorders affecting multiple organ systems. Recent events remind us that therapies may be associated with unexpected complications involving other organs. As gastroenterologists who wish to provide our patients with IBD the most comprehensive care, we need to remember our roots—we are all internists first and gastroenterologists second. EDWARD V. LOFTUS, Jr Division of Gastroenterology and Hepatology Mayo Clinic College of Medicine Rochester, Minnesota
References 1. Bernstein CN, Wajda A, Blanchard JF. The clustering of other chronic inflammatory diseases in inflammatory bowel disease: a population-based study. Gastroenterology 2005;129:827– 836. 2. Gupta G, Gelfand JM, Lewis JD. Increased risk of demyelinating diseases in patients with inflammatory bowel disease. Gastroenterology 2005;129:819 – 826. 3. 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. 4. Bernstein CN, Blanchard JF, Rawsthorne P, Yu N. The prevalence of extraintestinal diseases in inflammatory bowel disease: a population-based study. Am J Gastroenterol 2001;96:1116 –1122. 5. Bernstein CN, Blanchard JF, Kliewer E, Wajda A. Cancer risk in patients with inflammatory bowel disease: a population-based study. Cancer 2001;91:854 – 862. 6. 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. 7. Bernstein CN, Blanchard JF, Houston DS, Wajda A. The incidence of deep venous thrombosis and pulmonary embolism among patients with inflammatory bowel disease: a population-based cohort study. Thromb Haemost 2001;85:430 – 434.
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8. Lewis JD, Brensinger C, Bilker WB, Strom BL. Validity and completeness of the General Practice Research Database for studies of inflammatory bowel disease. Pharmacoepidemiol Drug Safety 2002;11:211–218. 9. Lewis JD, Bilker WB, Brensinger C, Deren JJ, Vaughn DJ, Strom BL. Inflammatory bowel disease is not associated with an increased risk of lymphoma. Gastroenterology 2001;121:1080 – 1087. 10. Lewis JD, Aberra FN, Lichtenstein GR, Bilker WB, Brensinger C, Strom BL. Seasonal variation in flares of inflammatory bowel disease. Gastroenterology 2004;126:665– 673. 11. Aberra FN, Brensinger CM, Bilker WB, Lichtenstein GR, Lewis JD. Antibiotic use and the risk of flare of inflammatory bowel diseas. Clin Gastroenterol Hepatol 2005;3:459 – 465. 12. Card T, Hubbard R, Logan RF. Mortality in inflammatory bowel disease: a population-based cohort study. Gastroenterology 2003;125:1583–1590. 13. Card T, West J, Hubbard R, Logan RF. Hip fractures in patients with inflammatory bowel disease and their relationship to corticosteroid use: a population based cohort study. Gut 2004;53: 251–255. 14. Van Staa TP, Travis S, Leufkens HG, Logan RF. 5-aminosalicylic acids and the risk of renal disease: a large British epidemiologic study. Gastroenterology 2004;126:1733–1739. 15. Marrie RA, Wolfson C, Sturkenboom MC, et al. Multiple sclerosis and antecedent infections: a case-control study. Neurology 2000;54:2307–2310. 16. Hernan MA, Jick SS, Olek MJ, Jick H. Recombinant hepatitis B vaccine and the risk of multiple sclerosis: a prospective study. Neurology 2004;63:838 – 842. 17. Becker KG, Simon RM, Bailey-Wilson JE, et al. Clustering of non-major histocompatibility complex susceptibility candidate loci in human autoimmune diseases. Proc Natl Acad Sci U S A 1998;95:9979 –9984. 18. Storch I, Sachar D, Katz S. Pulmonary manifestations of inflammatory bowel disease. Inflamm Bowel Dis 2003;9:104 –115. 19. Casey MB, Tazelaar HD, Myers JL, et al. Noninfectious lung pathology in patients with Crohn’s disease. Am J Surg Pathol 2003;27:213–219. 20. 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. 21. 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;110:1339 –1345. 22. Winther KV, Jess T, Langholz E, Munkholm P, Binder V. Survival and cause-specific mortality in ulcerative colitis: follow-up of a population-based cohort in Copenhagen County. Gastroenterology 2003;125:1576 –1582. 23. Rang EH, Brooke BN, Hermon-Taylor J. Association of ulcerative colitis with multiple sclerosis. Lancet 1982;2:4. 24. Kimura K, Hunter SF, Thollander MS, et al. Concurrence of inflammatory bowel disease and multiple sclerosis. Mayo Clin Proc 2000;75:802– 806.
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25. Edwards LJ, Constantinescu CS. A prospective study of conditions associated with multiple sclerosis in a cohort of 658 consecutive outpatients attending a multiple sclerosis clinic. Multiple Sclerosis 2004;10:575–581. 26. Geissler A, Andus T, Roth M. Focal white-matter lesions in brain of patients with inflammatory bowel disease. Lancet 1995;345: 897– 898. 27. Gondim FA, Brannagan TH III, Sander HW, Chin RL, Latov N. Peripheral neuropathy in patients with inflammatory bowel disease. Brain 2005;128:867– 879. 28. Mohan N, Edwards ET, Cupps TR, et al. Demyelination occurring during anti-tumor necrosis factor alpha therapy for inflammatory arthritides. Arthritis Rheum 2001;44:2862–2869. 29. Foroozan R, Buono LM, Sergott RC, Savino PJ. Retrobulbar optic neuritis associated with infliximab. Arch Ophthalmol 2002;120: 985–987. 30. Nanavati SA, Ergun GA, Schwartz JT. Avoiding infliximab in the treatment of Crohn’s disease in patients with multiple sclerosis. Am J Gastroenterol 2003;98:2333–2334. 31. ten Tusscher MP, Jacobs PJ, Busch MJ, de Graaf L, Diemont WL. Bilateral anterior toxic optic neuropathy and the use of infliximab (letter). BMJ 2003;326:579. 32. Mejico LJ. Infliximab-associated retrobulbar optic neuritis. Arch Ophthalmol 2004;122:793–794. 33. Strong BY, Erny BC, Herzenberg H, Razzeca KJ. Retrobulbar optic neuritis associated with infliximab in a patient with Crohn disease (letter). Ann Intern Med 2004;140:W34. 34. Thomas CW Jr, Weinshenker BG, Sandborn WJ. Demyelination during anti-tumor necrosis factor alpha therapy with infliximab for Crohn’s disease. Inflamm Bowel Dis 2004;10:28 –31. 35. The Lenercept Multiple Sclerosis Study Group and the University of British Columbia MS/MRI Analysis Group. TNF neutralization in MS: results of a randomized, placebo-controlled multicenter study. Neurology 1999;53:457– 465. 36. Kleinschmidt-DeMasters BK, Tyler KL. Progressive multifocal leukoencephalopathy complicating treatment with natalizumab and interferon beta-1a for multiple sclerosis. N Engl J Med 2005;353: 369 –374. 37. Langer-Gould A, Atlas SW, Green AJ, Bollen AW, Pelletier D. Progressive multifocal leukoencephalopathy in a patient treated with natalizumab. N Engl J Med 2005;353:375–381. 38. Van Assche G, Van Ranst M, Sciot R, et al. Progressive multifocal leukoencephalopathy after natalizumab therapy for Crohn’s disease. N Engl J Med 2005;353:362–368.
Address requests for reprints to: Edward V. Loftus, Jr, MD, Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First Street, SW, Rochester, Minnesota 55905. e-mail: [email protected]; fax: (507) 266-0335. Dr Loftus has received research support from Procter & Gamble Pharmaceuticals, and has served as a consultant for UCB Pharma, Abbott Laboratories, and Prometheus Laboratories. © 2005 by the American Gastroenterological Association 0016-5085/05/$30.00 doi:10.1053/j.gastro.2005.07.042
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Inflammatory Bowel Disease Extending Its Reach See articles on pages 819 and 827.
s medical students and residents, we learned about the classic extraintestinal manifestations of inflammatory bowel disease (IBD): ankylosing spondylitis, peripheral arthritis, uveitis, pyoderma gangrenosum, erythema nodosum, and primary sclerosing cholangitis. In recent years, we have seen an extensive amount of literature emerge on less familiar extraintestinal complications of ulcerative colitis (UC) and Crohn’s disease; most notably osteoporosis and, to a lesser extent, thromboembolism. Two articles in this month’s GASTROENTEROLOGY remind us that the effects of IBD extend to every corner of the body, including the lung and the central nervous system.1,2 The 2 studies use roughly similar techniques—large databases, containing both patients with IBD and population controls, were searched for diagnoses of interest. A description of each database is necessary to understand the strengths and the limitations of these studies. During the past decade, Bernstein et al3 have created a population-based cohort of patients with IBD from Manitoba, Canada, using an administrative provincial health database and a validated algorithm based on codes from the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM). The algorithm was validated by medical record review of a sample of patients and resulted in greater than 90% accuracy for the diagnosis of IBD. These investigators have used this database and cohort to report on the descriptive epidemiology of Crohn’s disease and UC3; furthermore, they have contributed to the literature on a whole host of IBD-related outcomes, including the risk of classic extraintestinal manifestations,4 cancer,5 bone fractures,6 and venous thromboembolism.7 The University of Manitoba IBD cohort has grown over time to include more than 8000 patients.1 In the present study, the investigators searched their IBD database for ICD-9-CM codes for various immune-mediated diseases (eg, asthma, bronchitis, arthritis, thyroiditis, multiple sclerosis [MS], neuropathy, myasthenia gravis, chronic renal disease, psoriasis, and pericarditis) and calculated a period prevalence (1984 to 2003).1 A control group consisting of 10 Manitobans matched to each of the IBD cases on age, sex, postal code, and date of IBD diagnosis was identified, and a period prevalence for immune-mediated diseases in this cohort was similarly calculated. The ratio of auto-
A
immune disease prevalence in the 2 groups was then calculated.1 Gupta et al2 used the resources of the General Practice Research Database (GPRD) from the United Kingdom to investigate the association between IBD and immunemediated neurological disorders such as MS, optic neuritis (ON), and unspecified demyelinating disorders. The GPRD contains computerized medical records of general practitioners whose case panels in total comprise 6% of the entire British population; therefore, it serves as a proxy for a population-based study. Diagnostic codes in the GPRD are based on the Oxford Medical Indexing System (OXMIS). The investigators had previously shown by medical record review that their algorithm for identifying IBD by using OXMIS codes was reasonably accurate.8 The investigators have used this very large cohort of patients with IBD (n ⬎ 20,000) to investigate the relative and absolute risk of non-Hodgkin lymphoma, to study the influence of antibiotics on the risk of exacerbations of IBD, and to determine if exacerbations of IBD followed seasonal patterns.9 –11 Other investigators have used the GPRD to estimate mortality, fracture risk, and renal disease risk in patients with IBD.12–14 In the present study, they identified OXMIS codes for MS, demyelination, ON, and retrobulbar neuritis in both the IBD cohort and in a control cohort composed of 4 patients with GPRD matched to each of the IBD cases on year of birth, sex, and primary care practice.2 (Other investigators have shown that OXMIS codes for MS are accurate.15,16) The analysis was performed in 2 ways. The cross-sectional approach used an approach similar to Bernstein et al,1 in which the prevalence of the diagnoses of interest (either before or after IBD diagnosis) in the IBD cohort was compared to the prevalence in the control cohort. The cohort analysis compared the incidence of neurologic diagnoses after a diagnosis of IBD in the IBD cohort with the incidence of these diagnoses in the control cohort.2 What were the results? In the Manitoba study, the prevalence of immune-mediated disease in both the IBD cohort and the control cohort varied depending on the particular algorithm used to define the diagnosis of interest.1 Because the investigators did not undertake a medical record review to validate coding algorithms for these conditions, they wisely chose to present a range of prevalences defined at the high end by the least specific algorithm (at least 1 health contact with appropriate ICD-9-CM code) and at the low end by the most specific
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(at least 5 health contacts with ICD-9-CM code). For example, the prevalence of asthma ranged from 8% to 21% in the UC cases, 7% to 20% in the Crohn’s disease cases, and 5% to 16% in the controls. Fortunately, the prevalence ratios did not change significantly in most cases. Thus, for UC, the prevalence ratio for asthma ranged from 1.5 to 1.7, and for Crohn’s disease, the ratio for asthma ranged from 1.3 to 1.4. In other words, patients with UC were 50%–70% more likely than population-based controls to have asthma, whereas patients with Crohn’s disease were 30%– 40% more likely. Using the most rigorous algorithm, significant associations were observed between UC and the following conditions: asthma; bronchitis; arthritis; MS; and chronic renal disease, psoriasis, and pericarditis. For patients with Crohn’s disease, the prevalence of asthma, bronchitis, arthritis, psoriasis, and pericarditis were significantly higher than among controls. (MS was not significantly more prevalent among the Crohn’s disease cohort in this study.) Looking at the data in a different way, Manitobans with one of these immune-mediated conditions were more likely than those without to have been diagnosed with IBD, although minor differences in these associations were identified when stratified by IBD subtype or sex. In the GPRD study, the primary focus was on MS, ON, and demyelinating diseases.2 The cross-sectional analysis suggested that patients with Crohn’s disease were 54% more likely than community controls to have been diagnosed with MS, ON, or other demyelinating condition and patients with UC were 75% more likely. Patients with IBD who were treated with azathioprine or 6-mercaptopurine seemed less likely to develop these conditions than those not treated. The association between IBD and MS, ON, and demyelination appeared to be stronger among patients with UC who smoked than among non-smokers, whereas smoking did not appear to significantly influence neurologic risk among the patients with Crohn’s disease. In the cohort analysis, patients with UC were between 2 and 3 times more likely than controls to be diagnosed later with MS, ON, or demyelination. Patients with Crohn’s disease were about twice as likely as controls to be diagnosed later with one of these conditions, but this did not quite meet statistical significance. What do the results mean, and why should we care? These studies are packed with so much information that space precludes detailed commentary, but a few points should be made. The results of both studies lend credence to the emerging concept that patients with 1 immune-mediated condition are more likely than the general population to have another autoimmune disease.
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Although this had been recognized for more classic autoimmune conditions, these studies provide more definitive proof that the association holds true for UC and Crohn’s disease, too. Many immune-mediated conditions are thought, like IBD, to be polygenic, and it is likely that some of these conditions share susceptibility genes, both in the major histocompatibility region of chromosome 6 and in non–major histocompatibility areas.17 Secondly, the finding by Bernstein et al1 of a significant association between IBD and pulmonary diseases such as asthma and bronchitis highlights an underappreciated extraintestinal manifestation—pulmonary involvement. The lung is clearly a target organ in IBD, especially UC. A wide variety of pulmonary conditions have been reported in IBD, and this topic has been recently reviewed.18 Chronic bronchitis, bronchiectasis, bronchiolitis obliterans with organizing pneumonia, pulmonary vasculitis, and ␣-1 anti-trypsin deficiency have all been reported in association with UC. Pulmonary involvement with Crohn’s disease has been reported less commonly but ranges from colobronchial or esophagopulmonary fistula to tracheal involvement to bronchiolitis to granulomatous lung disease.19 Complicating the picture is the possibility of drug-induced lung disease—in the case of IBD, the most common offenders are mesalamine, sulfasalazine, and methotrexate. Pulmonary function testing in consecutive IBD patients yields abnormalities, usually diminution in forced expiratory volume or diffusing capacity, in approximately 50%.18 Many of these patients are seemingly without pulmonary symptoms, leading many clinicians (this author included) to not actively press patients with IBD for respiratory symptoms. However, the long-term consequences of untreated pulmonary involvement in IBD may be substantial. At least 3 studies of cause-specific mortality in population-based IBD cohorts have identified an increased risk of death due to pulmonary diseases.20 –22 One might expect this risk to be elevated in patients with Crohn’s disease, because they are more likely to be cigarette smokers, and decreased in UC patients, who tend to be nonsmokers. However, the exact opposite is found—the deaths due to respiratory disease are elevated in UC, not Crohn’s, ranging from 50% to 87% higher than expected in the background population.20 –22 As Bernstein et al1 point out in their conclusions, respiratory complaints in patients with IBD should be taken seriously, and probably should be investigated with pulmonary function testing at the very least. Finally, both studies detected an increased prevalence among IBD patients of immune-mediated neurologic disorders including MS, ON, and other demyelinating
September 2005
diseases.1,2 An association between IBD and MS has been investigated previously,23,24 but in these studies, the size of the cohorts investigated were not sufficiently large enough to produce robust results. One recent study of a referral-based cohort of patients with MS identified a higher-than-expected prevalence of IBD.25 In both of the present studies, the association between IBD and MS appears stronger with UC than with Crohn’s disease.1,2 The mechanism behind this association remains unclear, but presumably is due in part to shared susceptibility genes.17 The association between IBD and neurologic disorders remains underappreciated. Imaging studies of IBD patients without neurologic symptoms show white matter lesions in a substantial minority,26 and peripheral neuropathies of various types have been described in conjunction with IBD.27 In the latter case, there are reports of improvement with immunomodulatory therapy such as intravenous immunoglobulins.27 Awareness of the link between IBD and MS, ON, and demyelination is all the more important in the era of infliximab and other biologic agents. First, a number of case reports and small case series have noted that blockade of tumor necrosis factor ␣ with either etanercept or infliximab appeared to be associated with demyelinating disorders in patients with IBD or inflammatory arthritis.28 –34 Second, a randomized controlled trial of an anti–tumor necrosis factor ␣ agent, lenercept, for treatment of MS reported a higher rate of MS exacerbations in the group receiving active drug.35 For these reasons, the prescribing information for anti–tumor necrosis factor ␣ therapies now contains warnings about the risk of demyelinating diseases in patients receiving these agents. These drugs are contraindicated in patients with known demyelinating disorders. Our sensitivity for detecting neurologic complications of biologic therapies should be heightened by recent events associated with natalizumab (Tysabri; Elan Corporation, PLC, Dublin, Ireland; and Biogen Idec, Cambridge, MA), a monoclonal antibody directed against ␣4 integrin, a type of adhesion molecule. This agent had been approved by the Food and Drug Administration for the treatment of MS in 2004, and a development program for the treatment of Crohn’s disease was well underway. In early 2005, the drug was withdrawn from the market after progressive multifocal leukoencephalopathy (PML) was reported in 2 patients with MS who had received natalizumab in clinical trials.36,37 Initially, some believed this catastrophic complication may have been caused by combination therapy with natalizumab and interferon -1a (Avonex; Biogen Idec). However, Van Assche et al38 reinvestigated a patient with Crohn’s disease who had received natalizumab in a clinical trial
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and died in 2003 from what was thought to be an astrocytoma, and realized that the patient had actually died of PML. This patient had received multiple immunosuppressive agents in the past, but azathioprine had been discontinued 8 months before (and infliximab 20 months before) the development of neurologic symptoms. It is too early to fully understand the pathogenesis of PML in these patients. The disease typically occurs in profoundly immunosuppressed patients and is associated with reactivation of JC polyoma virus. Antibodies to this agent are found in the majority of adults. The virus causes an asymptomatic primary infection in childhood and remains latent in the kidneys and in lymphoid tissue. Presumably, inhibition of certain adhesion molecules led to reactivation of JC virus, and the increasing serum viral load after 3 infusions of natalizumab in the patient with Crohn’s disease reported by Van Assche et al38 would support this. The studies of the Manitoba and the GPRD IBD cohorts underline the propensity of our patients with IBD for developing autoimmune disorders affecting multiple organ systems. Recent events remind us that therapies may be associated with unexpected complications involving other organs. As gastroenterologists who wish to provide our patients with IBD the most comprehensive care, we need to remember our roots—we are all internists first and gastroenterologists second. EDWARD V. LOFTUS, Jr Division of Gastroenterology and Hepatology Mayo Clinic College of Medicine Rochester, Minnesota
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Address requests for reprints to: Edward V. Loftus, Jr, MD, Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First Street, SW, Rochester, Minnesota 55905. e-mail: [email protected]; fax: (507) 266-0335. Dr Loftus has received research support from Procter & Gamble Pharmaceuticals, and has served as a consultant for UCB Pharma, Abbott Laboratories, and Prometheus Laboratories. © 2005 by the American Gastroenterological Association 0016-5085/05/$30.00 doi:10.1053/j.gastro.2005.07.042