Miriam E. Tucker

CHICAGO — Approximately 5% of antibody-negative/C-peptide-positive children and adolescents diagnosed with diabetes in the United States may have Maturity-Onset Diabetes of the Young rather than type 2 diabetes, Dr. Lisa Gilliam reported at the annual scientific sessions of the American Diabetes Association.

Maturity-Onset Diabetes of the Young (MODY), first described in the mid-1970s, is a clinically heterogeneous group of disorders characterized by nonketotic diabetes, an autosomal dominant pattern of inheritance, and typical onset below the age of 25 years. It can arise from mutations in any one of at least six different genes associated with beta-cell function. The most common form, MODY3, arises from a mutation in the HNF (hepatocyte nuclear factor)-1[α] gene (N. Engl. J. Med. 2001;345:971–80).

New findings suggest that MODY is underrecognized and often inappropriately treated. “Clinicians need to maintain a high level of suspicion for MODY in antibody-negative children who have residual beta-cell function, and certainly consider screening in individuals who meet the classic criteria for MODY,” said Dr. Gilliam, of the division of metabolism, endocrinology and nutrition at the University of Washington, Seattle, in an interview.

The data come from SEARCH, a federally funded study of physician-diagnosed diabetes in individuals under 20 years of age in six U.S. centers located in Southern California, Colorado, Ohio, Washington state, and South Carolina. The coordinating center is in Winston-Salem, N.C. (www.searchfordiabetes.org

Of 3,993 participants in whom diabetes-associated autoantibodies and fasting C-peptide were measured, 438 were autoantibody-negative. Direct sequencing for the HNF-1[α] gene was performed in a subset of 266 patients who were autoantibody-negative and who had fasting C-peptide levels greater than 0.8 ng/mL. Among those, 13 patients had 14 gene mutations, including 7 that had not previously been described.

Only 1 of the 13 patients had been clinically diagnosed with MODY, while 5 had been misdiagnosed with type 1 diabetes and 7 with type 2 diabetes. Seven were currently being treated with insulin, and none were taking sulfonylureas, which is the recommended pharmacologic treatment for MODY3. MODY patients are “exquisitely sensitive” to sulfonylureas, which are cheaper and easier to take than multiple daily insulin injections, Dr. Gilliam explained.

Several clinical characteristics helped distinguish MODY3 from type 1 diabetes. Compared with those 3,484 individuals with type 1 diabetes in this study, the 13 MODY3 patients were less likely to have had weight loss (46% vs. 74%) or polyuria (54% vs. 93%) at diagnosis. The MODY group also tended to be older, heavier (body mass index z score 1.5 vs. 0.6), much more likely to have a parent with diabetes (62% vs. 14%), and much less likely to have medium- to high-risk HLA types (46% vs. 85%). Just 3 of the 13 were non-Hispanic white (23%), compared with 69% of the type 1 group.

In contrast, virtually no clinical or biochemical characteristic was identified that could help in distinguishing MODY3 from type 2 diabetes on an individual basis. Although the MODY group was somewhat younger and less obese than the type 2 patients, there was a great deal of overlap between the two groups. The type 2 patients were just as likely as the MODY group to have a positive family history for diabetes—including an autosomal dominant three-generation family history—and fasting C-peptide levels were similar, Dr. Gilliam said.

“With the prevalence of obesity and type 2 diabetes increasing in the pediatric population, it's becoming more challenging to distinguish MODY from type 2 diabetes,” she noted.

Because genetic screening is very expensive, at this point it's not feasible to recommend it in every antibody-negative child or adolescent with residual fasting C-peptide. “However, particularly as costs come down for this type of screening, I predict that the screening cost will be outweighed by the benefit to the subset of patients who would be diagnosed appropriately with MODY,” she said in the interview.

Specifically, that benefit would include lower cost, less hassle, and greater treatment efficacy for patients who could be switched from insulin to a sulfonylurea, she noted.

Genetic testing for MODY is available at 11 clinical laboratories around the world, including 2 in the United States. Such facilities can be found by searching with the keyword “MODY” at www.genetests.org

ELSEVIER GLOBAL MEDICAL NEWS

CHICAGO — Approximately 5% of antibody-negative/C-peptide-positive children and adolescents diagnosed with diabetes in the United States may have Maturity-Onset Diabetes of the Young rather than type 2 diabetes, Dr. Lisa Gilliam reported at the annual scientific sessions of the American Diabetes Association.

Maturity-Onset Diabetes of the Young (MODY), first described in the mid-1970s, is a clinically heterogeneous group of disorders characterized by nonketotic diabetes, an autosomal dominant pattern of inheritance, and typical onset below the age of 25 years. It can arise from mutations in any one of at least six different genes associated with beta-cell function. The most common form, MODY3, arises from a mutation in the HNF (hepatocyte nuclear factor)-1[α] gene (N. Engl. J. Med. 2001;345:971–80).

New findings suggest that MODY is underrecognized and often inappropriately treated. “Clinicians need to maintain a high level of suspicion for MODY in antibody-negative children who have residual beta-cell function, and certainly consider screening in individuals who meet the classic criteria for MODY,” said Dr. Gilliam, of the division of metabolism, endocrinology and nutrition at the University of Washington, Seattle, in an interview.

The data come from SEARCH, a federally funded study of physician-diagnosed diabetes in individuals under 20 years of age in six U.S. centers located in Southern California, Colorado, Ohio, Washington state, and South Carolina. The coordinating center is in Winston-Salem, N.C. (www.searchfordiabetes.org

Of 3,993 participants in whom diabetes-associated autoantibodies and fasting C-peptide were measured, 438 were autoantibody-negative. Direct sequencing for the HNF-1[α] gene was performed in a subset of 266 patients who were autoantibody-negative and who had fasting C-peptide levels greater than 0.8 ng/mL. Among those, 13 patients had 14 gene mutations, including 7 that had not previously been described.

Only 1 of the 13 patients had been clinically diagnosed with MODY, while 5 had been misdiagnosed with type 1 diabetes and 7 with type 2 diabetes. Seven were currently being treated with insulin, and none were taking sulfonylureas, which is the recommended pharmacologic treatment for MODY3. MODY patients are “exquisitely sensitive” to sulfonylureas, which are cheaper and easier to take than multiple daily insulin injections, Dr. Gilliam explained.

Several clinical characteristics helped distinguish MODY3 from type 1 diabetes. Compared with those 3,484 individuals with type 1 diabetes in this study, the 13 MODY3 patients were less likely to have had weight loss (46% vs. 74%) or polyuria (54% vs. 93%) at diagnosis. The MODY group also tended to be older, heavier (body mass index z score 1.5 vs. 0.6), much more likely to have a parent with diabetes (62% vs. 14%), and much less likely to have medium- to high-risk HLA types (46% vs. 85%). Just 3 of the 13 were non-Hispanic white (23%), compared with 69% of the type 1 group.

In contrast, virtually no clinical or biochemical characteristic was identified that could help in distinguishing MODY3 from type 2 diabetes on an individual basis. Although the MODY group was somewhat younger and less obese than the type 2 patients, there was a great deal of overlap between the two groups. The type 2 patients were just as likely as the MODY group to have a positive family history for diabetes—including an autosomal dominant three-generation family history—and fasting C-peptide levels were similar, Dr. Gilliam said.

“With the prevalence of obesity and type 2 diabetes increasing in the pediatric population, it's becoming more challenging to distinguish MODY from type 2 diabetes,” she noted.

Because genetic screening is very expensive, at this point it's not feasible to recommend it in every antibody-negative child or adolescent with residual fasting C-peptide. “However, particularly as costs come down for this type of screening, I predict that the screening cost will be outweighed by the benefit to the subset of patients who would be diagnosed appropriately with MODY,” she said in the interview.

Specifically, that benefit would include lower cost, less hassle, and greater treatment efficacy for patients who could be switched from insulin to a sulfonylurea, she noted.

Genetic testing for MODY is available at 11 clinical laboratories around the world, including 2 in the United States. Such facilities can be found by searching with the keyword “MODY” at www.genetests.org

ELSEVIER GLOBAL MEDICAL NEWS

CHICAGO — Approximately 5% of antibody-negative/C-peptide-positive children and adolescents diagnosed with diabetes in the United States may have Maturity-Onset Diabetes of the Young rather than type 2 diabetes, Dr. Lisa Gilliam reported at the annual scientific sessions of the American Diabetes Association.

Maturity-Onset Diabetes of the Young (MODY), first described in the mid-1970s, is a clinically heterogeneous group of disorders characterized by nonketotic diabetes, an autosomal dominant pattern of inheritance, and typical onset below the age of 25 years. It can arise from mutations in any one of at least six different genes associated with beta-cell function. The most common form, MODY3, arises from a mutation in the HNF (hepatocyte nuclear factor)-1[α] gene (N. Engl. J. Med. 2001;345:971–80).

New findings suggest that MODY is underrecognized and often inappropriately treated. “Clinicians need to maintain a high level of suspicion for MODY in antibody-negative children who have residual beta-cell function, and certainly consider screening in individuals who meet the classic criteria for MODY,” said Dr. Gilliam, of the division of metabolism, endocrinology and nutrition at the University of Washington, Seattle, in an interview.

The data come from SEARCH, a federally funded study of physician-diagnosed diabetes in individuals under 20 years of age in six U.S. centers located in Southern California, Colorado, Ohio, Washington state, and South Carolina. The coordinating center is in Winston-Salem, N.C. (www.searchfordiabetes.org

Of 3,993 participants in whom diabetes-associated autoantibodies and fasting C-peptide were measured, 438 were autoantibody-negative. Direct sequencing for the HNF-1[α] gene was performed in a subset of 266 patients who were autoantibody-negative and who had fasting C-peptide levels greater than 0.8 ng/mL. Among those, 13 patients had 14 gene mutations, including 7 that had not previously been described.

Only 1 of the 13 patients had been clinically diagnosed with MODY, while 5 had been misdiagnosed with type 1 diabetes and 7 with type 2 diabetes. Seven were currently being treated with insulin, and none were taking sulfonylureas, which is the recommended pharmacologic treatment for MODY3. MODY patients are “exquisitely sensitive” to sulfonylureas, which are cheaper and easier to take than multiple daily insulin injections, Dr. Gilliam explained.

Several clinical characteristics helped distinguish MODY3 from type 1 diabetes. Compared with those 3,484 individuals with type 1 diabetes in this study, the 13 MODY3 patients were less likely to have had weight loss (46% vs. 74%) or polyuria (54% vs. 93%) at diagnosis. The MODY group also tended to be older, heavier (body mass index z score 1.5 vs. 0.6), much more likely to have a parent with diabetes (62% vs. 14%), and much less likely to have medium- to high-risk HLA types (46% vs. 85%). Just 3 of the 13 were non-Hispanic white (23%), compared with 69% of the type 1 group.

In contrast, virtually no clinical or biochemical characteristic was identified that could help in distinguishing MODY3 from type 2 diabetes on an individual basis. Although the MODY group was somewhat younger and less obese than the type 2 patients, there was a great deal of overlap between the two groups. The type 2 patients were just as likely as the MODY group to have a positive family history for diabetes—including an autosomal dominant three-generation family history—and fasting C-peptide levels were similar, Dr. Gilliam said.

“With the prevalence of obesity and type 2 diabetes increasing in the pediatric population, it's becoming more challenging to distinguish MODY from type 2 diabetes,” she noted.

Because genetic screening is very expensive, at this point it's not feasible to recommend it in every antibody-negative child or adolescent with residual fasting C-peptide. “However, particularly as costs come down for this type of screening, I predict that the screening cost will be outweighed by the benefit to the subset of patients who would be diagnosed appropriately with MODY,” she said in the interview.

Specifically, that benefit would include lower cost, less hassle, and greater treatment efficacy for patients who could be switched from insulin to a sulfonylurea, she noted.

Genetic testing for MODY is available at 11 clinical laboratories around the world, including 2 in the United States. Such facilities can be found by searching with the keyword “MODY” at www.genetests.org

ELSEVIER GLOBAL MEDICAL NEWS

CHICAGO — Findings from a recent study suggest that the combined real-time continuous glucose monitor/insulin pump system reduces glycemic variability and improves glucose control in selected insulin pump users with type 1 diabetes, Dr. Irl B. Hirsch reported at the annual scientific sessions of the American Diabetes Association.

A significant finding of the 6-month study was that the benefits of real-time continuous glucose monitoring (RT-CGM) were realized only among patients who wore the sensor device consistently. “A key point is that while we're learning to use this new technology, we have to choose our patients carefully,” said Dr. Hirsch, professor of medicine and medical director of the Diabetes Care Center at the University of Washington, Seattle.

In the study, 138 adolescents and adults with poorly-controlled type 1 diabetes (defined as having a hemoglobin A1c of 7.5% or greater) despite 6 months or more of insulin pump therapy were randomized to either wear the combined pump/RT-CGM device (MiniMed Paradigm 722 System) and to perform self-monitoring of blood glucose (SMBG) four or more times per day, or to perform SMBG while wearing the MiniMed pump by itself. All insulin adjustments were based on SMBG values. Clinical staff made contact with all the patients on a weekly or biweekly basis throughout the study period. The study was funded by Medtronic, maker of the devices.

The group was 90% white, nearly two-thirds female, and had a mean diabetes duration of 18 years. There were 40 adolescents with a mean age of 14 years, and 98 adults with a mean age of 41 years. Mean hemoglobin A1c (HbA1c) levels did not differ between the two groups at baseline.

At 13 weeks, mean HbA1c levels had dropped significantly and to a nearly identical degree in both groups, from 8.4% to 7.8% in the controls and from 8.5% to 7.7% in the CGM group. There were no further significant drops in either group, and by week 26, both groups had a mean HbA1c of 7.8%. However, the proportion reaching the HbA1c target of less than 7% was significantly greater in the CGM patients, at 38%, versus just 19% of the controls. Similar results were seen when the adults were analyzed separately: There were no differences in HbA1c lowering between the two groups overall, but a significantly better 39% of the CGM group reached an HbA1c of less than 7%, compared with 25% of the controls.

Among the adolescents, only the CGM group had a significant drop in HbA1c from baseline, from 8.8% to 8.0% at 26 weeks, with 35% reaching an HbA1c below 7%, compared with just 9% of controls. Dr. Hirsch reported.

Differences in the amount of hypoglycemia—but not hyperglycemia—could help explain why the proportion dropping below 7.0% between the two groups was significantly different, whereas the overall HbA1c values were not. While there were no differences in the time and amplitude of exposure (in mg/dL per minute) for hyperglycemia between the two groups, the controls spent significantly more time at glucose levels below 70 mg/dL than did the CGM group (0.8 vs. 0.3 mg/dL per minute), suggesting that they had more glucose variability. “The A1c and the hyperglycemic exposure were the same, but hypoglycemia was less with the sensor group. That means there had to be more variability in the controls and the A1c isn't sensitive enough to pick that up,” Dr. Hirsch surmised.

Compliance strongly predicted the results among the CGM patients. With “compliance” defined as wearing the sensor 6 days per week (meaning it was possible to be more than 100% compliant) HbA1c levels among the patients with 100% or greater compliance dropped from 8.6% at baseline to 7.7% at 26 weeks. Those with 80%–100% compliance dropped similarly, from 8.4% to 7.7%, as did those with 60%–80% compliance, 8.2% to 7.5%. All of those reductions were significant. However, when compliance dropped below 60%, mean HbA1c actually rose slightly (but not significantly), from 9.5% to 9.6%.

Benefits were realized only among patients who wore the sensor device consistently. DR. HIRSCH

CHICAGO — Findings from a recent study suggest that the combined real-time continuous glucose monitor/insulin pump system reduces glycemic variability and improves glucose control in selected insulin pump users with type 1 diabetes, Dr. Irl B. Hirsch reported at the annual scientific sessions of the American Diabetes Association.

A significant finding of the 6-month study was that the benefits of real-time continuous glucose monitoring (RT-CGM) were realized only among patients who wore the sensor device consistently. “A key point is that while we're learning to use this new technology, we have to choose our patients carefully,” said Dr. Hirsch, professor of medicine and medical director of the Diabetes Care Center at the University of Washington, Seattle.

In the study, 138 adolescents and adults with poorly-controlled type 1 diabetes (defined as having a hemoglobin A1c of 7.5% or greater) despite 6 months or more of insulin pump therapy were randomized to either wear the combined pump/RT-CGM device (MiniMed Paradigm 722 System) and to perform self-monitoring of blood glucose (SMBG) four or more times per day, or to perform SMBG while wearing the MiniMed pump by itself. All insulin adjustments were based on SMBG values. Clinical staff made contact with all the patients on a weekly or biweekly basis throughout the study period. The study was funded by Medtronic, maker of the devices.

The group was 90% white, nearly two-thirds female, and had a mean diabetes duration of 18 years. There were 40 adolescents with a mean age of 14 years, and 98 adults with a mean age of 41 years. Mean hemoglobin A1c (HbA1c) levels did not differ between the two groups at baseline.

At 13 weeks, mean HbA1c levels had dropped significantly and to a nearly identical degree in both groups, from 8.4% to 7.8% in the controls and from 8.5% to 7.7% in the CGM group. There were no further significant drops in either group, and by week 26, both groups had a mean HbA1c of 7.8%. However, the proportion reaching the HbA1c target of less than 7% was significantly greater in the CGM patients, at 38%, versus just 19% of the controls. Similar results were seen when the adults were analyzed separately: There were no differences in HbA1c lowering between the two groups overall, but a significantly better 39% of the CGM group reached an HbA1c of less than 7%, compared with 25% of the controls.

Among the adolescents, only the CGM group had a significant drop in HbA1c from baseline, from 8.8% to 8.0% at 26 weeks, with 35% reaching an HbA1c below 7%, compared with just 9% of controls. Dr. Hirsch reported.

Differences in the amount of hypoglycemia—but not hyperglycemia—could help explain why the proportion dropping below 7.0% between the two groups was significantly different, whereas the overall HbA1c values were not. While there were no differences in the time and amplitude of exposure (in mg/dL per minute) for hyperglycemia between the two groups, the controls spent significantly more time at glucose levels below 70 mg/dL than did the CGM group (0.8 vs. 0.3 mg/dL per minute), suggesting that they had more glucose variability. “The A1c and the hyperglycemic exposure were the same, but hypoglycemia was less with the sensor group. That means there had to be more variability in the controls and the A1c isn't sensitive enough to pick that up,” Dr. Hirsch surmised.

Compliance strongly predicted the results among the CGM patients. With “compliance” defined as wearing the sensor 6 days per week (meaning it was possible to be more than 100% compliant) HbA1c levels among the patients with 100% or greater compliance dropped from 8.6% at baseline to 7.7% at 26 weeks. Those with 80%–100% compliance dropped similarly, from 8.4% to 7.7%, as did those with 60%–80% compliance, 8.2% to 7.5%. All of those reductions were significant. However, when compliance dropped below 60%, mean HbA1c actually rose slightly (but not significantly), from 9.5% to 9.6%.

Benefits were realized only among patients who wore the sensor device consistently. DR. HIRSCH

CHICAGO — Findings from a recent study suggest that the combined real-time continuous glucose monitor/insulin pump system reduces glycemic variability and improves glucose control in selected insulin pump users with type 1 diabetes, Dr. Irl B. Hirsch reported at the annual scientific sessions of the American Diabetes Association.

A significant finding of the 6-month study was that the benefits of real-time continuous glucose monitoring (RT-CGM) were realized only among patients who wore the sensor device consistently. “A key point is that while we're learning to use this new technology, we have to choose our patients carefully,” said Dr. Hirsch, professor of medicine and medical director of the Diabetes Care Center at the University of Washington, Seattle.

In the study, 138 adolescents and adults with poorly-controlled type 1 diabetes (defined as having a hemoglobin A1c of 7.5% or greater) despite 6 months or more of insulin pump therapy were randomized to either wear the combined pump/RT-CGM device (MiniMed Paradigm 722 System) and to perform self-monitoring of blood glucose (SMBG) four or more times per day, or to perform SMBG while wearing the MiniMed pump by itself. All insulin adjustments were based on SMBG values. Clinical staff made contact with all the patients on a weekly or biweekly basis throughout the study period. The study was funded by Medtronic, maker of the devices.

The group was 90% white, nearly two-thirds female, and had a mean diabetes duration of 18 years. There were 40 adolescents with a mean age of 14 years, and 98 adults with a mean age of 41 years. Mean hemoglobin A1c (HbA1c) levels did not differ between the two groups at baseline.

At 13 weeks, mean HbA1c levels had dropped significantly and to a nearly identical degree in both groups, from 8.4% to 7.8% in the controls and from 8.5% to 7.7% in the CGM group. There were no further significant drops in either group, and by week 26, both groups had a mean HbA1c of 7.8%. However, the proportion reaching the HbA1c target of less than 7% was significantly greater in the CGM patients, at 38%, versus just 19% of the controls. Similar results were seen when the adults were analyzed separately: There were no differences in HbA1c lowering between the two groups overall, but a significantly better 39% of the CGM group reached an HbA1c of less than 7%, compared with 25% of the controls.

Among the adolescents, only the CGM group had a significant drop in HbA1c from baseline, from 8.8% to 8.0% at 26 weeks, with 35% reaching an HbA1c below 7%, compared with just 9% of controls. Dr. Hirsch reported.

Differences in the amount of hypoglycemia—but not hyperglycemia—could help explain why the proportion dropping below 7.0% between the two groups was significantly different, whereas the overall HbA1c values were not. While there were no differences in the time and amplitude of exposure (in mg/dL per minute) for hyperglycemia between the two groups, the controls spent significantly more time at glucose levels below 70 mg/dL than did the CGM group (0.8 vs. 0.3 mg/dL per minute), suggesting that they had more glucose variability. “The A1c and the hyperglycemic exposure were the same, but hypoglycemia was less with the sensor group. That means there had to be more variability in the controls and the A1c isn't sensitive enough to pick that up,” Dr. Hirsch surmised.

Compliance strongly predicted the results among the CGM patients. With “compliance” defined as wearing the sensor 6 days per week (meaning it was possible to be more than 100% compliant) HbA1c levels among the patients with 100% or greater compliance dropped from 8.6% at baseline to 7.7% at 26 weeks. Those with 80%–100% compliance dropped similarly, from 8.4% to 7.7%, as did those with 60%–80% compliance, 8.2% to 7.5%. All of those reductions were significant. However, when compliance dropped below 60%, mean HbA1c actually rose slightly (but not significantly), from 9.5% to 9.6%.

Benefits were realized only among patients who wore the sensor device consistently. DR. HIRSCH

Twenty-four weeks should be considered the routine duration of treatment with peginterferon α-2a and ribavirin for patients with hepatitis C virus genotypes 2 and 3, said Dr. Mitchell L. Shiffman, of the Virginia Commonwealth University Medical Center, Richmond, and his associates.

In a study comparing 24 weeks versus 16 weeks of treatment among 1,455 randomized patients with hepatitis C virus (HCV) genotypes 2 or 3, treatment lasting just 16 weeks resulted in a lower overall sustained response rate–primarily due to a higher subsequent relapse rate–compared with 24 weeks of treatment.

However, the data suggested that the shorter duration may be sufficient for certain subgroups. “Patients with a lower pretreatment viral load or a rapid virologic response appear to have the highest probability of having a sustained response with 16 weeks of therapy, and such therapy may be a reasonable option for these patients,” the investigators said (N. Engl. J. Med. 2007;357:124-34).

In an accompanying editorial, Dr. T. Jake Liang, of the National Institute of Diabetes and Digestive and Kidney Diseases, wrote: “Patients with HCV genotype 3, high viral load, advanced fibrosis, and obesity who are black, older, and male should be treated for 24 weeks, and whites with HCV genotype 2 and with the opposite characteristics could be treated for a shorter duration.”

The study, funded by Roche, was conducted at 132 centers worldwide between November 2003 and September 2005. Patients received either 16 or 24 weeks of treatment with 180 mcg of subcutaneous peginterferon β-2a once weekly plus 400 mg oral ribavirin twice daily. Investigators were blinded to their patients' treatment duration assignment until week 16.

The proportion with a sustained virologic response, defined as an undetectable serum HCV RNA level (less than 50 IU/mL) at 24 weeks after the end of treatment, was significantly lower among the patients treated for just 16 weeks versus 24 weeks in the per-protocol analysis (65% vs. 76%). The same was true in a more stringently modified intent-to-treat analysis, in which sustained virologic responses were seen in 62% of 732 patients treated for 16 weeks, compared with 70% of 731 treated for 24 weeks. The odds ratio for sustained virologic response for 24 weeks versus 16 weeks of treatment was 1.56, wrote the authors.

The virologic response rate immediately at the end of treatment was significantly higher in the 16-week treatment group, because more patients in the 24-week group had no response and were withdrawn prematurely. Thus, the significant difference in the sustained virologic response rate at 24 weeks post treatment reflects a higher relapse rate among the 16-week group (31% vs. 18%). “The trade-off in reducing the treatment duration is an increased relapse rate,” the authors commented.

Within both treatment duration groups, the patients infected with HCV genotype 2 had higher virologic responses at the end of follow-up than did those with genotype 3. Relapse rates for those with genotype 2 were 30% among those treated for 16 weeks and 15% in the 24-week group. Among those with genotype 3, 31% of patients treated for 16 weeks relapsed during follow-up, compared with 22% of those treated for 24 weeks. Overall, the odds ratio of attaining a sustained virologic response with genotype 2 versus 3 was 1.88.

Other significant predictors of sustained virologic response included lower pretreatment HCV RNA level, younger age, lower weight, higher alanine aminotransferase quotient (the patient's alanine aminotransferase level divided by the upper limit of the normal range), and the absence of bridging fibrosis or cirrhosis.

A rapid virologic response, defined as an undetectable HCV RNA level by week 4 of treatment, was achieved in 67% of patients in the 16-week group and in 64% of the 24-week group. Sustained virologic response rates were consistently lower among patients who did not have rapid responses than among those who did. And, among those without a rapid response, sustained virologic response rates were consistently higher in the 24-week group than in the 16-week group.

Overall, the proportions of patients reporting adverse events and serious adverse events were similar in the two groups, and the rates of withdrawal were not significantly different.

Twenty-four weeks should be considered the routine duration of treatment with peginterferon α-2a and ribavirin for patients with hepatitis C virus genotypes 2 and 3, said Dr. Mitchell L. Shiffman, of the Virginia Commonwealth University Medical Center, Richmond, and his associates.

In a study comparing 24 weeks versus 16 weeks of treatment among 1,455 randomized patients with hepatitis C virus (HCV) genotypes 2 or 3, treatment lasting just 16 weeks resulted in a lower overall sustained response rate–primarily due to a higher subsequent relapse rate–compared with 24 weeks of treatment.

However, the data suggested that the shorter duration may be sufficient for certain subgroups. “Patients with a lower pretreatment viral load or a rapid virologic response appear to have the highest probability of having a sustained response with 16 weeks of therapy, and such therapy may be a reasonable option for these patients,” the investigators said (N. Engl. J. Med. 2007;357:124-34).

In an accompanying editorial, Dr. T. Jake Liang, of the National Institute of Diabetes and Digestive and Kidney Diseases, wrote: “Patients with HCV genotype 3, high viral load, advanced fibrosis, and obesity who are black, older, and male should be treated for 24 weeks, and whites with HCV genotype 2 and with the opposite characteristics could be treated for a shorter duration.”

The study, funded by Roche, was conducted at 132 centers worldwide between November 2003 and September 2005. Patients received either 16 or 24 weeks of treatment with 180 mcg of subcutaneous peginterferon β-2a once weekly plus 400 mg oral ribavirin twice daily. Investigators were blinded to their patients' treatment duration assignment until week 16.

The proportion with a sustained virologic response, defined as an undetectable serum HCV RNA level (less than 50 IU/mL) at 24 weeks after the end of treatment, was significantly lower among the patients treated for just 16 weeks versus 24 weeks in the per-protocol analysis (65% vs. 76%). The same was true in a more stringently modified intent-to-treat analysis, in which sustained virologic responses were seen in 62% of 732 patients treated for 16 weeks, compared with 70% of 731 treated for 24 weeks. The odds ratio for sustained virologic response for 24 weeks versus 16 weeks of treatment was 1.56, wrote the authors.

The virologic response rate immediately at the end of treatment was significantly higher in the 16-week treatment group, because more patients in the 24-week group had no response and were withdrawn prematurely. Thus, the significant difference in the sustained virologic response rate at 24 weeks post treatment reflects a higher relapse rate among the 16-week group (31% vs. 18%). “The trade-off in reducing the treatment duration is an increased relapse rate,” the authors commented.

Within both treatment duration groups, the patients infected with HCV genotype 2 had higher virologic responses at the end of follow-up than did those with genotype 3. Relapse rates for those with genotype 2 were 30% among those treated for 16 weeks and 15% in the 24-week group. Among those with genotype 3, 31% of patients treated for 16 weeks relapsed during follow-up, compared with 22% of those treated for 24 weeks. Overall, the odds ratio of attaining a sustained virologic response with genotype 2 versus 3 was 1.88.

Other significant predictors of sustained virologic response included lower pretreatment HCV RNA level, younger age, lower weight, higher alanine aminotransferase quotient (the patient's alanine aminotransferase level divided by the upper limit of the normal range), and the absence of bridging fibrosis or cirrhosis.

A rapid virologic response, defined as an undetectable HCV RNA level by week 4 of treatment, was achieved in 67% of patients in the 16-week group and in 64% of the 24-week group. Sustained virologic response rates were consistently lower among patients who did not have rapid responses than among those who did. And, among those without a rapid response, sustained virologic response rates were consistently higher in the 24-week group than in the 16-week group.

Overall, the proportions of patients reporting adverse events and serious adverse events were similar in the two groups, and the rates of withdrawal were not significantly different.

Twenty-four weeks should be considered the routine duration of treatment with peginterferon α-2a and ribavirin for patients with hepatitis C virus genotypes 2 and 3, said Dr. Mitchell L. Shiffman, of the Virginia Commonwealth University Medical Center, Richmond, and his associates.

In a study comparing 24 weeks versus 16 weeks of treatment among 1,455 randomized patients with hepatitis C virus (HCV) genotypes 2 or 3, treatment lasting just 16 weeks resulted in a lower overall sustained response rate–primarily due to a higher subsequent relapse rate–compared with 24 weeks of treatment.

However, the data suggested that the shorter duration may be sufficient for certain subgroups. “Patients with a lower pretreatment viral load or a rapid virologic response appear to have the highest probability of having a sustained response with 16 weeks of therapy, and such therapy may be a reasonable option for these patients,” the investigators said (N. Engl. J. Med. 2007;357:124-34).

In an accompanying editorial, Dr. T. Jake Liang, of the National Institute of Diabetes and Digestive and Kidney Diseases, wrote: “Patients with HCV genotype 3, high viral load, advanced fibrosis, and obesity who are black, older, and male should be treated for 24 weeks, and whites with HCV genotype 2 and with the opposite characteristics could be treated for a shorter duration.”

The study, funded by Roche, was conducted at 132 centers worldwide between November 2003 and September 2005. Patients received either 16 or 24 weeks of treatment with 180 mcg of subcutaneous peginterferon β-2a once weekly plus 400 mg oral ribavirin twice daily. Investigators were blinded to their patients' treatment duration assignment until week 16.

The proportion with a sustained virologic response, defined as an undetectable serum HCV RNA level (less than 50 IU/mL) at 24 weeks after the end of treatment, was significantly lower among the patients treated for just 16 weeks versus 24 weeks in the per-protocol analysis (65% vs. 76%). The same was true in a more stringently modified intent-to-treat analysis, in which sustained virologic responses were seen in 62% of 732 patients treated for 16 weeks, compared with 70% of 731 treated for 24 weeks. The odds ratio for sustained virologic response for 24 weeks versus 16 weeks of treatment was 1.56, wrote the authors.

The virologic response rate immediately at the end of treatment was significantly higher in the 16-week treatment group, because more patients in the 24-week group had no response and were withdrawn prematurely. Thus, the significant difference in the sustained virologic response rate at 24 weeks post treatment reflects a higher relapse rate among the 16-week group (31% vs. 18%). “The trade-off in reducing the treatment duration is an increased relapse rate,” the authors commented.

Within both treatment duration groups, the patients infected with HCV genotype 2 had higher virologic responses at the end of follow-up than did those with genotype 3. Relapse rates for those with genotype 2 were 30% among those treated for 16 weeks and 15% in the 24-week group. Among those with genotype 3, 31% of patients treated for 16 weeks relapsed during follow-up, compared with 22% of those treated for 24 weeks. Overall, the odds ratio of attaining a sustained virologic response with genotype 2 versus 3 was 1.88.

Other significant predictors of sustained virologic response included lower pretreatment HCV RNA level, younger age, lower weight, higher alanine aminotransferase quotient (the patient's alanine aminotransferase level divided by the upper limit of the normal range), and the absence of bridging fibrosis or cirrhosis.

A rapid virologic response, defined as an undetectable HCV RNA level by week 4 of treatment, was achieved in 67% of patients in the 16-week group and in 64% of the 24-week group. Sustained virologic response rates were consistently lower among patients who did not have rapid responses than among those who did. And, among those without a rapid response, sustained virologic response rates were consistently higher in the 24-week group than in the 16-week group.

Overall, the proportions of patients reporting adverse events and serious adverse events were similar in the two groups, and the rates of withdrawal were not significantly different.

CHICAGO – The cholesterol-lowering drug colesevelam HCl improves glycemic control in patients with type 2 diabetes who are inadequately controlled with metformin monotherapy, Dr. Harold E. Bays reported in a poster presentation at the annual scientific sessions of the American Diabetes Association.

The bile acid sequestrant colesevelam HCl, sold under the name WelChol, has been approved in the United States for LDL cholesterol lowering since 2000. In January, WelChol's manufacturer, Daiichi Sankyo Inc., filed a supplemental new drug application with the Food and Drug Administration for a new glucose-lowering indication. Overall results of a pivotal randomized, placebo-controlled trial involving 316 adults with type 2 diabetes who were inadequately controlled with other oral agents, were presented earlier this year at a meeting of the American Association of Clinical Endocrinologists.

At that meeting, Dr. Bays, of Louisville (Ky.) Metabolic and Atherosclerosis Research Center Inc., presented the results of a subgroup analysis of the 155 patients who were on metformin monotherapy, in which 79 received 3.75 g/day of colesevelam and 76 took placebo. At week 26, the intent-to-treat analysis revealed a significant reduction in mean hemoglobin A1c (HbA1c) of 0.47% with colesevelam and a 17.8 micromol/L drop in fasting plasma glucose, both relative to placebo. Significantly more patients in the colesevelam group had reductions in HbA1c of more than 0.7% by week 26 (41% vs. 22%).

Mean changes in laboratory parameters, vital signs, and weight from baseline were similar in the two groups. Drug-related treatment-emergent adverse effects occurred in 18% of the colesevelam group and 12% of the placebo group, but most were mild or moderate. The only serious adverse event occurred in a placebo subject.

A second poster, presented by Dr. Ronald B. Goldberg of the University of Miami, showed that colesevelam significantly improved lipid profiles in the 316 study patients with type 2 diabetes, including reductions from baseline of 16% for LDL cholesterol, 10% for non-HDL cholesterol, 7% for total cholesterol, and 8% for Apo B.

CHICAGO – The cholesterol-lowering drug colesevelam HCl improves glycemic control in patients with type 2 diabetes who are inadequately controlled with metformin monotherapy, Dr. Harold E. Bays reported in a poster presentation at the annual scientific sessions of the American Diabetes Association.

The bile acid sequestrant colesevelam HCl, sold under the name WelChol, has been approved in the United States for LDL cholesterol lowering since 2000. In January, WelChol's manufacturer, Daiichi Sankyo Inc., filed a supplemental new drug application with the Food and Drug Administration for a new glucose-lowering indication. Overall results of a pivotal randomized, placebo-controlled trial involving 316 adults with type 2 diabetes who were inadequately controlled with other oral agents, were presented earlier this year at a meeting of the American Association of Clinical Endocrinologists.

At that meeting, Dr. Bays, of Louisville (Ky.) Metabolic and Atherosclerosis Research Center Inc., presented the results of a subgroup analysis of the 155 patients who were on metformin monotherapy, in which 79 received 3.75 g/day of colesevelam and 76 took placebo. At week 26, the intent-to-treat analysis revealed a significant reduction in mean hemoglobin A1c (HbA1c) of 0.47% with colesevelam and a 17.8 micromol/L drop in fasting plasma glucose, both relative to placebo. Significantly more patients in the colesevelam group had reductions in HbA1c of more than 0.7% by week 26 (41% vs. 22%).

Mean changes in laboratory parameters, vital signs, and weight from baseline were similar in the two groups. Drug-related treatment-emergent adverse effects occurred in 18% of the colesevelam group and 12% of the placebo group, but most were mild or moderate. The only serious adverse event occurred in a placebo subject.

A second poster, presented by Dr. Ronald B. Goldberg of the University of Miami, showed that colesevelam significantly improved lipid profiles in the 316 study patients with type 2 diabetes, including reductions from baseline of 16% for LDL cholesterol, 10% for non-HDL cholesterol, 7% for total cholesterol, and 8% for Apo B.

CHICAGO – The cholesterol-lowering drug colesevelam HCl improves glycemic control in patients with type 2 diabetes who are inadequately controlled with metformin monotherapy, Dr. Harold E. Bays reported in a poster presentation at the annual scientific sessions of the American Diabetes Association.

The bile acid sequestrant colesevelam HCl, sold under the name WelChol, has been approved in the United States for LDL cholesterol lowering since 2000. In January, WelChol's manufacturer, Daiichi Sankyo Inc., filed a supplemental new drug application with the Food and Drug Administration for a new glucose-lowering indication. Overall results of a pivotal randomized, placebo-controlled trial involving 316 adults with type 2 diabetes who were inadequately controlled with other oral agents, were presented earlier this year at a meeting of the American Association of Clinical Endocrinologists.

At that meeting, Dr. Bays, of Louisville (Ky.) Metabolic and Atherosclerosis Research Center Inc., presented the results of a subgroup analysis of the 155 patients who were on metformin monotherapy, in which 79 received 3.75 g/day of colesevelam and 76 took placebo. At week 26, the intent-to-treat analysis revealed a significant reduction in mean hemoglobin A1c (HbA1c) of 0.47% with colesevelam and a 17.8 micromol/L drop in fasting plasma glucose, both relative to placebo. Significantly more patients in the colesevelam group had reductions in HbA1c of more than 0.7% by week 26 (41% vs. 22%).

Mean changes in laboratory parameters, vital signs, and weight from baseline were similar in the two groups. Drug-related treatment-emergent adverse effects occurred in 18% of the colesevelam group and 12% of the placebo group, but most were mild or moderate. The only serious adverse event occurred in a placebo subject.

A second poster, presented by Dr. Ronald B. Goldberg of the University of Miami, showed that colesevelam significantly improved lipid profiles in the 316 study patients with type 2 diabetes, including reductions from baseline of 16% for LDL cholesterol, 10% for non-HDL cholesterol, 7% for total cholesterol, and 8% for Apo B.

CHICAGO – Diabetic eye disease is expected to triple in the United States by the year 2050, investigators from the Centers for Disease Control and Prevention reported at the annual scientific sessions of the American Diabetes Association.

“The future changes in the number of people with diabetes and the U.S. population will likely lead to dramatic increases in the number of Americans with diabetic retinopathy, glaucoma, and cataract. Efforts to prevent, delay, and better manage the diabetes epidemic will help in reducing the burden of diabetes eye complications,” said Dr. Jinan Saaddine and her associates in a poster presentation.

According to a recent estimate, there will be 48 million people diagnosed with diabetes by the year 2050 (Diabetes Care 2006;29:2114-6). Using that number, with data from the National Health Interview Survey and a series of articles on eye disease prevalence published in the April 2004 issue of the Archives of Ophthalmology, the authors projected that the number of people in the United States with diabetic retinopathy will increase from 5.5 million in 2004 to 16.0 million in 2050. The number with vision-threatening diabetic retinopathy is also expected to triple over that period, from 1.2 million to 3.4 million.

At the same time, the number of diabetic patients with cataracts will triple from 3.0 million to 9.9 million, and the number with glaucoma will more than quadruple, from 335,600 to 1,447,000, they predicted.

The increases in diabetic retinopathy are expected to be especially pronounced for those aged 65 years and older, with overall rates rising from 2.5 million to 9.9 million, and rates of vision-threatening disease from 0.5 to 1.9 million. Glaucoma among Hispanics with diabetes is also likely to rise particularly sharply, with a 12-fold increase in those aged 65 years and over.

CHICAGO – Diabetic eye disease is expected to triple in the United States by the year 2050, investigators from the Centers for Disease Control and Prevention reported at the annual scientific sessions of the American Diabetes Association.

“The future changes in the number of people with diabetes and the U.S. population will likely lead to dramatic increases in the number of Americans with diabetic retinopathy, glaucoma, and cataract. Efforts to prevent, delay, and better manage the diabetes epidemic will help in reducing the burden of diabetes eye complications,” said Dr. Jinan Saaddine and her associates in a poster presentation.

According to a recent estimate, there will be 48 million people diagnosed with diabetes by the year 2050 (Diabetes Care 2006;29:2114-6). Using that number, with data from the National Health Interview Survey and a series of articles on eye disease prevalence published in the April 2004 issue of the Archives of Ophthalmology, the authors projected that the number of people in the United States with diabetic retinopathy will increase from 5.5 million in 2004 to 16.0 million in 2050. The number with vision-threatening diabetic retinopathy is also expected to triple over that period, from 1.2 million to 3.4 million.

At the same time, the number of diabetic patients with cataracts will triple from 3.0 million to 9.9 million, and the number with glaucoma will more than quadruple, from 335,600 to 1,447,000, they predicted.

The increases in diabetic retinopathy are expected to be especially pronounced for those aged 65 years and older, with overall rates rising from 2.5 million to 9.9 million, and rates of vision-threatening disease from 0.5 to 1.9 million. Glaucoma among Hispanics with diabetes is also likely to rise particularly sharply, with a 12-fold increase in those aged 65 years and over.

CHICAGO – Diabetic eye disease is expected to triple in the United States by the year 2050, investigators from the Centers for Disease Control and Prevention reported at the annual scientific sessions of the American Diabetes Association.

“The future changes in the number of people with diabetes and the U.S. population will likely lead to dramatic increases in the number of Americans with diabetic retinopathy, glaucoma, and cataract. Efforts to prevent, delay, and better manage the diabetes epidemic will help in reducing the burden of diabetes eye complications,” said Dr. Jinan Saaddine and her associates in a poster presentation.

According to a recent estimate, there will be 48 million people diagnosed with diabetes by the year 2050 (Diabetes Care 2006;29:2114-6). Using that number, with data from the National Health Interview Survey and a series of articles on eye disease prevalence published in the April 2004 issue of the Archives of Ophthalmology, the authors projected that the number of people in the United States with diabetic retinopathy will increase from 5.5 million in 2004 to 16.0 million in 2050. The number with vision-threatening diabetic retinopathy is also expected to triple over that period, from 1.2 million to 3.4 million.

At the same time, the number of diabetic patients with cataracts will triple from 3.0 million to 9.9 million, and the number with glaucoma will more than quadruple, from 335,600 to 1,447,000, they predicted.

The increases in diabetic retinopathy are expected to be especially pronounced for those aged 65 years and older, with overall rates rising from 2.5 million to 9.9 million, and rates of vision-threatening disease from 0.5 to 1.9 million. Glaucoma among Hispanics with diabetes is also likely to rise particularly sharply, with a 12-fold increase in those aged 65 years and over.

CHICAGO – About 5% of antibody-negative/C-peptide-positive children and adolescents diagnosed with diabetes in the United States may have Maturity-Onset Diabetes of the Young rather than type 2 diabetes, Dr. Lisa Gilliam reported at the annual scientific sessions of the American Diabetes Association.

Maturity-Onset Diabetes of the Young (MODY) is a clinically heterogeneous group of disorders characterized by nonketotic diabetes, an autosomal dominant pattern of inheritance, and typical onset below the age of 25 years. It can arise from mutations in any one of at least six different genes associated with beta-cell function. The most common form, MODY3, arises from a mutation in the HNF [hepatocyte nuclear factor]-1[α] gene (N. Engl. J. Med. 2001;345:971-80).

New findings suggest that MODY is underrecognized and often inappropriately treated. Physicians “need to maintain a high level of suspicion for MODY in antibody-negative children who have residual beta-cell function, and certainly consider screening in individuals who meet the classic criteria for MODY,” said Dr. Gilliam, of the division of metabolism, endocrinology and nutrition at the University of Washington, Seattle, in an interview.

The data come from SEARCH, a federally funded study of physician-diagnosed diabetes in individuals under 20 years of age in six U.S. centers located in Southern California, Colorado, Ohio, Washington state, South Carolina, and North Carolina. Of 3,993 participants in whom diabetes-associated autoantibodies and fasting C-peptide were measured, 438 were autoantibody-negative. Direct sequencing for the HNF-1[α] gene was performed in a subset of 266 patients who were autoantibody-negative and who had fasting C-peptide levels greater than 0.8 ng/mL. Of those, 13 patients had 14 gene mutations, including 7 that had not previously been described.

Only 1 of the 13 patients had been clinically diagnosed with MODY, whereas 5 had been misdiagnosed with type 1 diabetes, and 7 with type 2 diabetes. Seven were currently being treated with insulin, and none was taking sulfonylureas, which is the recommended pharmacologic treatment for MODY3. MODY patients are sensitive to sulfonylureas, which are cheaper and easier to take than multiple daily insulin injections, Dr. Gilliam explained.

Several clinical characteristics helped distinguish MODY3 from type 1 diabetes. Compared with those 3,484 individuals with type 1 diabetes in this study, the 13 MODY3 patients were less likely to have had weight loss (46% vs. 74%) or polyuria (54% vs. 93%) at diagnosis. The MODY group also tended to be older, heavier, much more likely to have a parent with diabetes (62% vs. 14%), and much less likely to have medium- to high-risk HLA types (46% vs. 85%). Just 3 of the 13 were non-Hispanic white (23%), compared with 69% of the type 1 group.

In contrast, virtually no clinical or biochemical characteristic was identified that could help in distinguishing MODY3 from type 2 diabetes on an individual basis. Although the MODY group was somewhat younger and less obese than the type 2 patients, there was a great deal of overlap between the two groups. The type 2 patients were as likely as the MODY group to have a positive family history for diabetes–including an autosomal dominant three-generation family history–and fasting C-peptide levels were similar.

“With the prevalence of obesity and type 2 diabetes increasing in the pediatric population, it's becoming more challenging to distinguish MODY from type 2 diabetes,” she noted. Genetic screening is very expensive, at this point it's not feasible to recommend it in every antibody-negative child or adolescent with residual fasting C-peptide.

CHICAGO – About 5% of antibody-negative/C-peptide-positive children and adolescents diagnosed with diabetes in the United States may have Maturity-Onset Diabetes of the Young rather than type 2 diabetes, Dr. Lisa Gilliam reported at the annual scientific sessions of the American Diabetes Association.

Maturity-Onset Diabetes of the Young (MODY) is a clinically heterogeneous group of disorders characterized by nonketotic diabetes, an autosomal dominant pattern of inheritance, and typical onset below the age of 25 years. It can arise from mutations in any one of at least six different genes associated with beta-cell function. The most common form, MODY3, arises from a mutation in the HNF [hepatocyte nuclear factor]-1[α] gene (N. Engl. J. Med. 2001;345:971-80).

New findings suggest that MODY is underrecognized and often inappropriately treated. Physicians “need to maintain a high level of suspicion for MODY in antibody-negative children who have residual beta-cell function, and certainly consider screening in individuals who meet the classic criteria for MODY,” said Dr. Gilliam, of the division of metabolism, endocrinology and nutrition at the University of Washington, Seattle, in an interview.

The data come from SEARCH, a federally funded study of physician-diagnosed diabetes in individuals under 20 years of age in six U.S. centers located in Southern California, Colorado, Ohio, Washington state, South Carolina, and North Carolina. Of 3,993 participants in whom diabetes-associated autoantibodies and fasting C-peptide were measured, 438 were autoantibody-negative. Direct sequencing for the HNF-1[α] gene was performed in a subset of 266 patients who were autoantibody-negative and who had fasting C-peptide levels greater than 0.8 ng/mL. Of those, 13 patients had 14 gene mutations, including 7 that had not previously been described.

Only 1 of the 13 patients had been clinically diagnosed with MODY, whereas 5 had been misdiagnosed with type 1 diabetes, and 7 with type 2 diabetes. Seven were currently being treated with insulin, and none was taking sulfonylureas, which is the recommended pharmacologic treatment for MODY3. MODY patients are sensitive to sulfonylureas, which are cheaper and easier to take than multiple daily insulin injections, Dr. Gilliam explained.

Several clinical characteristics helped distinguish MODY3 from type 1 diabetes. Compared with those 3,484 individuals with type 1 diabetes in this study, the 13 MODY3 patients were less likely to have had weight loss (46% vs. 74%) or polyuria (54% vs. 93%) at diagnosis. The MODY group also tended to be older, heavier, much more likely to have a parent with diabetes (62% vs. 14%), and much less likely to have medium- to high-risk HLA types (46% vs. 85%). Just 3 of the 13 were non-Hispanic white (23%), compared with 69% of the type 1 group.

In contrast, virtually no clinical or biochemical characteristic was identified that could help in distinguishing MODY3 from type 2 diabetes on an individual basis. Although the MODY group was somewhat younger and less obese than the type 2 patients, there was a great deal of overlap between the two groups. The type 2 patients were as likely as the MODY group to have a positive family history for diabetes–including an autosomal dominant three-generation family history–and fasting C-peptide levels were similar.

“With the prevalence of obesity and type 2 diabetes increasing in the pediatric population, it's becoming more challenging to distinguish MODY from type 2 diabetes,” she noted. Genetic screening is very expensive, at this point it's not feasible to recommend it in every antibody-negative child or adolescent with residual fasting C-peptide.

CHICAGO – About 5% of antibody-negative/C-peptide-positive children and adolescents diagnosed with diabetes in the United States may have Maturity-Onset Diabetes of the Young rather than type 2 diabetes, Dr. Lisa Gilliam reported at the annual scientific sessions of the American Diabetes Association.

Maturity-Onset Diabetes of the Young (MODY) is a clinically heterogeneous group of disorders characterized by nonketotic diabetes, an autosomal dominant pattern of inheritance, and typical onset below the age of 25 years. It can arise from mutations in any one of at least six different genes associated with beta-cell function. The most common form, MODY3, arises from a mutation in the HNF [hepatocyte nuclear factor]-1[α] gene (N. Engl. J. Med. 2001;345:971-80).

New findings suggest that MODY is underrecognized and often inappropriately treated. Physicians “need to maintain a high level of suspicion for MODY in antibody-negative children who have residual beta-cell function, and certainly consider screening in individuals who meet the classic criteria for MODY,” said Dr. Gilliam, of the division of metabolism, endocrinology and nutrition at the University of Washington, Seattle, in an interview.

The data come from SEARCH, a federally funded study of physician-diagnosed diabetes in individuals under 20 years of age in six U.S. centers located in Southern California, Colorado, Ohio, Washington state, South Carolina, and North Carolina. Of 3,993 participants in whom diabetes-associated autoantibodies and fasting C-peptide were measured, 438 were autoantibody-negative. Direct sequencing for the HNF-1[α] gene was performed in a subset of 266 patients who were autoantibody-negative and who had fasting C-peptide levels greater than 0.8 ng/mL. Of those, 13 patients had 14 gene mutations, including 7 that had not previously been described.

Only 1 of the 13 patients had been clinically diagnosed with MODY, whereas 5 had been misdiagnosed with type 1 diabetes, and 7 with type 2 diabetes. Seven were currently being treated with insulin, and none was taking sulfonylureas, which is the recommended pharmacologic treatment for MODY3. MODY patients are sensitive to sulfonylureas, which are cheaper and easier to take than multiple daily insulin injections, Dr. Gilliam explained.

Several clinical characteristics helped distinguish MODY3 from type 1 diabetes. Compared with those 3,484 individuals with type 1 diabetes in this study, the 13 MODY3 patients were less likely to have had weight loss (46% vs. 74%) or polyuria (54% vs. 93%) at diagnosis. The MODY group also tended to be older, heavier, much more likely to have a parent with diabetes (62% vs. 14%), and much less likely to have medium- to high-risk HLA types (46% vs. 85%). Just 3 of the 13 were non-Hispanic white (23%), compared with 69% of the type 1 group.

In contrast, virtually no clinical or biochemical characteristic was identified that could help in distinguishing MODY3 from type 2 diabetes on an individual basis. Although the MODY group was somewhat younger and less obese than the type 2 patients, there was a great deal of overlap between the two groups. The type 2 patients were as likely as the MODY group to have a positive family history for diabetes–including an autosomal dominant three-generation family history–and fasting C-peptide levels were similar.

“With the prevalence of obesity and type 2 diabetes increasing in the pediatric population, it's becoming more challenging to distinguish MODY from type 2 diabetes,” she noted. Genetic screening is very expensive, at this point it's not feasible to recommend it in every antibody-negative child or adolescent with residual fasting C-peptide.

BALTIMORE — GlaxoSmithKline's influenza vaccine, Fluarix, is noninferior to Sanofi Pasteur's Fluzone in adults aged 18–95 years, Dr. James D. Campbell reported at a conference on vaccine research sponsored by the National Foundation for Infectious Diseases.

The two vaccines were comparable in terms of immunogenicity, tolerability, and safety in a postmarketing study conducted by GSK at the request of the U.S. Food and Drug Administration following the licensure of Fluarix in 2005.

Immunogenicity of both vaccines was lower in adults aged 65 years and older, however, suggesting the need for improved formulations for this population, said Dr. Campbell of the center for vaccine development at the University of Maryland, Baltimore.

The 1,820 adults randomized to either Fluarix or Fluzone had a median age of 68 years, 92% were white, and 59% were women. Approximately two-thirds of each vaccine group were aged 65 years and older. A total of 1,739 subjects—872 of whom received Fluarix and 867 of whom received Fluzone—completed the study protocol.

Local reactions with both vaccines were nearly all mild or moderate, most lasting just a few days. Severe (grade 3) reactions occurred in 0.2% of the group taking Fluarix and 1.4% of those taking Fluzone. Headache and fatigue were the most common general reactions, occurring in 12%–13% with each vaccine. Severe general reactions were equally rare in both groups, at 1.2% with Fluarix and 1.6% with Fluzone. No category of unsolicited adverse events was markedly more common after either vaccine. Serious adverse events occurred in 5% of participants in each group; none of the adverse events were deemed related to the vaccine, Dr. Campbell said.

Immunologic noninferiority was the primary end point, defined by a geometric mean antibody titer (GMT) response to Fluarix not less than two-thirds that of Fluzone, and a less than 10% difference in seroconversion at day 21 between the two vaccines. Fluarix was immunologically noninferior to Fluzone for all three vaccine strains in the study population as a whole and in the elderly subset.

However, both seroconversion and GMT responses to the H1N1 strain were slightly better with Fluarix; Fluzone produced a slightly higher GMT response to the B strain than did Fluarix, but seroconversion rates were similar.

Both types of responses were diminished in the elderly subjects, compared with the entire group, but did not differ by vaccine. Seroprotection is estimated at 82%–98% for both vaccines, Dr. Campbell said.

BALTIMORE — GlaxoSmithKline's influenza vaccine, Fluarix, is noninferior to Sanofi Pasteur's Fluzone in adults aged 18–95 years, Dr. James D. Campbell reported at a conference on vaccine research sponsored by the National Foundation for Infectious Diseases.

The two vaccines were comparable in terms of immunogenicity, tolerability, and safety in a postmarketing study conducted by GSK at the request of the U.S. Food and Drug Administration following the licensure of Fluarix in 2005.

Immunogenicity of both vaccines was lower in adults aged 65 years and older, however, suggesting the need for improved formulations for this population, said Dr. Campbell of the center for vaccine development at the University of Maryland, Baltimore.

The 1,820 adults randomized to either Fluarix or Fluzone had a median age of 68 years, 92% were white, and 59% were women. Approximately two-thirds of each vaccine group were aged 65 years and older. A total of 1,739 subjects—872 of whom received Fluarix and 867 of whom received Fluzone—completed the study protocol.

Local reactions with both vaccines were nearly all mild or moderate, most lasting just a few days. Severe (grade 3) reactions occurred in 0.2% of the group taking Fluarix and 1.4% of those taking Fluzone. Headache and fatigue were the most common general reactions, occurring in 12%–13% with each vaccine. Severe general reactions were equally rare in both groups, at 1.2% with Fluarix and 1.6% with Fluzone. No category of unsolicited adverse events was markedly more common after either vaccine. Serious adverse events occurred in 5% of participants in each group; none of the adverse events were deemed related to the vaccine, Dr. Campbell said.

Immunologic noninferiority was the primary end point, defined by a geometric mean antibody titer (GMT) response to Fluarix not less than two-thirds that of Fluzone, and a less than 10% difference in seroconversion at day 21 between the two vaccines. Fluarix was immunologically noninferior to Fluzone for all three vaccine strains in the study population as a whole and in the elderly subset.

However, both seroconversion and GMT responses to the H1N1 strain were slightly better with Fluarix; Fluzone produced a slightly higher GMT response to the B strain than did Fluarix, but seroconversion rates were similar.

Both types of responses were diminished in the elderly subjects, compared with the entire group, but did not differ by vaccine. Seroprotection is estimated at 82%–98% for both vaccines, Dr. Campbell said.

BALTIMORE — GlaxoSmithKline's influenza vaccine, Fluarix, is noninferior to Sanofi Pasteur's Fluzone in adults aged 18–95 years, Dr. James D. Campbell reported at a conference on vaccine research sponsored by the National Foundation for Infectious Diseases.

The two vaccines were comparable in terms of immunogenicity, tolerability, and safety in a postmarketing study conducted by GSK at the request of the U.S. Food and Drug Administration following the licensure of Fluarix in 2005.

Immunogenicity of both vaccines was lower in adults aged 65 years and older, however, suggesting the need for improved formulations for this population, said Dr. Campbell of the center for vaccine development at the University of Maryland, Baltimore.

The 1,820 adults randomized to either Fluarix or Fluzone had a median age of 68 years, 92% were white, and 59% were women. Approximately two-thirds of each vaccine group were aged 65 years and older. A total of 1,739 subjects—872 of whom received Fluarix and 867 of whom received Fluzone—completed the study protocol.

Local reactions with both vaccines were nearly all mild or moderate, most lasting just a few days. Severe (grade 3) reactions occurred in 0.2% of the group taking Fluarix and 1.4% of those taking Fluzone. Headache and fatigue were the most common general reactions, occurring in 12%–13% with each vaccine. Severe general reactions were equally rare in both groups, at 1.2% with Fluarix and 1.6% with Fluzone. No category of unsolicited adverse events was markedly more common after either vaccine. Serious adverse events occurred in 5% of participants in each group; none of the adverse events were deemed related to the vaccine, Dr. Campbell said.

Immunologic noninferiority was the primary end point, defined by a geometric mean antibody titer (GMT) response to Fluarix not less than two-thirds that of Fluzone, and a less than 10% difference in seroconversion at day 21 between the two vaccines. Fluarix was immunologically noninferior to Fluzone for all three vaccine strains in the study population as a whole and in the elderly subset.

However, both seroconversion and GMT responses to the H1N1 strain were slightly better with Fluarix; Fluzone produced a slightly higher GMT response to the B strain than did Fluarix, but seroconversion rates were similar.

Both types of responses were diminished in the elderly subjects, compared with the entire group, but did not differ by vaccine. Seroprotection is estimated at 82%–98% for both vaccines, Dr. Campbell said.

PITTSBURGH — Neuroimaging may soon become an important clinical tool for the diagnosis and treatment of mood disorders, Dr. Mary L. Phillips said at the Seventh International Conference on Bipolar Disorder.

Emerging data suggest that functional magnetic resonance imaging (fMRI) can identify specific neural biomarkers that may help distinguish patients with bipolar disorder from those with unipolar disorder. These data may also help physicians assess which patients will respond to which psychotropic medications and possibly even predict which healthy individuals at high genetic risk will go on to develop bipolar disorder, said Dr. Phillips, who is with both the University of Pittsburgh, where she is professor of psychiatry and director of the functional neuroimaging program, and the Institute of Psychiatry in London, where she is with the section of neuroscience and emotion.

“We've moved beyond blue sky high-level science for its own sake. We're now using neuroimaging to ask and answer real-life clinical problems,” she said at a press briefing held during the conference.

Improving the diagnostic capability of those who treat bipolar disorder is a research priority and is likely to be the first bedside use of the technology. Bipolar disorder is frequently misdiagnosed as unipolar depression, often for as long as 8–10 years, before patients receive a correct diagnosis and treatment.

Using fMRI to record neural responses to pictures of people with facial expressions of varying emotions, Dr. Phillips and her London associates found distinct differences between a group of 12 patients with a diagnosis of bipolar I disorder, 9 with major depressive disorder, and 11 healthy control subjects.

The bipolar group demonstrated increases in both subcortical (ventral, striatal, thalamic, and hippocampal) and ventral prefrontal cortical responses, particularly to expressions of mild and intense fear, mild happiness, and mild sadness; activity was diminished in the dorsal prefrontal cortical area to the majority of facial expressions (Biol. Psychiatry 2004;55:578–87).

The results are in line with the fact that one of the specific subcortical areas that show abnormally elevated activity, the ventral striatum, is associated with the processing of expressions of emotion and reward. Interestingly, activity in this area was most elevated by pictures of faces showing expressions of mild happiness rather than to faces showing more extreme emotions. This may be explained by the fact that mild expressions of happiness are more frequently observed in everyday life, and may be seen as especially rewarding in people with bipolar disorder, Dr. Phillips said in an interview.

The dorsal prefrontal cortical area, where the bipolar patients demonstrated reduced brain activity, comprises the regions primarily associated with regulation of emotion. Reduced activity in these regions may therefore underlie the emotional lability experienced by people with bipolar disorder, she said.

In contrast, the group with unipolar depression showed diminished neural responses to all emotional expressions except mild sadness. Severity of depression correlated positively with hippocampal response to mild sadness in both patient groups, while the healthy controls demonstrated increased subcortical responses to intense happiness and mild fear, and increased dorsal prefrontal cortical responses to intense expressions of sadness.

Dr. Phillips is now replicating these findings in Pittsburgh, with larger groups of bipolar patients. Results in the Pittsburgh patients have shown that the same patterns occur in subjects with active and with remitted disease, suggesting that the test would be specific to the disease state, regardless of current symptoms. Those data are currently being prepared for submission to a journal.

“I see in the not-too-far-distant future that we might be able to perform a brain imaging scan the same way that people get chest x-rays. It's not going to be the only tool we have, but it will be part of a battery of tests, along with blood tests and paper-and-pencil cognitive tests,” Dr. Phillips predicted.

However, she cautioned that because the use of fMRI in psychiatry is still relatively new, there are not as yet enough normative data with which to compare people with various psychiatric abnormalities. Those data are now being gathered. “So perhaps not tomorrow, but within the next 10 years, I would like to see at least a basic paradigm, such as face task,” she said at the press briefing.

“If we can do anything to identify and accurately diagnose people with bipolar disorder earlier, that has to be a good thing,” Dr. Phillips said at the conference, which was sponsored by the University of Pittsburgh.

PITTSBURGH — Neuroimaging may soon become an important clinical tool for the diagnosis and treatment of mood disorders, Dr. Mary L. Phillips said at the Seventh International Conference on Bipolar Disorder.

Emerging data suggest that functional magnetic resonance imaging (fMRI) can identify specific neural biomarkers that may help distinguish patients with bipolar disorder from those with unipolar disorder. These data may also help physicians assess which patients will respond to which psychotropic medications and possibly even predict which healthy individuals at high genetic risk will go on to develop bipolar disorder, said Dr. Phillips, who is with both the University of Pittsburgh, where she is professor of psychiatry and director of the functional neuroimaging program, and the Institute of Psychiatry in London, where she is with the section of neuroscience and emotion.

“We've moved beyond blue sky high-level science for its own sake. We're now using neuroimaging to ask and answer real-life clinical problems,” she said at a press briefing held during the conference.

Improving the diagnostic capability of those who treat bipolar disorder is a research priority and is likely to be the first bedside use of the technology. Bipolar disorder is frequently misdiagnosed as unipolar depression, often for as long as 8–10 years, before patients receive a correct diagnosis and treatment.

Using fMRI to record neural responses to pictures of people with facial expressions of varying emotions, Dr. Phillips and her London associates found distinct differences between a group of 12 patients with a diagnosis of bipolar I disorder, 9 with major depressive disorder, and 11 healthy control subjects.

The bipolar group demonstrated increases in both subcortical (ventral, striatal, thalamic, and hippocampal) and ventral prefrontal cortical responses, particularly to expressions of mild and intense fear, mild happiness, and mild sadness; activity was diminished in the dorsal prefrontal cortical area to the majority of facial expressions (Biol. Psychiatry 2004;55:578–87).

The results are in line with the fact that one of the specific subcortical areas that show abnormally elevated activity, the ventral striatum, is associated with the processing of expressions of emotion and reward. Interestingly, activity in this area was most elevated by pictures of faces showing expressions of mild happiness rather than to faces showing more extreme emotions. This may be explained by the fact that mild expressions of happiness are more frequently observed in everyday life, and may be seen as especially rewarding in people with bipolar disorder, Dr. Phillips said in an interview.

The dorsal prefrontal cortical area, where the bipolar patients demonstrated reduced brain activity, comprises the regions primarily associated with regulation of emotion. Reduced activity in these regions may therefore underlie the emotional lability experienced by people with bipolar disorder, she said.

In contrast, the group with unipolar depression showed diminished neural responses to all emotional expressions except mild sadness. Severity of depression correlated positively with hippocampal response to mild sadness in both patient groups, while the healthy controls demonstrated increased subcortical responses to intense happiness and mild fear, and increased dorsal prefrontal cortical responses to intense expressions of sadness.

Dr. Phillips is now replicating these findings in Pittsburgh, with larger groups of bipolar patients. Results in the Pittsburgh patients have shown that the same patterns occur in subjects with active and with remitted disease, suggesting that the test would be specific to the disease state, regardless of current symptoms. Those data are currently being prepared for submission to a journal.

“I see in the not-too-far-distant future that we might be able to perform a brain imaging scan the same way that people get chest x-rays. It's not going to be the only tool we have, but it will be part of a battery of tests, along with blood tests and paper-and-pencil cognitive tests,” Dr. Phillips predicted.

However, she cautioned that because the use of fMRI in psychiatry is still relatively new, there are not as yet enough normative data with which to compare people with various psychiatric abnormalities. Those data are now being gathered. “So perhaps not tomorrow, but within the next 10 years, I would like to see at least a basic paradigm, such as face task,” she said at the press briefing.

“If we can do anything to identify and accurately diagnose people with bipolar disorder earlier, that has to be a good thing,” Dr. Phillips said at the conference, which was sponsored by the University of Pittsburgh.

PITTSBURGH — Neuroimaging may soon become an important clinical tool for the diagnosis and treatment of mood disorders, Dr. Mary L. Phillips said at the Seventh International Conference on Bipolar Disorder.

Emerging data suggest that functional magnetic resonance imaging (fMRI) can identify specific neural biomarkers that may help distinguish patients with bipolar disorder from those with unipolar disorder. These data may also help physicians assess which patients will respond to which psychotropic medications and possibly even predict which healthy individuals at high genetic risk will go on to develop bipolar disorder, said Dr. Phillips, who is with both the University of Pittsburgh, where she is professor of psychiatry and director of the functional neuroimaging program, and the Institute of Psychiatry in London, where she is with the section of neuroscience and emotion.

“We've moved beyond blue sky high-level science for its own sake. We're now using neuroimaging to ask and answer real-life clinical problems,” she said at a press briefing held during the conference.

Improving the diagnostic capability of those who treat bipolar disorder is a research priority and is likely to be the first bedside use of the technology. Bipolar disorder is frequently misdiagnosed as unipolar depression, often for as long as 8–10 years, before patients receive a correct diagnosis and treatment.

Using fMRI to record neural responses to pictures of people with facial expressions of varying emotions, Dr. Phillips and her London associates found distinct differences between a group of 12 patients with a diagnosis of bipolar I disorder, 9 with major depressive disorder, and 11 healthy control subjects.

The bipolar group demonstrated increases in both subcortical (ventral, striatal, thalamic, and hippocampal) and ventral prefrontal cortical responses, particularly to expressions of mild and intense fear, mild happiness, and mild sadness; activity was diminished in the dorsal prefrontal cortical area to the majority of facial expressions (Biol. Psychiatry 2004;55:578–87).

The results are in line with the fact that one of the specific subcortical areas that show abnormally elevated activity, the ventral striatum, is associated with the processing of expressions of emotion and reward. Interestingly, activity in this area was most elevated by pictures of faces showing expressions of mild happiness rather than to faces showing more extreme emotions. This may be explained by the fact that mild expressions of happiness are more frequently observed in everyday life, and may be seen as especially rewarding in people with bipolar disorder, Dr. Phillips said in an interview.

The dorsal prefrontal cortical area, where the bipolar patients demonstrated reduced brain activity, comprises the regions primarily associated with regulation of emotion. Reduced activity in these regions may therefore underlie the emotional lability experienced by people with bipolar disorder, she said.

In contrast, the group with unipolar depression showed diminished neural responses to all emotional expressions except mild sadness. Severity of depression correlated positively with hippocampal response to mild sadness in both patient groups, while the healthy controls demonstrated increased subcortical responses to intense happiness and mild fear, and increased dorsal prefrontal cortical responses to intense expressions of sadness.

Dr. Phillips is now replicating these findings in Pittsburgh, with larger groups of bipolar patients. Results in the Pittsburgh patients have shown that the same patterns occur in subjects with active and with remitted disease, suggesting that the test would be specific to the disease state, regardless of current symptoms. Those data are currently being prepared for submission to a journal.

“I see in the not-too-far-distant future that we might be able to perform a brain imaging scan the same way that people get chest x-rays. It's not going to be the only tool we have, but it will be part of a battery of tests, along with blood tests and paper-and-pencil cognitive tests,” Dr. Phillips predicted.

However, she cautioned that because the use of fMRI in psychiatry is still relatively new, there are not as yet enough normative data with which to compare people with various psychiatric abnormalities. Those data are now being gathered. “So perhaps not tomorrow, but within the next 10 years, I would like to see at least a basic paradigm, such as face task,” she said at the press briefing.

“If we can do anything to identify and accurately diagnose people with bipolar disorder earlier, that has to be a good thing,” Dr. Phillips said at the conference, which was sponsored by the University of Pittsburgh.

CHICAGO — Until the controversy surrounding rosiglitazone has been resolved, physicians might consider the advice offered by three diabetes specialists during a panel discussion held during the annual scientific sessions of the American Diabetes Association.

The 2-hour session drew an overflow crowd despite being a last-minute addition to the already jam-packed ADA program. It featured presentations from Dr. Steven E. Nissen and Dr. Philip D. Home, along with panelists Dr. David M. Nathan, Dr. Barry J. Goldstein, and Dr. John B. Buse.

Dr. Nissen, of the Cleveland Clinic, reviewed the results of his meta-analysis of 42 trials that revealed a significant increase in the risk of myocardial infarction with rosiglitazone (N. Engl. J. Med. 2007;356:2457–71).

Dr. Home, of Newcastle University, Newcastle upon Tyne, England, then summarized the inconclusive findings of the 3.75-year analysis of data from the Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycemia in Diabetes (RECORD) study, designed as a 6-year trial to assess the safety of rosiglitazone. The unplanned interim analysis had been published rapidly in response to the media attention (N. Engl. J. Med. 2007 June 5 [Epub doi:10.1056/NEJMoa073394]) and Congressional scrutiny garnered by Dr. Nissen's report.

Dr. Nathan, who is chief of the Diabetes Center at Massachusetts General Hospital, Boston, and who wrote editorials for both Dr. Nissen's and Dr. Home's articles, remarked, “There are insufficient data to come to any conclusions that would convince us all. That has given rise to this enormous controversy.”

A joint meeting of the Food and Drug Administration's Endocrinologic and Metabolic Drugs Advisory Committee and Drug Safety and Risk Management Advisory Committee, scheduled for July 30, is likely to bring forth more data.

In the meantime, Dr. Buse, Dr. Goldstein, and Dr. Nathan offered advice about how they would approach the following three clinical scenarios:

▸ A patient with diabetes in poor control who is not currently taking rosiglitazone. Dr. Buse and Dr. Nathan agreed that they would not start a patient on rosiglitazone (Avandia) at this point, at least until more data become available.

“I think at this time, I wouldn't personally choose to start someone on Avandia therapy de novo until these issues are settled to the extent that they're likely to be settled in the next few months,” Dr. Buse said.

Dr. Nathan pointed out that the well-known adverse lipid profile of rosiglitazone, compared with pioglitazone, already made it a less attractive option. Indeed, he said, the data on fluid retention and heart failure—combined with the newer data on fractures and decreased bone density—render the whole thiazolidinedione (TZD) class less attractive than other agents. “I don't understand why people would, given the choice of other agents to lower glycemia, start anyone on rosiglitazone,” he said.

But Dr. Goldstein suggested that rosiglitazone in low doses might still play a role in combination therapy in patients with insulin resistance. He advised following the ADA's treatment algorithm, published in 2006, which recommends metformin as first-line therapy with the TZDs as a possible add-on in patients who don't achieve glycemic goals (Diabetes Care 2006;29:1963–72).

“There's no reason to start with a TZD as monotherapy unless the patient is intolerant to metformin. But at a lower dose, they can be used in combination,” said Dr. Goldstein, director of endocrinology, diabetes, and metabolic disease at Jefferson Medical College, Philadelphia.

▸ A patient with diabetes who is in good control on a regimen that includes rosiglitazone. All three panelists felt that they wouldn't rock the boat in this situation. “If [hemoglobin] A_1c, LDL cholesterol, triglycerides, and [HDL cholesterol] are all controlled, I think there would be more risk to switching someone … over the next 1.5–2 months … until we know everything we're going to know for the next 2 years,” when the RECORD results are available, Dr. Buse said.

Dr. Goldstein said that such a patient “should certainly stay on either [TZD] until we learn more.” And, said Dr. Nathan, “I would think twice about changing someone who's achieving all the other goals.”

▸ A patient with diabetes who is taking rosiglitazone but is not in good control. All three felt that consideration should be given to stopping rosiglitazone in this situation. Dr. Buse remarked, “If you're going to have to rethink the regimen, I think it's appropriate to rethink the Avandia as well.” But even then, he added, it might be difficult to take a patient off the drug because of either personal preference or formulary issues.

Dr. Goldstein noted that such patients are often taking several oral glucose-lowering agents, most commonly metformin and a sulfonylurea in combination with a TZD, and that insulin is generally considered to be the next step. Given that it's rare for patients to be on insulin combined with three oral agents, and that the weight gain and fluid retention problems associated with TZDs are often exacerbated by insulin, “the TZD is often the one that's dropped when insulin is added.”

But Dr. Nathan was more direct: “If the patient is not achieving goals, I would stop Avandia and change the regimen.”

Dr. Buse disclosed no financial ties with either GlaxoSmithKline Inc., maker of rosiglitazone, or Takeda Pharmaceutical Co., maker of pioglitazone. Dr. Goldstein has ties to both, whereas Dr. Nathan has received research support from GSK. All three have relationships with makers of other diabetes drugs.

CHICAGO — Until the controversy surrounding rosiglitazone has been resolved, physicians might consider the advice offered by three diabetes specialists during a panel discussion held during the annual scientific sessions of the American Diabetes Association.

The 2-hour session drew an overflow crowd despite being a last-minute addition to the already jam-packed ADA program. It featured presentations from Dr. Steven E. Nissen and Dr. Philip D. Home, along with panelists Dr. David M. Nathan, Dr. Barry J. Goldstein, and Dr. John B. Buse.

Dr. Nissen, of the Cleveland Clinic, reviewed the results of his meta-analysis of 42 trials that revealed a significant increase in the risk of myocardial infarction with rosiglitazone (N. Engl. J. Med. 2007;356:2457–71).

Dr. Home, of Newcastle University, Newcastle upon Tyne, England, then summarized the inconclusive findings of the 3.75-year analysis of data from the Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycemia in Diabetes (RECORD) study, designed as a 6-year trial to assess the safety of rosiglitazone. The unplanned interim analysis had been published rapidly in response to the media attention (N. Engl. J. Med. 2007 June 5 [Epub doi:10.1056/NEJMoa073394]) and Congressional scrutiny garnered by Dr. Nissen's report.

Dr. Nathan, who is chief of the Diabetes Center at Massachusetts General Hospital, Boston, and who wrote editorials for both Dr. Nissen's and Dr. Home's articles, remarked, “There are insufficient data to come to any conclusions that would convince us all. That has given rise to this enormous controversy.”

A joint meeting of the Food and Drug Administration's Endocrinologic and Metabolic Drugs Advisory Committee and Drug Safety and Risk Management Advisory Committee, scheduled for July 30, is likely to bring forth more data.

In the meantime, Dr. Buse, Dr. Goldstein, and Dr. Nathan offered advice about how they would approach the following three clinical scenarios:

▸ A patient with diabetes in poor control who is not currently taking rosiglitazone. Dr. Buse and Dr. Nathan agreed that they would not start a patient on rosiglitazone (Avandia) at this point, at least until more data become available.

“I think at this time, I wouldn't personally choose to start someone on Avandia therapy de novo until these issues are settled to the extent that they're likely to be settled in the next few months,” Dr. Buse said.

Dr. Nathan pointed out that the well-known adverse lipid profile of rosiglitazone, compared with pioglitazone, already made it a less attractive option. Indeed, he said, the data on fluid retention and heart failure—combined with the newer data on fractures and decreased bone density—render the whole thiazolidinedione (TZD) class less attractive than other agents. “I don't understand why people would, given the choice of other agents to lower glycemia, start anyone on rosiglitazone,” he said.

But Dr. Goldstein suggested that rosiglitazone in low doses might still play a role in combination therapy in patients with insulin resistance. He advised following the ADA's treatment algorithm, published in 2006, which recommends metformin as first-line therapy with the TZDs as a possible add-on in patients who don't achieve glycemic goals (Diabetes Care 2006;29:1963–72).

“There's no reason to start with a TZD as monotherapy unless the patient is intolerant to metformin. But at a lower dose, they can be used in combination,” said Dr. Goldstein, director of endocrinology, diabetes, and metabolic disease at Jefferson Medical College, Philadelphia.

▸ A patient with diabetes who is in good control on a regimen that includes rosiglitazone. All three panelists felt that they wouldn't rock the boat in this situation. “If [hemoglobin] A_1c, LDL cholesterol, triglycerides, and [HDL cholesterol] are all controlled, I think there would be more risk to switching someone … over the next 1.5–2 months … until we know everything we're going to know for the next 2 years,” when the RECORD results are available, Dr. Buse said.

Dr. Goldstein said that such a patient “should certainly stay on either [TZD] until we learn more.” And, said Dr. Nathan, “I would think twice about changing someone who's achieving all the other goals.”

▸ A patient with diabetes who is taking rosiglitazone but is not in good control. All three felt that consideration should be given to stopping rosiglitazone in this situation. Dr. Buse remarked, “If you're going to have to rethink the regimen, I think it's appropriate to rethink the Avandia as well.” But even then, he added, it might be difficult to take a patient off the drug because of either personal preference or formulary issues.

Dr. Goldstein noted that such patients are often taking several oral glucose-lowering agents, most commonly metformin and a sulfonylurea in combination with a TZD, and that insulin is generally considered to be the next step. Given that it's rare for patients to be on insulin combined with three oral agents, and that the weight gain and fluid retention problems associated with TZDs are often exacerbated by insulin, “the TZD is often the one that's dropped when insulin is added.”

But Dr. Nathan was more direct: “If the patient is not achieving goals, I would stop Avandia and change the regimen.”

Dr. Buse disclosed no financial ties with either GlaxoSmithKline Inc., maker of rosiglitazone, or Takeda Pharmaceutical Co., maker of pioglitazone. Dr. Goldstein has ties to both, whereas Dr. Nathan has received research support from GSK. All three have relationships with makers of other diabetes drugs.

CHICAGO — Until the controversy surrounding rosiglitazone has been resolved, physicians might consider the advice offered by three diabetes specialists during a panel discussion held during the annual scientific sessions of the American Diabetes Association.

The 2-hour session drew an overflow crowd despite being a last-minute addition to the already jam-packed ADA program. It featured presentations from Dr. Steven E. Nissen and Dr. Philip D. Home, along with panelists Dr. David M. Nathan, Dr. Barry J. Goldstein, and Dr. John B. Buse.

Dr. Nissen, of the Cleveland Clinic, reviewed the results of his meta-analysis of 42 trials that revealed a significant increase in the risk of myocardial infarction with rosiglitazone (N. Engl. J. Med. 2007;356:2457–71).

Dr. Home, of Newcastle University, Newcastle upon Tyne, England, then summarized the inconclusive findings of the 3.75-year analysis of data from the Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycemia in Diabetes (RECORD) study, designed as a 6-year trial to assess the safety of rosiglitazone. The unplanned interim analysis had been published rapidly in response to the media attention (N. Engl. J. Med. 2007 June 5 [Epub doi:10.1056/NEJMoa073394]) and Congressional scrutiny garnered by Dr. Nissen's report.

Dr. Nathan, who is chief of the Diabetes Center at Massachusetts General Hospital, Boston, and who wrote editorials for both Dr. Nissen's and Dr. Home's articles, remarked, “There are insufficient data to come to any conclusions that would convince us all. That has given rise to this enormous controversy.”

A joint meeting of the Food and Drug Administration's Endocrinologic and Metabolic Drugs Advisory Committee and Drug Safety and Risk Management Advisory Committee, scheduled for July 30, is likely to bring forth more data.

In the meantime, Dr. Buse, Dr. Goldstein, and Dr. Nathan offered advice about how they would approach the following three clinical scenarios:

▸ A patient with diabetes in poor control who is not currently taking rosiglitazone. Dr. Buse and Dr. Nathan agreed that they would not start a patient on rosiglitazone (Avandia) at this point, at least until more data become available.

“I think at this time, I wouldn't personally choose to start someone on Avandia therapy de novo until these issues are settled to the extent that they're likely to be settled in the next few months,” Dr. Buse said.

Dr. Nathan pointed out that the well-known adverse lipid profile of rosiglitazone, compared with pioglitazone, already made it a less attractive option. Indeed, he said, the data on fluid retention and heart failure—combined with the newer data on fractures and decreased bone density—render the whole thiazolidinedione (TZD) class less attractive than other agents. “I don't understand why people would, given the choice of other agents to lower glycemia, start anyone on rosiglitazone,” he said.

But Dr. Goldstein suggested that rosiglitazone in low doses might still play a role in combination therapy in patients with insulin resistance. He advised following the ADA's treatment algorithm, published in 2006, which recommends metformin as first-line therapy with the TZDs as a possible add-on in patients who don't achieve glycemic goals (Diabetes Care 2006;29:1963–72).

“There's no reason to start with a TZD as monotherapy unless the patient is intolerant to metformin. But at a lower dose, they can be used in combination,” said Dr. Goldstein, director of endocrinology, diabetes, and metabolic disease at Jefferson Medical College, Philadelphia.

▸ A patient with diabetes who is in good control on a regimen that includes rosiglitazone. All three panelists felt that they wouldn't rock the boat in this situation. “If [hemoglobin] A_1c, LDL cholesterol, triglycerides, and [HDL cholesterol] are all controlled, I think there would be more risk to switching someone … over the next 1.5–2 months … until we know everything we're going to know for the next 2 years,” when the RECORD results are available, Dr. Buse said.

Dr. Goldstein said that such a patient “should certainly stay on either [TZD] until we learn more.” And, said Dr. Nathan, “I would think twice about changing someone who's achieving all the other goals.”

▸ A patient with diabetes who is taking rosiglitazone but is not in good control. All three felt that consideration should be given to stopping rosiglitazone in this situation. Dr. Buse remarked, “If you're going to have to rethink the regimen, I think it's appropriate to rethink the Avandia as well.” But even then, he added, it might be difficult to take a patient off the drug because of either personal preference or formulary issues.

Dr. Goldstein noted that such patients are often taking several oral glucose-lowering agents, most commonly metformin and a sulfonylurea in combination with a TZD, and that insulin is generally considered to be the next step. Given that it's rare for patients to be on insulin combined with three oral agents, and that the weight gain and fluid retention problems associated with TZDs are often exacerbated by insulin, “the TZD is often the one that's dropped when insulin is added.”

But Dr. Nathan was more direct: “If the patient is not achieving goals, I would stop Avandia and change the regimen.”

Dr. Buse disclosed no financial ties with either GlaxoSmithKline Inc., maker of rosiglitazone, or Takeda Pharmaceutical Co., maker of pioglitazone. Dr. Goldstein has ties to both, whereas Dr. Nathan has received research support from GSK. All three have relationships with makers of other diabetes drugs.

BALTIMORE — A new understanding of the “anemia of inflammation” may help point the way to new treatments in the future, but in the meantime it illustrates why iron supplementation does not raise hemoglobin levels in patients with rheumatoid arthritis and other inflammatory diseases, Dr. Joan Bathon said at a conference on rheumatic diseases sponsored by the Johns Hopkins University.

Formerly known as “anemia of chronic diseases” because it is commonly seen in inflammatory diseases such as rheumatoid arthritis (RA) as well as in chronic infections and some cancers, the condition is now known by the term “anemia of inflammation,” which better reflects its etiology. It is not the result of bleeding, hemolysis, nutritional deficit (vitamin B₁₂, folate, iron), or a marrow disorder, said Dr. Bathon, professor of medicine at Johns Hopkins, Baltimore.

Lacking an understanding of the underlying etiology, health care providers will often give these patients iron supplementation. However, “we know that iron treatment does not really alleviate this anemia,” she said.

Anemia is extremely common among RA patients. In a study comparing 2,120 consecutive RA patients (contributing 26,221 hemoglobin determinations) with 3,843 patients who had noninflammatory rheumatic disorders (7,251 hemoglobin determinations) seen between 1974 and 2004 in a clinical practice setting, the prevalence of chronic anemia was 35.3% when a hemoglobin cutoff of less than 12 g/dL was used.

Hemoglobin levels were consistently lower among the RA patients than among those with noninflammatory conditions, by a mean of 0.8 g/dL.

Those data, reported at the 2005 American College of Rheumatology meeting by Dr. Frederick Wolfe of the National Data Bank for Rheumatic Diseases, Wichita, Kan., suggest that “more than one-third of patients with RA are anemic, if you use a broad definition,” according to Dr. Bathon.

That study also found that among the RA patients, lower hemoglobin was associated with high disease activity; C-reactive protein levels were strongly predictive of anemia; and quality of life was reduced by 5.5% among the patients with anemia after adjustment for age and gender.

In general, patients with anemia of inflammation have decreased total circulating iron levels and binding capacity, yet their total body iron (ferritin) stores are increased.

At the same time, erythropoietin production is blunted, as is the response to endogenous erythropoietin. Red blood cell survival is modestly decreased. “Exogenous iron and/or exogenous erythropoietin do not fully resolve the anemia,” she said.

Although iron is essential for oxygen transport and other vital functions, it also generates free radicals that can lead to oxidative damage, manifesting in conditions such as atherosclerosis, diabetes, or cancer.

But humans can't eliminate excess iron. Therefore, uptake from the gastrointestinal tract is tightly regulated and efficiently recycled. “No matter how much you give orally, there's only a limited amount the body can pick up,” Dr. Bathon explained.

Recently, a small peptide hormone called hepcidin was identified as the principal regulator of systemic iron homeostasis. Synthesized in the liver, hepcidin inhibits the intestinal absorption of iron and suppresses release of iron from macrophage and hepatocyte stores.

Measurement of hepcidin levels is now being investigated as a possible diagnostic tool for various iron disorders. In one study, a novel urine hepcidin assay using mass spectrometry was able to discriminate among patients with secondary iron overload, iron-deficient anemia, and hereditary hemochromatosis (Blood 2005;106:3268–70).

Hepcidin production would be expected to be increased in RA patients, but that hasn't been studied, Dr. Bathon said.

Other data suggest that interleukin-6—but not interleukin-1 (IL-1) or tumor necrosis factor-α (TNF-α)—promotes anemia of inflammation by synthesizing hepcidin (J. Clin. Invest. 2004;113:1271–6), and some investigators have suggested that an antibody directed against IL-6 might therefore offer potential treatment for inflammation-induced anemia (Ann. Rheum. Dis. 2000;59 [Suppl. 1]:i21–7).

But, even though TNF-α and IL-1 don't induce hepcidin in some models, it's not clear whether the process is entirely mediated by IL-6.

In fact, treatment of RA patients with TNF-α blockers often does improve their anemia. It's not yet clear which treatment would be a better method—inhibition of IL-6 or TNF—for resolving anemia inflammation, Dr. Bathon said.

The role of erythropoietin for treating anemia of inflammation is also currently unclear. Although the response to exogenous erythropoietin tends to be blunted in RA patients in proportion to the severity of their inflammation, data from a few small studies do suggest that the treatment may nonetheless be beneficial by lessening their anemia.

One such study, involving 17 patients who received a total 32 weeks of treatment, showed an overall excellent hematologic response without toxicity but with no meaningful change in rheumatologic clinical status (Am. J. Med. 1990;89:161–8).

More recently, 30 patients with RA and anemia were treated with 150 IU/kg recombinant human erythropoietin twice weekly for 12 weeks, along with 200 mg of intravenous iron sucrose per week in the 23 patients who developed functional iron deficiency.

Average hemoglobin increased from 10.7 to 13.2 g/dL after a mean treatment period of 8 weeks. With recombinant human erythrpoietin treatment, patients also experienced increased muscle strength, decreased fatigue, fewer swollen or tender joints, and other improvements in disease activity variables (J. Rheumatol. 2001;28:2430–6).

But, Dr. Bathon said in an interview with RHEUMATOLOGY NEWS, erythropoietin “hasn't been studied enough to provide guidelines for its use, except perhaps prior to surgery where a lot of bleeding is anticipated.”

Moreover, “it's kind of fallen by the wayside,” in large part because “treatment of RA largely resolves the anemia.”

Indeed, it may simply be that addressing the cause of the underlying inflammation—in RA, infections, or other chronic conditions—will correct its accompanying anemia as well.

BALTIMORE — A new understanding of the “anemia of inflammation” may help point the way to new treatments in the future, but in the meantime it illustrates why iron supplementation does not raise hemoglobin levels in patients with rheumatoid arthritis and other inflammatory diseases, Dr. Joan Bathon said at a conference on rheumatic diseases sponsored by the Johns Hopkins University.

Formerly known as “anemia of chronic diseases” because it is commonly seen in inflammatory diseases such as rheumatoid arthritis (RA) as well as in chronic infections and some cancers, the condition is now known by the term “anemia of inflammation,” which better reflects its etiology. It is not the result of bleeding, hemolysis, nutritional deficit (vitamin B₁₂, folate, iron), or a marrow disorder, said Dr. Bathon, professor of medicine at Johns Hopkins, Baltimore.

Lacking an understanding of the underlying etiology, health care providers will often give these patients iron supplementation. However, “we know that iron treatment does not really alleviate this anemia,” she said.

Anemia is extremely common among RA patients. In a study comparing 2,120 consecutive RA patients (contributing 26,221 hemoglobin determinations) with 3,843 patients who had noninflammatory rheumatic disorders (7,251 hemoglobin determinations) seen between 1974 and 2004 in a clinical practice setting, the prevalence of chronic anemia was 35.3% when a hemoglobin cutoff of less than 12 g/dL was used.

Hemoglobin levels were consistently lower among the RA patients than among those with noninflammatory conditions, by a mean of 0.8 g/dL.

Those data, reported at the 2005 American College of Rheumatology meeting by Dr. Frederick Wolfe of the National Data Bank for Rheumatic Diseases, Wichita, Kan., suggest that “more than one-third of patients with RA are anemic, if you use a broad definition,” according to Dr. Bathon.

That study also found that among the RA patients, lower hemoglobin was associated with high disease activity; C-reactive protein levels were strongly predictive of anemia; and quality of life was reduced by 5.5% among the patients with anemia after adjustment for age and gender.

In general, patients with anemia of inflammation have decreased total circulating iron levels and binding capacity, yet their total body iron (ferritin) stores are increased.

At the same time, erythropoietin production is blunted, as is the response to endogenous erythropoietin. Red blood cell survival is modestly decreased. “Exogenous iron and/or exogenous erythropoietin do not fully resolve the anemia,” she said.

Although iron is essential for oxygen transport and other vital functions, it also generates free radicals that can lead to oxidative damage, manifesting in conditions such as atherosclerosis, diabetes, or cancer.

But humans can't eliminate excess iron. Therefore, uptake from the gastrointestinal tract is tightly regulated and efficiently recycled. “No matter how much you give orally, there's only a limited amount the body can pick up,” Dr. Bathon explained.

Recently, a small peptide hormone called hepcidin was identified as the principal regulator of systemic iron homeostasis. Synthesized in the liver, hepcidin inhibits the intestinal absorption of iron and suppresses release of iron from macrophage and hepatocyte stores.

Measurement of hepcidin levels is now being investigated as a possible diagnostic tool for various iron disorders. In one study, a novel urine hepcidin assay using mass spectrometry was able to discriminate among patients with secondary iron overload, iron-deficient anemia, and hereditary hemochromatosis (Blood 2005;106:3268–70).

Hepcidin production would be expected to be increased in RA patients, but that hasn't been studied, Dr. Bathon said.

Other data suggest that interleukin-6—but not interleukin-1 (IL-1) or tumor necrosis factor-α (TNF-α)—promotes anemia of inflammation by synthesizing hepcidin (J. Clin. Invest. 2004;113:1271–6), and some investigators have suggested that an antibody directed against IL-6 might therefore offer potential treatment for inflammation-induced anemia (Ann. Rheum. Dis. 2000;59 [Suppl. 1]:i21–7).

But, even though TNF-α and IL-1 don't induce hepcidin in some models, it's not clear whether the process is entirely mediated by IL-6.

In fact, treatment of RA patients with TNF-α blockers often does improve their anemia. It's not yet clear which treatment would be a better method—inhibition of IL-6 or TNF—for resolving anemia inflammation, Dr. Bathon said.

The role of erythropoietin for treating anemia of inflammation is also currently unclear. Although the response to exogenous erythropoietin tends to be blunted in RA patients in proportion to the severity of their inflammation, data from a few small studies do suggest that the treatment may nonetheless be beneficial by lessening their anemia.

One such study, involving 17 patients who received a total 32 weeks of treatment, showed an overall excellent hematologic response without toxicity but with no meaningful change in rheumatologic clinical status (Am. J. Med. 1990;89:161–8).

More recently, 30 patients with RA and anemia were treated with 150 IU/kg recombinant human erythropoietin twice weekly for 12 weeks, along with 200 mg of intravenous iron sucrose per week in the 23 patients who developed functional iron deficiency.

Average hemoglobin increased from 10.7 to 13.2 g/dL after a mean treatment period of 8 weeks. With recombinant human erythrpoietin treatment, patients also experienced increased muscle strength, decreased fatigue, fewer swollen or tender joints, and other improvements in disease activity variables (J. Rheumatol. 2001;28:2430–6).

But, Dr. Bathon said in an interview with RHEUMATOLOGY NEWS, erythropoietin “hasn't been studied enough to provide guidelines for its use, except perhaps prior to surgery where a lot of bleeding is anticipated.”

Moreover, “it's kind of fallen by the wayside,” in large part because “treatment of RA largely resolves the anemia.”

Indeed, it may simply be that addressing the cause of the underlying inflammation—in RA, infections, or other chronic conditions—will correct its accompanying anemia as well.

BALTIMORE — A new understanding of the “anemia of inflammation” may help point the way to new treatments in the future, but in the meantime it illustrates why iron supplementation does not raise hemoglobin levels in patients with rheumatoid arthritis and other inflammatory diseases, Dr. Joan Bathon said at a conference on rheumatic diseases sponsored by the Johns Hopkins University.

Formerly known as “anemia of chronic diseases” because it is commonly seen in inflammatory diseases such as rheumatoid arthritis (RA) as well as in chronic infections and some cancers, the condition is now known by the term “anemia of inflammation,” which better reflects its etiology. It is not the result of bleeding, hemolysis, nutritional deficit (vitamin B₁₂, folate, iron), or a marrow disorder, said Dr. Bathon, professor of medicine at Johns Hopkins, Baltimore.

Lacking an understanding of the underlying etiology, health care providers will often give these patients iron supplementation. However, “we know that iron treatment does not really alleviate this anemia,” she said.

Anemia is extremely common among RA patients. In a study comparing 2,120 consecutive RA patients (contributing 26,221 hemoglobin determinations) with 3,843 patients who had noninflammatory rheumatic disorders (7,251 hemoglobin determinations) seen between 1974 and 2004 in a clinical practice setting, the prevalence of chronic anemia was 35.3% when a hemoglobin cutoff of less than 12 g/dL was used.

Hemoglobin levels were consistently lower among the RA patients than among those with noninflammatory conditions, by a mean of 0.8 g/dL.

Those data, reported at the 2005 American College of Rheumatology meeting by Dr. Frederick Wolfe of the National Data Bank for Rheumatic Diseases, Wichita, Kan., suggest that “more than one-third of patients with RA are anemic, if you use a broad definition,” according to Dr. Bathon.

That study also found that among the RA patients, lower hemoglobin was associated with high disease activity; C-reactive protein levels were strongly predictive of anemia; and quality of life was reduced by 5.5% among the patients with anemia after adjustment for age and gender.

In general, patients with anemia of inflammation have decreased total circulating iron levels and binding capacity, yet their total body iron (ferritin) stores are increased.

At the same time, erythropoietin production is blunted, as is the response to endogenous erythropoietin. Red blood cell survival is modestly decreased. “Exogenous iron and/or exogenous erythropoietin do not fully resolve the anemia,” she said.

Although iron is essential for oxygen transport and other vital functions, it also generates free radicals that can lead to oxidative damage, manifesting in conditions such as atherosclerosis, diabetes, or cancer.

But humans can't eliminate excess iron. Therefore, uptake from the gastrointestinal tract is tightly regulated and efficiently recycled. “No matter how much you give orally, there's only a limited amount the body can pick up,” Dr. Bathon explained.

Recently, a small peptide hormone called hepcidin was identified as the principal regulator of systemic iron homeostasis. Synthesized in the liver, hepcidin inhibits the intestinal absorption of iron and suppresses release of iron from macrophage and hepatocyte stores.

Measurement of hepcidin levels is now being investigated as a possible diagnostic tool for various iron disorders. In one study, a novel urine hepcidin assay using mass spectrometry was able to discriminate among patients with secondary iron overload, iron-deficient anemia, and hereditary hemochromatosis (Blood 2005;106:3268–70).

Hepcidin production would be expected to be increased in RA patients, but that hasn't been studied, Dr. Bathon said.

Other data suggest that interleukin-6—but not interleukin-1 (IL-1) or tumor necrosis factor-α (TNF-α)—promotes anemia of inflammation by synthesizing hepcidin (J. Clin. Invest. 2004;113:1271–6), and some investigators have suggested that an antibody directed against IL-6 might therefore offer potential treatment for inflammation-induced anemia (Ann. Rheum. Dis. 2000;59 [Suppl. 1]:i21–7).

But, even though TNF-α and IL-1 don't induce hepcidin in some models, it's not clear whether the process is entirely mediated by IL-6.

In fact, treatment of RA patients with TNF-α blockers often does improve their anemia. It's not yet clear which treatment would be a better method—inhibition of IL-6 or TNF—for resolving anemia inflammation, Dr. Bathon said.

The role of erythropoietin for treating anemia of inflammation is also currently unclear. Although the response to exogenous erythropoietin tends to be blunted in RA patients in proportion to the severity of their inflammation, data from a few small studies do suggest that the treatment may nonetheless be beneficial by lessening their anemia.

One such study, involving 17 patients who received a total 32 weeks of treatment, showed an overall excellent hematologic response without toxicity but with no meaningful change in rheumatologic clinical status (Am. J. Med. 1990;89:161–8).

More recently, 30 patients with RA and anemia were treated with 150 IU/kg recombinant human erythropoietin twice weekly for 12 weeks, along with 200 mg of intravenous iron sucrose per week in the 23 patients who developed functional iron deficiency.

Average hemoglobin increased from 10.7 to 13.2 g/dL after a mean treatment period of 8 weeks. With recombinant human erythrpoietin treatment, patients also experienced increased muscle strength, decreased fatigue, fewer swollen or tender joints, and other improvements in disease activity variables (J. Rheumatol. 2001;28:2430–6).

But, Dr. Bathon said in an interview with RHEUMATOLOGY NEWS, erythropoietin “hasn't been studied enough to provide guidelines for its use, except perhaps prior to surgery where a lot of bleeding is anticipated.”

Moreover, “it's kind of fallen by the wayside,” in large part because “treatment of RA largely resolves the anemia.”

Indeed, it may simply be that addressing the cause of the underlying inflammation—in RA, infections, or other chronic conditions—will correct its accompanying anemia as well.