Molecular Discoveries Alter View of Inflammatory Bowel Disease
Molecular Discoveries Alter View of Inflammatory Bowel Disease
Within the past decade, knowledge of the molecular basis of inflammatory bowel disease (IBD), including Crohn disease (CD) and ulcerative colitis, has advanced owing to the explosive growth of research involving the human genome. Furthermore, a shared interest between molecular biologists and clinical researchers has contributed to an emerging understanding of IBD. Nucleotide-binding oligomerization domain 2 (NOD2) belongs to an apoptotic regulatory family of genes and has been linked to CD. In addition, research into nuclear factor kappa B (NF-kappa B), the proteasome, interleukins, and tumor necrosis factor alpha has improved our understanding of IBD. Our understanding of these molecules and other scientific discoveries offers hope for new diagnostic tests and therapeutic agents. In the future, genetic markers will predict disease susceptibility, therapeutic responsiveness, and long-term sequelae of modern therapeutics. Also on the horizon, molecular markers promise to define disease heterogeneity, thereby providing a rational basis for patient-specific therapies. The molecular discoveries that are changing our views of IBD will affect the clinician, the laboratory professional, and the patient.
Approximately 1 million Americans have Crohn disease (CD) or ulcerative colitis (UC), collectively known as inflammatory bowel disease (IBD). Conventional treatments often are effective in achieving symptomatic control, but in most cases, they fail to prevent relapse over prolonged periods. Owing to the transmural nature of the disease and the risk of fistulas, CD requires surgery in approximately half the affected population, accounting for the majority of the annual cost of disease management. Far from curing the disease, surgery is associated with an increased risk of disease relapse and subsequent medical intervention. Hence, the challenge of disease management requires achieving a therapeutic response, maintaining remission, and avoiding surgery for an extended period. In support of this effort, the expertise of the clinical pathology laboratory is required.
At present, investigators believe that IBD is caused by chronic inflammation resulting from an abnormal immune response directed, at least partially, toward microbial antigens. Considering UC and CD together, a number of studies have localized 5 susceptibility genes. Each of these susceptibility genes contributes, at least in part, to IBD. As of this date, it is believed that IBD requires the complex interactions of multiple genes, with any single gene accounting for a fraction of the overall risk of developing IBD. Ethnic complexities, disease heterogeneity, and the limitations of current research methods offer many challenges to our understanding of the disease.
These 5 linkages to loci were defined by a significant linkage in one study and replication of the linkage with a nominal P value of less than .01 in an independent study. For example, linkage between CD and a locus on chromosome 16 has been replicated by a number of research groups and is designated as IBD1. Another linkage, particularly strong for UC, has been found on chromosome 12q and is designated IBD2. A more complete discussion of this topic is given by Cho.
In addition to the confirmed loci, a number of other "suggestive" linkages exist: the HLA system and the interleukin (IL) gene cluster on chromosome 5 have received the most attention. The IL-1 receptor antagonist gene (IL-1ra) also may be an important contributor to IBD. Although different genetic studies and linkage conclusions are difficult to compare, the divergent results may be explained by case mix, ethnic differences, and the genetic heterogeneity of IBD.
For example, the data linking CD to chromosome 5 were obtained from a pediatric population that demonstrated early onset of the disease and a greater likelihood of having affected relatives. These findings, including the contribution of case mix, are supported by clinical studies that show a bimodal age distribution of disease onset and that age at diagnosis may define a different subgroup of CD. More specifically, early-onset CD is associated with a greater likelihood of small bowel involvement, more strictures, and a higher frequency of surgery. Hence, as expected, clinical heterogeneity of disease is mirrored in different molecular linkages to susceptibility genes found in studies of diverse populations.
In an attempt to better understand IBD, it is helpful to examine a traditional source of insight into the mechanisms of disease. The pathogenesis of IBD may be compared with the causes underlying 2 rare inherited disorders. The first, Blau syndrome, is an autosomal dominant chronic granulomatous disease, and the other is an autosomal dominant periodic febrile disorder, until recently referred to as familial Hibernian fever. In addition to helping define IBD's pathogenesis, these inherited disorders also point to possible therapeutic remedies.
New understandings from preclinical research, data from clinical trials, and changes in disease management are elevating the interest in molecular genetic markers. In particular, the benefits of one biologic agent are already being realized. Anti-tumor necrosis factor (TNF)-alpha medications are marketed for use in active rheumatoid arthritis and offer improved therapy for IBD. Infliximab (Remicade, Centocor, Malvern, PA) is given by infusion and is approved by the US Food and Drug Administration (FDA) for rheumatoid arthritis and CD, while etanercept (Enbrel, Immunex, Seattle, WA) may be given by subcutaneous injection and, at this time, is used primarily in rheumatoid arthritis. Because of impressive results, today's conventional management may yield to a new therapeutic approach that emphasizes early treatment with anti-TNF-alpha or other biologic agents.
Owing to molecular discoveries and new therapeutic agents, the clinical laboratory soon will offer new testing for patients with IBD. Measuring the activity of disease, monitoring for complications of therapy, predicting relapses, and defining the molecular heterogeneity of disease are likely areas of growth. Ultimately, the goal is to identify molecular markers that will predict the efficacy of targeted therapeutic agents.
Within the past decade, knowledge of the molecular basis of inflammatory bowel disease (IBD), including Crohn disease (CD) and ulcerative colitis, has advanced owing to the explosive growth of research involving the human genome. Furthermore, a shared interest between molecular biologists and clinical researchers has contributed to an emerging understanding of IBD. Nucleotide-binding oligomerization domain 2 (NOD2) belongs to an apoptotic regulatory family of genes and has been linked to CD. In addition, research into nuclear factor kappa B (NF-kappa B), the proteasome, interleukins, and tumor necrosis factor alpha has improved our understanding of IBD. Our understanding of these molecules and other scientific discoveries offers hope for new diagnostic tests and therapeutic agents. In the future, genetic markers will predict disease susceptibility, therapeutic responsiveness, and long-term sequelae of modern therapeutics. Also on the horizon, molecular markers promise to define disease heterogeneity, thereby providing a rational basis for patient-specific therapies. The molecular discoveries that are changing our views of IBD will affect the clinician, the laboratory professional, and the patient.
Approximately 1 million Americans have Crohn disease (CD) or ulcerative colitis (UC), collectively known as inflammatory bowel disease (IBD). Conventional treatments often are effective in achieving symptomatic control, but in most cases, they fail to prevent relapse over prolonged periods. Owing to the transmural nature of the disease and the risk of fistulas, CD requires surgery in approximately half the affected population, accounting for the majority of the annual cost of disease management. Far from curing the disease, surgery is associated with an increased risk of disease relapse and subsequent medical intervention. Hence, the challenge of disease management requires achieving a therapeutic response, maintaining remission, and avoiding surgery for an extended period. In support of this effort, the expertise of the clinical pathology laboratory is required.
At present, investigators believe that IBD is caused by chronic inflammation resulting from an abnormal immune response directed, at least partially, toward microbial antigens. Considering UC and CD together, a number of studies have localized 5 susceptibility genes. Each of these susceptibility genes contributes, at least in part, to IBD. As of this date, it is believed that IBD requires the complex interactions of multiple genes, with any single gene accounting for a fraction of the overall risk of developing IBD. Ethnic complexities, disease heterogeneity, and the limitations of current research methods offer many challenges to our understanding of the disease.
These 5 linkages to loci were defined by a significant linkage in one study and replication of the linkage with a nominal P value of less than .01 in an independent study. For example, linkage between CD and a locus on chromosome 16 has been replicated by a number of research groups and is designated as IBD1. Another linkage, particularly strong for UC, has been found on chromosome 12q and is designated IBD2. A more complete discussion of this topic is given by Cho.
In addition to the confirmed loci, a number of other "suggestive" linkages exist: the HLA system and the interleukin (IL) gene cluster on chromosome 5 have received the most attention. The IL-1 receptor antagonist gene (IL-1ra) also may be an important contributor to IBD. Although different genetic studies and linkage conclusions are difficult to compare, the divergent results may be explained by case mix, ethnic differences, and the genetic heterogeneity of IBD.
For example, the data linking CD to chromosome 5 were obtained from a pediatric population that demonstrated early onset of the disease and a greater likelihood of having affected relatives. These findings, including the contribution of case mix, are supported by clinical studies that show a bimodal age distribution of disease onset and that age at diagnosis may define a different subgroup of CD. More specifically, early-onset CD is associated with a greater likelihood of small bowel involvement, more strictures, and a higher frequency of surgery. Hence, as expected, clinical heterogeneity of disease is mirrored in different molecular linkages to susceptibility genes found in studies of diverse populations.
In an attempt to better understand IBD, it is helpful to examine a traditional source of insight into the mechanisms of disease. The pathogenesis of IBD may be compared with the causes underlying 2 rare inherited disorders. The first, Blau syndrome, is an autosomal dominant chronic granulomatous disease, and the other is an autosomal dominant periodic febrile disorder, until recently referred to as familial Hibernian fever. In addition to helping define IBD's pathogenesis, these inherited disorders also point to possible therapeutic remedies.
New understandings from preclinical research, data from clinical trials, and changes in disease management are elevating the interest in molecular genetic markers. In particular, the benefits of one biologic agent are already being realized. Anti-tumor necrosis factor (TNF)-alpha medications are marketed for use in active rheumatoid arthritis and offer improved therapy for IBD. Infliximab (Remicade, Centocor, Malvern, PA) is given by infusion and is approved by the US Food and Drug Administration (FDA) for rheumatoid arthritis and CD, while etanercept (Enbrel, Immunex, Seattle, WA) may be given by subcutaneous injection and, at this time, is used primarily in rheumatoid arthritis. Because of impressive results, today's conventional management may yield to a new therapeutic approach that emphasizes early treatment with anti-TNF-alpha or other biologic agents.
Owing to molecular discoveries and new therapeutic agents, the clinical laboratory soon will offer new testing for patients with IBD. Measuring the activity of disease, monitoring for complications of therapy, predicting relapses, and defining the molecular heterogeneity of disease are likely areas of growth. Ultimately, the goal is to identify molecular markers that will predict the efficacy of targeted therapeutic agents.