Nancy Walsh

NEW YORK — Data from large registries ultimately should provide answers about the long-term lymphoma risk associated with the tumor necrosis factor-blocking drugs, but for now, questions and contradictions remain.

Patients with rheumatoid arthritis (RA) have an elevated risk of lymphoma that has been estimated to be between two- and eightfold. How much of the risk relates to disease activity and how much relates to immunosuppressive treatment is not yet clear, Dr. Jeffrey Greenberg said in reviewing recent studies during a rheumatology meeting sponsored by New York University.

Helpful background evidence on the overall risk of lymphoma has emerged from a large Swedish registry that included 74,651 patients who received a diagnosis of RA between 1964 and 1995. Within this cohort, there were 378 cases of lymphoma; these patients were matched with 378 controls from the cohort who were cancer free when the lymphoma patients were diagnosed.

The cases were then analyzed for factors that might influence the development of lymphoma. The investigators also sought to determine whether RA-associated malignancy is disease- and inflammation-driven and could be associated with inadequate immunosuppres- sion, or whether it results directly from immunosuppression.

Level of disease activity strongly predicted risk in this study. Medium overall disease activity was associated with an 8-fold increase in lymphoma risk, while high disease activity was linked to a 70-fold increase. There also was a threefold increase in risk among patients with the highest erythrocyte sedimentation rates (Arthritis Rheum. 2006;54:692–701).

The investigators reported that having ever been treated with a traditional disease-modifying antirheumatic drug (DMARD) was not associated with an increased risk. Although increases in risk were seen with some individual drugs such as azathioprine, other drugs such as corticosteroids were associated with relative risk estimates of less than 1, reflecting a reduction in risk. Immunostimulation is the driving force in inflammation-associated lymphomas.

In a separate study, a different group of Swedish investigators looked at the risk of hematopoietic malignancies among RA patients being treated with TNF antagonists. The lymphoma risk was tripled in those being treated with these drugs compared with the general population, but the risk was no different from that in other RA patients (Ann. Rheum. Dis. 2005;64:1414–20).

Overall, in clinical trials thus far, the standardized incidence ratios for lymphoma for etanercept, infliximab, and adalimumab are 3.5, 7.0, and 5.5, respectively, said Dr. Greenberg, director of the Arthritis Translational Registry and Biorepository, New York University, New York. Those numbers do not account for background RA-related lymphoma risk, however, and therefore do not include the risk associated with treatment.

It's important to keep in mind that clinical trials are short in duration and are not powered to detect rare events such as malignancies, Dr. Greenberg said. To overcome this lack of power, another group of researchers undertook a meta-analysis of nine randomized trials of patients undergoing anti-TNF therapy, with 3,493 receiving active treatment and 1,512 receiving placebo. In this analysis, the pooled odds ratio for malignancy was 3.3, a finding that was “somewhat inconsistent” with the results seen in the Swedish studies (JAMA 2006;295:2275–85).

The meta-analysis had limitations, according to Dr. Greenberg. For example, it included only studies with infliximab and adalimumab; etanercept was omitted. The study also did not account for length of time on the drug. “They simply counted the number of people exposed to the drug versus placebo,” he said. This was in contrast to the method the Food and Drug Administration used in its analysis of the safety of all three TNF blockers, which found no elevations in malignancy rates in patients on these drugs (JAMA 2006;296:2201–2).

As to the method of analyzing drug exposure and risk, “There's an argument to be made on either side—it's not black and white—but the results of the meta-analysis have to be taken with a grain of salt,” Dr. Greenberg said.

The opposite approach, of analyzing risk according to time of exposure, had quite different results in another recent report. In an abstract presented at the 2006 meeting of the European League Against Rheumatism, a total of 124 lymphomas were seen during 109,884 patient-years of follow-up.

There were 79 observed cases of lymphoma, compared with 45 expected cases, giving a standardized incidence rate of 1.8, which does not differ from background risk in RA.

There also were no statistically significant increases in risk associated with any specific treatments, including DMARDs and biologics (Ann. Rheum. Dis. 2006;65[suppl. 2]:512–3).

So with regard to the effects of biologic treatment on lymphoma risk, there are still more questions than answers, Dr. Greenberg said. The way risk is determined also needs to change. “As we move toward personalized medicine, we need to move from population-based risk estimates, where we tell a patient, 'You have a 1.5-fold risk of developing a malignancy in the next 10 years,' to a position where we can say, 'Based on your genetic profile, you have a 10-fold risk of malignancy but an extremely high likelihood of benefiting from this drug.' Then we can balance risk and benefit on a personal level rather than relying on overall population-based estimates,” Dr. Greenberg said.

NEW YORK — Data from large registries ultimately should provide answers about the long-term lymphoma risk associated with the tumor necrosis factor-blocking drugs, but for now, questions and contradictions remain.

Patients with rheumatoid arthritis (RA) have an elevated risk of lymphoma that has been estimated to be between two- and eightfold. How much of the risk relates to disease activity and how much relates to immunosuppressive treatment is not yet clear, Dr. Jeffrey Greenberg said in reviewing recent studies during a rheumatology meeting sponsored by New York University.

Helpful background evidence on the overall risk of lymphoma has emerged from a large Swedish registry that included 74,651 patients who received a diagnosis of RA between 1964 and 1995. Within this cohort, there were 378 cases of lymphoma; these patients were matched with 378 controls from the cohort who were cancer free when the lymphoma patients were diagnosed.

The cases were then analyzed for factors that might influence the development of lymphoma. The investigators also sought to determine whether RA-associated malignancy is disease- and inflammation-driven and could be associated with inadequate immunosuppres- sion, or whether it results directly from immunosuppression.

Level of disease activity strongly predicted risk in this study. Medium overall disease activity was associated with an 8-fold increase in lymphoma risk, while high disease activity was linked to a 70-fold increase. There also was a threefold increase in risk among patients with the highest erythrocyte sedimentation rates (Arthritis Rheum. 2006;54:692–701).

The investigators reported that having ever been treated with a traditional disease-modifying antirheumatic drug (DMARD) was not associated with an increased risk. Although increases in risk were seen with some individual drugs such as azathioprine, other drugs such as corticosteroids were associated with relative risk estimates of less than 1, reflecting a reduction in risk. Immunostimulation is the driving force in inflammation-associated lymphomas.

In a separate study, a different group of Swedish investigators looked at the risk of hematopoietic malignancies among RA patients being treated with TNF antagonists. The lymphoma risk was tripled in those being treated with these drugs compared with the general population, but the risk was no different from that in other RA patients (Ann. Rheum. Dis. 2005;64:1414–20).

Overall, in clinical trials thus far, the standardized incidence ratios for lymphoma for etanercept, infliximab, and adalimumab are 3.5, 7.0, and 5.5, respectively, said Dr. Greenberg, director of the Arthritis Translational Registry and Biorepository, New York University, New York. Those numbers do not account for background RA-related lymphoma risk, however, and therefore do not include the risk associated with treatment.

It's important to keep in mind that clinical trials are short in duration and are not powered to detect rare events such as malignancies, Dr. Greenberg said. To overcome this lack of power, another group of researchers undertook a meta-analysis of nine randomized trials of patients undergoing anti-TNF therapy, with 3,493 receiving active treatment and 1,512 receiving placebo. In this analysis, the pooled odds ratio for malignancy was 3.3, a finding that was “somewhat inconsistent” with the results seen in the Swedish studies (JAMA 2006;295:2275–85).

The meta-analysis had limitations, according to Dr. Greenberg. For example, it included only studies with infliximab and adalimumab; etanercept was omitted. The study also did not account for length of time on the drug. “They simply counted the number of people exposed to the drug versus placebo,” he said. This was in contrast to the method the Food and Drug Administration used in its analysis of the safety of all three TNF blockers, which found no elevations in malignancy rates in patients on these drugs (JAMA 2006;296:2201–2).

As to the method of analyzing drug exposure and risk, “There's an argument to be made on either side—it's not black and white—but the results of the meta-analysis have to be taken with a grain of salt,” Dr. Greenberg said.

The opposite approach, of analyzing risk according to time of exposure, had quite different results in another recent report. In an abstract presented at the 2006 meeting of the European League Against Rheumatism, a total of 124 lymphomas were seen during 109,884 patient-years of follow-up.

There were 79 observed cases of lymphoma, compared with 45 expected cases, giving a standardized incidence rate of 1.8, which does not differ from background risk in RA.

There also were no statistically significant increases in risk associated with any specific treatments, including DMARDs and biologics (Ann. Rheum. Dis. 2006;65[suppl. 2]:512–3).

So with regard to the effects of biologic treatment on lymphoma risk, there are still more questions than answers, Dr. Greenberg said. The way risk is determined also needs to change. “As we move toward personalized medicine, we need to move from population-based risk estimates, where we tell a patient, 'You have a 1.5-fold risk of developing a malignancy in the next 10 years,' to a position where we can say, 'Based on your genetic profile, you have a 10-fold risk of malignancy but an extremely high likelihood of benefiting from this drug.' Then we can balance risk and benefit on a personal level rather than relying on overall population-based estimates,” Dr. Greenberg said.

NEW YORK — Data from large registries ultimately should provide answers about the long-term lymphoma risk associated with the tumor necrosis factor-blocking drugs, but for now, questions and contradictions remain.

Patients with rheumatoid arthritis (RA) have an elevated risk of lymphoma that has been estimated to be between two- and eightfold. How much of the risk relates to disease activity and how much relates to immunosuppressive treatment is not yet clear, Dr. Jeffrey Greenberg said in reviewing recent studies during a rheumatology meeting sponsored by New York University.

Helpful background evidence on the overall risk of lymphoma has emerged from a large Swedish registry that included 74,651 patients who received a diagnosis of RA between 1964 and 1995. Within this cohort, there were 378 cases of lymphoma; these patients were matched with 378 controls from the cohort who were cancer free when the lymphoma patients were diagnosed.

The cases were then analyzed for factors that might influence the development of lymphoma. The investigators also sought to determine whether RA-associated malignancy is disease- and inflammation-driven and could be associated with inadequate immunosuppres- sion, or whether it results directly from immunosuppression.

Level of disease activity strongly predicted risk in this study. Medium overall disease activity was associated with an 8-fold increase in lymphoma risk, while high disease activity was linked to a 70-fold increase. There also was a threefold increase in risk among patients with the highest erythrocyte sedimentation rates (Arthritis Rheum. 2006;54:692–701).

The investigators reported that having ever been treated with a traditional disease-modifying antirheumatic drug (DMARD) was not associated with an increased risk. Although increases in risk were seen with some individual drugs such as azathioprine, other drugs such as corticosteroids were associated with relative risk estimates of less than 1, reflecting a reduction in risk. Immunostimulation is the driving force in inflammation-associated lymphomas.

In a separate study, a different group of Swedish investigators looked at the risk of hematopoietic malignancies among RA patients being treated with TNF antagonists. The lymphoma risk was tripled in those being treated with these drugs compared with the general population, but the risk was no different from that in other RA patients (Ann. Rheum. Dis. 2005;64:1414–20).

Overall, in clinical trials thus far, the standardized incidence ratios for lymphoma for etanercept, infliximab, and adalimumab are 3.5, 7.0, and 5.5, respectively, said Dr. Greenberg, director of the Arthritis Translational Registry and Biorepository, New York University, New York. Those numbers do not account for background RA-related lymphoma risk, however, and therefore do not include the risk associated with treatment.

It's important to keep in mind that clinical trials are short in duration and are not powered to detect rare events such as malignancies, Dr. Greenberg said. To overcome this lack of power, another group of researchers undertook a meta-analysis of nine randomized trials of patients undergoing anti-TNF therapy, with 3,493 receiving active treatment and 1,512 receiving placebo. In this analysis, the pooled odds ratio for malignancy was 3.3, a finding that was “somewhat inconsistent” with the results seen in the Swedish studies (JAMA 2006;295:2275–85).

The meta-analysis had limitations, according to Dr. Greenberg. For example, it included only studies with infliximab and adalimumab; etanercept was omitted. The study also did not account for length of time on the drug. “They simply counted the number of people exposed to the drug versus placebo,” he said. This was in contrast to the method the Food and Drug Administration used in its analysis of the safety of all three TNF blockers, which found no elevations in malignancy rates in patients on these drugs (JAMA 2006;296:2201–2).

As to the method of analyzing drug exposure and risk, “There's an argument to be made on either side—it's not black and white—but the results of the meta-analysis have to be taken with a grain of salt,” Dr. Greenberg said.

The opposite approach, of analyzing risk according to time of exposure, had quite different results in another recent report. In an abstract presented at the 2006 meeting of the European League Against Rheumatism, a total of 124 lymphomas were seen during 109,884 patient-years of follow-up.

There were 79 observed cases of lymphoma, compared with 45 expected cases, giving a standardized incidence rate of 1.8, which does not differ from background risk in RA.

There also were no statistically significant increases in risk associated with any specific treatments, including DMARDs and biologics (Ann. Rheum. Dis. 2006;65[suppl. 2]:512–3).

So with regard to the effects of biologic treatment on lymphoma risk, there are still more questions than answers, Dr. Greenberg said. The way risk is determined also needs to change. “As we move toward personalized medicine, we need to move from population-based risk estimates, where we tell a patient, 'You have a 1.5-fold risk of developing a malignancy in the next 10 years,' to a position where we can say, 'Based on your genetic profile, you have a 10-fold risk of malignancy but an extremely high likelihood of benefiting from this drug.' Then we can balance risk and benefit on a personal level rather than relying on overall population-based estimates,” Dr. Greenberg said.

NEW YORK — Combined elevations in two traditional markers—the sensitive complement protein C3a and antibodies to double-stranded DNA—can be used to predict severe disease flares in systemic lupus erythematosus and to guide implementation of preemptive treatment, Dr. H. Michael Belmont said at a rheumatology meeting sponsored by New York University.

These markers are useful in the diagnosis of systemic lupus erythematosus (SLE), and are routinely used to track disease activity and predict flares, but whether serial measurements could be used to follow clinically quiescent disease and serve as a basis for therapeutic decision making has remained controversial.

In an earlier study, asymptomatic patients with rising titers of anti-double-stranded DNA (anti-dsDNA) who were treated with prednisone had fewer severe flares and required less immunosuppressive therapy, but the difference compared with placebo did not reach statistical significance (Lancet 1995;345:1595–9).

“We therefore embarked on the serologically active, clinically stable lupus trial, with the intent of evaluating the effect of short-term, moderate-dose corticosteroid treatment in preventing or averting flares when there was a simultaneous elevation of both plasma C3a and anti-dsDNA in patients whose disease was stable or inactive,” said Dr. Belmont, director of the lupus clinic, at Bellevue Hospital and codirector of the lupus clinic at the Hospital for Joint Diseases, both in New York.

A total of 154 patients were enrolled into the 18-month observational phase of the trial. To be eligible, patients were required to have a history of anti-dsDNA positivity and to be receiving no more than 15 mg/day of prednisone. Inactive disease was defined as a Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) of 4 or less; and stable disease was defined as a SLEDAI of 5–12.

At monthly visits, levels of various complement proteins and anti-dsDNA antibodies were measured, and clinical disease activity was evaluated according to the Safety of Estrogens in Lupus Erythematosus: National Assessment (SELENA) version of SLEDAI and by physician's global assessment.

Serologic flare was defined as an elevation of anti-dsDNA antibodies of 25% or more, combined with an elevation in C3a levels by 50% to an absolute level of 500 ng/mL or more.

Patients who remained clinically stable but who experienced a serologic flare were then randomized to receive placebo or daily doses of 30 mg prednisone more than their baseline doses for 2 weeks. This was then tapered to 20 mg more than the baseline dose for another week and to 10 mg more than baseline for an additional week.

“The hypothesis was that we would find fewer severe flares with preemptive treatment with prednisone than with placebo,” Dr. Belmont said.

A total of 41 patients were randomized, 20 to placebo and 21 to prednisone. Randomization was successful in that patients in the active treatment and placebo groups were comparable in all clinically important ways, he said.

The major finding of the study was that none of the patients in the prednisone group experienced severe flares, while six patients in the placebo group had severe flares, said Dr. Belmont. The benefit for having received steroids was statistically significant, he said.

Three of the severe flares involved nephritis, one was neuropsychiatric lupus, one involved pyoderma gangrenosum with pancytopenia, and one was fever and lupus pneumonitis.

Six patients, four of whom were in the prednisone group, had mild to moderate flares. Most of these were characterized by arthritis and required no additional treatment.

Benefits over and above preventing severe flare, including improvements in SLEDAI scores, also were seen in the prednisone group (Arthritis Rheum. 2006;54:3623–32). This study also questioned the price patients would pay in terms of adverse events for receiving the preemptive treatment of 30 mg prednisone more than baseline for 2 weeks.

“It was reassuring, in that side effects that could be associated with having increased steroids were no greater than in the placebo group,” Dr. Belmont said.

The most common adverse events were upper respiratory tract infections, which were seen in three patients in the prednisone group and in six in the placebo group, and urinary tract infections, which were seen in three patients in the prednisone group and in two in the placebo group.

The preemptive treatment strategy using moderate-dose steroids did not result in an overall increased corticosteroid exposure in the treated group, compared with the placebo group, because the patients on placebo who experienced severe flares required high doses of prednisone. Two also needed the addition of cytotoxic agents. “This was important information,” Dr. Belmont said.

“Using this study design as a guide, consideration should now be given to the preemptive use of short-term, moderate doses of corticosteroids in clinically stable, serologically active SLE patients to prevent severe flares and prolonged exposure to high-dose corticosteroids,” he concluded.

NEW YORK — Combined elevations in two traditional markers—the sensitive complement protein C3a and antibodies to double-stranded DNA—can be used to predict severe disease flares in systemic lupus erythematosus and to guide implementation of preemptive treatment, Dr. H. Michael Belmont said at a rheumatology meeting sponsored by New York University.

These markers are useful in the diagnosis of systemic lupus erythematosus (SLE), and are routinely used to track disease activity and predict flares, but whether serial measurements could be used to follow clinically quiescent disease and serve as a basis for therapeutic decision making has remained controversial.

In an earlier study, asymptomatic patients with rising titers of anti-double-stranded DNA (anti-dsDNA) who were treated with prednisone had fewer severe flares and required less immunosuppressive therapy, but the difference compared with placebo did not reach statistical significance (Lancet 1995;345:1595–9).

“We therefore embarked on the serologically active, clinically stable lupus trial, with the intent of evaluating the effect of short-term, moderate-dose corticosteroid treatment in preventing or averting flares when there was a simultaneous elevation of both plasma C3a and anti-dsDNA in patients whose disease was stable or inactive,” said Dr. Belmont, director of the lupus clinic, at Bellevue Hospital and codirector of the lupus clinic at the Hospital for Joint Diseases, both in New York.

A total of 154 patients were enrolled into the 18-month observational phase of the trial. To be eligible, patients were required to have a history of anti-dsDNA positivity and to be receiving no more than 15 mg/day of prednisone. Inactive disease was defined as a Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) of 4 or less; and stable disease was defined as a SLEDAI of 5–12.

At monthly visits, levels of various complement proteins and anti-dsDNA antibodies were measured, and clinical disease activity was evaluated according to the Safety of Estrogens in Lupus Erythematosus: National Assessment (SELENA) version of SLEDAI and by physician's global assessment.

Serologic flare was defined as an elevation of anti-dsDNA antibodies of 25% or more, combined with an elevation in C3a levels by 50% to an absolute level of 500 ng/mL or more.

Patients who remained clinically stable but who experienced a serologic flare were then randomized to receive placebo or daily doses of 30 mg prednisone more than their baseline doses for 2 weeks. This was then tapered to 20 mg more than the baseline dose for another week and to 10 mg more than baseline for an additional week.

“The hypothesis was that we would find fewer severe flares with preemptive treatment with prednisone than with placebo,” Dr. Belmont said.

A total of 41 patients were randomized, 20 to placebo and 21 to prednisone. Randomization was successful in that patients in the active treatment and placebo groups were comparable in all clinically important ways, he said.

The major finding of the study was that none of the patients in the prednisone group experienced severe flares, while six patients in the placebo group had severe flares, said Dr. Belmont. The benefit for having received steroids was statistically significant, he said.

Three of the severe flares involved nephritis, one was neuropsychiatric lupus, one involved pyoderma gangrenosum with pancytopenia, and one was fever and lupus pneumonitis.

Six patients, four of whom were in the prednisone group, had mild to moderate flares. Most of these were characterized by arthritis and required no additional treatment.

Benefits over and above preventing severe flare, including improvements in SLEDAI scores, also were seen in the prednisone group (Arthritis Rheum. 2006;54:3623–32). This study also questioned the price patients would pay in terms of adverse events for receiving the preemptive treatment of 30 mg prednisone more than baseline for 2 weeks.

“It was reassuring, in that side effects that could be associated with having increased steroids were no greater than in the placebo group,” Dr. Belmont said.

The most common adverse events were upper respiratory tract infections, which were seen in three patients in the prednisone group and in six in the placebo group, and urinary tract infections, which were seen in three patients in the prednisone group and in two in the placebo group.

The preemptive treatment strategy using moderate-dose steroids did not result in an overall increased corticosteroid exposure in the treated group, compared with the placebo group, because the patients on placebo who experienced severe flares required high doses of prednisone. Two also needed the addition of cytotoxic agents. “This was important information,” Dr. Belmont said.

“Using this study design as a guide, consideration should now be given to the preemptive use of short-term, moderate doses of corticosteroids in clinically stable, serologically active SLE patients to prevent severe flares and prolonged exposure to high-dose corticosteroids,” he concluded.

NEW YORK — Combined elevations in two traditional markers—the sensitive complement protein C3a and antibodies to double-stranded DNA—can be used to predict severe disease flares in systemic lupus erythematosus and to guide implementation of preemptive treatment, Dr. H. Michael Belmont said at a rheumatology meeting sponsored by New York University.

These markers are useful in the diagnosis of systemic lupus erythematosus (SLE), and are routinely used to track disease activity and predict flares, but whether serial measurements could be used to follow clinically quiescent disease and serve as a basis for therapeutic decision making has remained controversial.

In an earlier study, asymptomatic patients with rising titers of anti-double-stranded DNA (anti-dsDNA) who were treated with prednisone had fewer severe flares and required less immunosuppressive therapy, but the difference compared with placebo did not reach statistical significance (Lancet 1995;345:1595–9).

“We therefore embarked on the serologically active, clinically stable lupus trial, with the intent of evaluating the effect of short-term, moderate-dose corticosteroid treatment in preventing or averting flares when there was a simultaneous elevation of both plasma C3a and anti-dsDNA in patients whose disease was stable or inactive,” said Dr. Belmont, director of the lupus clinic, at Bellevue Hospital and codirector of the lupus clinic at the Hospital for Joint Diseases, both in New York.

A total of 154 patients were enrolled into the 18-month observational phase of the trial. To be eligible, patients were required to have a history of anti-dsDNA positivity and to be receiving no more than 15 mg/day of prednisone. Inactive disease was defined as a Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) of 4 or less; and stable disease was defined as a SLEDAI of 5–12.

At monthly visits, levels of various complement proteins and anti-dsDNA antibodies were measured, and clinical disease activity was evaluated according to the Safety of Estrogens in Lupus Erythematosus: National Assessment (SELENA) version of SLEDAI and by physician's global assessment.

Serologic flare was defined as an elevation of anti-dsDNA antibodies of 25% or more, combined with an elevation in C3a levels by 50% to an absolute level of 500 ng/mL or more.

Patients who remained clinically stable but who experienced a serologic flare were then randomized to receive placebo or daily doses of 30 mg prednisone more than their baseline doses for 2 weeks. This was then tapered to 20 mg more than the baseline dose for another week and to 10 mg more than baseline for an additional week.

“The hypothesis was that we would find fewer severe flares with preemptive treatment with prednisone than with placebo,” Dr. Belmont said.

A total of 41 patients were randomized, 20 to placebo and 21 to prednisone. Randomization was successful in that patients in the active treatment and placebo groups were comparable in all clinically important ways, he said.

The major finding of the study was that none of the patients in the prednisone group experienced severe flares, while six patients in the placebo group had severe flares, said Dr. Belmont. The benefit for having received steroids was statistically significant, he said.

Three of the severe flares involved nephritis, one was neuropsychiatric lupus, one involved pyoderma gangrenosum with pancytopenia, and one was fever and lupus pneumonitis.

Six patients, four of whom were in the prednisone group, had mild to moderate flares. Most of these were characterized by arthritis and required no additional treatment.

Benefits over and above preventing severe flare, including improvements in SLEDAI scores, also were seen in the prednisone group (Arthritis Rheum. 2006;54:3623–32). This study also questioned the price patients would pay in terms of adverse events for receiving the preemptive treatment of 30 mg prednisone more than baseline for 2 weeks.

“It was reassuring, in that side effects that could be associated with having increased steroids were no greater than in the placebo group,” Dr. Belmont said.

The most common adverse events were upper respiratory tract infections, which were seen in three patients in the prednisone group and in six in the placebo group, and urinary tract infections, which were seen in three patients in the prednisone group and in two in the placebo group.

The preemptive treatment strategy using moderate-dose steroids did not result in an overall increased corticosteroid exposure in the treated group, compared with the placebo group, because the patients on placebo who experienced severe flares required high doses of prednisone. Two also needed the addition of cytotoxic agents. “This was important information,” Dr. Belmont said.

“Using this study design as a guide, consideration should now be given to the preemptive use of short-term, moderate doses of corticosteroids in clinically stable, serologically active SLE patients to prevent severe flares and prolonged exposure to high-dose corticosteroids,” he concluded.

Staining for adiponectin in a kidney biopsy from a patient with class IV SLE nephritis shows injury. Dr. Brad H. Rovin

NEW YORK — Monitoring the urinary excretion of monocyte chemoattractant protein-1 and adiponectin may prove to be a novel and specific means of evaluating renal activity and injury in patients with systemic lupus erythematosus, according to Dr. Brad H. Rovin.

There is substantial evidence suggesting that the proinflammatory chemokine monocyte chemoattractant protein-1 (MCP-1) is involved in the pathogenesis of renal injury in nephritis associated with systemic lupus erythematosus (SLE). “The main function of inflammatory chemokines is to regulate the deployment of leukocytes to tissue sites undergoing pathological change. These chemokines also activate leukocytes and may promote tissue fibrosis,” Dr. Rovin said at a rheumatology meeting sponsored by New York University.

The relationship of MCP-1 with lupus nephritis has now been investigated in patients enrolled during the past 5 years in the longitudinal Ohio SLE Study. The cohort includes 71 patients with lupus nephritis and 35 patients with SLE but with no evidence of renal involvement.

With a mean follow-up time of approximately 32 months, there have been 70 renal flares and 88 nonrenal flares in the patients.

Urinalysis performed every 2 months found that the mean level of MCP-1 of patients at renal flare was significantly higher than that of any of controls, with 73% of flare values being above the 95th percentile of those of disease control patients (J. Am. Soc. Nephrol. 2005;16:467–73). Patients with class IV glomerulonephritis, with crescents and necrosis, had the highest levels of MCP-1, which reached 12,000 pg/mg creatinine.

High levels of MCP-1 during flare also were associated with manifestations of renal injury including changes in serum creatinine levels and proteinuria.

Among patients with impaired renal function whose serum creatinine was elevated at 1.2–5.5 mg/dL, the mean MCP-1 was significantly higher, at 2,719 pg/mg creatinine, than in those with normal renal function, who had a mean level of 846 pg/mg creatinine.

At the time of flare, most patients had been receiving immunosuppressive therapy with prednisone and agents such as mycophenolate mofetil, and even such substantial therapy was inadequate to suppress MCP-1. “This shows that the current therapies we have to treat lupus nephritis do not adequately suppress the expression of this particular chemokine,” said Dr. Rovin, professor and director of the division of nephrology, Ohio State University, Columbus.

Response to increased immunosuppressive treatment following flare also correlated with MCP-1. In the majority of patients, MCP-1 decreased with treatment, although only gradually, but in a subset, MCP-1 remained persistently elevated. “We wonder if this is a biomarker for ongoing inflammatory injury in the kidney, and if these patients might benefit from prolonged therapy. We don't know the answer to that,” he said.

These findings suggest that monitoring this cytokine might be a novel way of monitoring disease activity and response to treatment, he said. And because MCP-1 appears not to be simply a biomarker but actually is involved in organ injury, therapies directed at the cytokine itself may be beneficial and are being investigated.

A proteomic approach also has identified the adipocyte-derived cytokine adiponectin as another “totally unexpected” marker of lupus nephritis, he said.

Adiponectin, which is also produced by other cells such as fibroblasts and synovial cells during periods of inflammation, originally was studied in metabolic disorders and was found to enhance insulin sensitivity and to be underexpressed in obesity and diabetes.

It has now been shown to modulate inflammation, with both anti-inflammatory and proinflammatory effects. Its proinflammatory effects include the activation of the transcription factor NF-κ B (NF-KB) and increasing the production of MCP-1 and interleukin-8 by endothelial cells and blood monocytes (Clin. Immunol. 2006;120:99–105).

Recent work has found that both adiponectin and its receptor are expressed in the kidney, suggesting the possibility that this cytokine also has a direct, but as yet unspecified, effect on renal cell function, Dr. Rovin said.

As is the case with MCP-1, levels of adiponectin in the urine are increased during renal flare but not during nonrenal flare, correlating with plasma levels and magnitude of proteinuria (Kidney Int. 2005;64:1825–33).

Staining for adiponectin in a kidney biopsy from a patient with class IV SLE nephritis shows injury. Dr. Brad H. Rovin

NEW YORK — Monitoring the urinary excretion of monocyte chemoattractant protein-1 and adiponectin may prove to be a novel and specific means of evaluating renal activity and injury in patients with systemic lupus erythematosus, according to Dr. Brad H. Rovin.

There is substantial evidence suggesting that the proinflammatory chemokine monocyte chemoattractant protein-1 (MCP-1) is involved in the pathogenesis of renal injury in nephritis associated with systemic lupus erythematosus (SLE). “The main function of inflammatory chemokines is to regulate the deployment of leukocytes to tissue sites undergoing pathological change. These chemokines also activate leukocytes and may promote tissue fibrosis,” Dr. Rovin said at a rheumatology meeting sponsored by New York University.

The relationship of MCP-1 with lupus nephritis has now been investigated in patients enrolled during the past 5 years in the longitudinal Ohio SLE Study. The cohort includes 71 patients with lupus nephritis and 35 patients with SLE but with no evidence of renal involvement.

With a mean follow-up time of approximately 32 months, there have been 70 renal flares and 88 nonrenal flares in the patients.

Urinalysis performed every 2 months found that the mean level of MCP-1 of patients at renal flare was significantly higher than that of any of controls, with 73% of flare values being above the 95th percentile of those of disease control patients (J. Am. Soc. Nephrol. 2005;16:467–73). Patients with class IV glomerulonephritis, with crescents and necrosis, had the highest levels of MCP-1, which reached 12,000 pg/mg creatinine.

High levels of MCP-1 during flare also were associated with manifestations of renal injury including changes in serum creatinine levels and proteinuria.

Among patients with impaired renal function whose serum creatinine was elevated at 1.2–5.5 mg/dL, the mean MCP-1 was significantly higher, at 2,719 pg/mg creatinine, than in those with normal renal function, who had a mean level of 846 pg/mg creatinine.

At the time of flare, most patients had been receiving immunosuppressive therapy with prednisone and agents such as mycophenolate mofetil, and even such substantial therapy was inadequate to suppress MCP-1. “This shows that the current therapies we have to treat lupus nephritis do not adequately suppress the expression of this particular chemokine,” said Dr. Rovin, professor and director of the division of nephrology, Ohio State University, Columbus.

Response to increased immunosuppressive treatment following flare also correlated with MCP-1. In the majority of patients, MCP-1 decreased with treatment, although only gradually, but in a subset, MCP-1 remained persistently elevated. “We wonder if this is a biomarker for ongoing inflammatory injury in the kidney, and if these patients might benefit from prolonged therapy. We don't know the answer to that,” he said.

These findings suggest that monitoring this cytokine might be a novel way of monitoring disease activity and response to treatment, he said. And because MCP-1 appears not to be simply a biomarker but actually is involved in organ injury, therapies directed at the cytokine itself may be beneficial and are being investigated.

A proteomic approach also has identified the adipocyte-derived cytokine adiponectin as another “totally unexpected” marker of lupus nephritis, he said.

Adiponectin, which is also produced by other cells such as fibroblasts and synovial cells during periods of inflammation, originally was studied in metabolic disorders and was found to enhance insulin sensitivity and to be underexpressed in obesity and diabetes.

It has now been shown to modulate inflammation, with both anti-inflammatory and proinflammatory effects. Its proinflammatory effects include the activation of the transcription factor NF-κ B (NF-KB) and increasing the production of MCP-1 and interleukin-8 by endothelial cells and blood monocytes (Clin. Immunol. 2006;120:99–105).

Recent work has found that both adiponectin and its receptor are expressed in the kidney, suggesting the possibility that this cytokine also has a direct, but as yet unspecified, effect on renal cell function, Dr. Rovin said.

As is the case with MCP-1, levels of adiponectin in the urine are increased during renal flare but not during nonrenal flare, correlating with plasma levels and magnitude of proteinuria (Kidney Int. 2005;64:1825–33).

Staining for adiponectin in a kidney biopsy from a patient with class IV SLE nephritis shows injury. Dr. Brad H. Rovin

NEW YORK — Monitoring the urinary excretion of monocyte chemoattractant protein-1 and adiponectin may prove to be a novel and specific means of evaluating renal activity and injury in patients with systemic lupus erythematosus, according to Dr. Brad H. Rovin.

There is substantial evidence suggesting that the proinflammatory chemokine monocyte chemoattractant protein-1 (MCP-1) is involved in the pathogenesis of renal injury in nephritis associated with systemic lupus erythematosus (SLE). “The main function of inflammatory chemokines is to regulate the deployment of leukocytes to tissue sites undergoing pathological change. These chemokines also activate leukocytes and may promote tissue fibrosis,” Dr. Rovin said at a rheumatology meeting sponsored by New York University.

The relationship of MCP-1 with lupus nephritis has now been investigated in patients enrolled during the past 5 years in the longitudinal Ohio SLE Study. The cohort includes 71 patients with lupus nephritis and 35 patients with SLE but with no evidence of renal involvement.

With a mean follow-up time of approximately 32 months, there have been 70 renal flares and 88 nonrenal flares in the patients.

Urinalysis performed every 2 months found that the mean level of MCP-1 of patients at renal flare was significantly higher than that of any of controls, with 73% of flare values being above the 95th percentile of those of disease control patients (J. Am. Soc. Nephrol. 2005;16:467–73). Patients with class IV glomerulonephritis, with crescents and necrosis, had the highest levels of MCP-1, which reached 12,000 pg/mg creatinine.

High levels of MCP-1 during flare also were associated with manifestations of renal injury including changes in serum creatinine levels and proteinuria.

Among patients with impaired renal function whose serum creatinine was elevated at 1.2–5.5 mg/dL, the mean MCP-1 was significantly higher, at 2,719 pg/mg creatinine, than in those with normal renal function, who had a mean level of 846 pg/mg creatinine.

At the time of flare, most patients had been receiving immunosuppressive therapy with prednisone and agents such as mycophenolate mofetil, and even such substantial therapy was inadequate to suppress MCP-1. “This shows that the current therapies we have to treat lupus nephritis do not adequately suppress the expression of this particular chemokine,” said Dr. Rovin, professor and director of the division of nephrology, Ohio State University, Columbus.

Response to increased immunosuppressive treatment following flare also correlated with MCP-1. In the majority of patients, MCP-1 decreased with treatment, although only gradually, but in a subset, MCP-1 remained persistently elevated. “We wonder if this is a biomarker for ongoing inflammatory injury in the kidney, and if these patients might benefit from prolonged therapy. We don't know the answer to that,” he said.

These findings suggest that monitoring this cytokine might be a novel way of monitoring disease activity and response to treatment, he said. And because MCP-1 appears not to be simply a biomarker but actually is involved in organ injury, therapies directed at the cytokine itself may be beneficial and are being investigated.

A proteomic approach also has identified the adipocyte-derived cytokine adiponectin as another “totally unexpected” marker of lupus nephritis, he said.

Adiponectin, which is also produced by other cells such as fibroblasts and synovial cells during periods of inflammation, originally was studied in metabolic disorders and was found to enhance insulin sensitivity and to be underexpressed in obesity and diabetes.

It has now been shown to modulate inflammation, with both anti-inflammatory and proinflammatory effects. Its proinflammatory effects include the activation of the transcription factor NF-κ B (NF-KB) and increasing the production of MCP-1 and interleukin-8 by endothelial cells and blood monocytes (Clin. Immunol. 2006;120:99–105).

Recent work has found that both adiponectin and its receptor are expressed in the kidney, suggesting the possibility that this cytokine also has a direct, but as yet unspecified, effect on renal cell function, Dr. Rovin said.

As is the case with MCP-1, levels of adiponectin in the urine are increased during renal flare but not during nonrenal flare, correlating with plasma levels and magnitude of proteinuria (Kidney Int. 2005;64:1825–33).

CHICAGO — A high rate of malignancy was found in a retrospective review of incidentally discovered thyroid nodules among patients with a history of other cancers, Dr. Scott M. Wilhelm reported at the annual meeting of the Central Surgical Association.

Traditionally discovered palpable nodules reportedly have a 5% malignancy rate, but some studies have suggested that nonpalpable nodules found during other radiographic procedures carry malignancy rates ranging from 8% to 29%.

Office-based ultrasound confirmed the presence of a nodule 1 cm or more in diameter in 35 of 41 patients who were referred for evaluation after CT scans identified thyroid nodules, said Dr. Wilhelm, assistant professor, Case Western Reserve University, Cleveland.

Most (78%) of the patients were female. The primary site in 23 of the patients was gastrointestinal, including colon, pancreas, and small bowel, whereas the primary site was breast in 11 patients and prostate in 4. Three patients had lymphoma, and nine had various other tumors.

In some patients, there was more than one primary tumor, Dr. Wilhelm said.

The remaining six patients had nodules that were smaller than 1 cm or had no nodules, and were considered to represent false-positive CT scans.

Biopsy results were benign in 15 (42.8%) of the 35 patients, malignant in 2 (5.7%), indeterminate in 16 (45.7%), and nondiagnostic in 2 (5.7%). The malignancies were papillary thyroid cancers, whereas the indeterminate biopsies were classified as follicular neoplasms or suspicious, but not definitive, for papillary thyroid cancer.

A total of 20 patients had diagnoses that warranted surgical resection. One additional patient whose biopsy was benign was subsequently picked up on an OctreoScan study.

“At the time there was very little in the literature on this, so we offered her resection as well,” said Dr. Wilhelm.

Seventeen of the 21 patients underwent resection, with results including four papillary thyroid carcinomas, four micropapillary cancers ranging in size from 4 mm to 8 mm, and seven benign lesions.

Two thyroid metastases also were found, one from renal cell carcinoma and one from melanoma.

Three patients had a history of radiation exposure to the head and neck. In two of the three patients, the exposure had occurred 40 years earlier, during treatment for infantile thymus in one and for eczema in the other. Both patients had atypical biopsies and underwent surgery, but the pathologies were benign.

The third patient had been treated 10 years earlier for breast cancer, undergoing radiation therapy for a supraclavicular lymph node, and was found to have micropapillary thyroid cancer.

“The rate of malignancy in our incidental thyroid nodules was 24%, but we felt it appropriate to exclude the micropapillary cancers, so that left us with 15%, which is three times the rate of malignancy seen in traditionally discovered palpable nodules,” Dr. Wilhelm said at the meeting.

These microscopic foci are very common but pose little risk to patients. In autopsy studies that include these, up to 30% of the population will be found to have nodules, which is why they were excluded in this study, he said.

Some earlier studies did not specify whether micropapillary cancers were included, which may account for rates that were even higher than in this investigation.

The overall increase in thyroid cancer in recent years may be contributing to the high rates of malignancy: American Cancer Society data from 2002 show an actual number of 22,700 new cases and an estimated number of 33,550 for 2007.

“In this study, we also may have selected out patients with unusual genetics,” Dr. Wilhelm said. “We had nine patients who had two primaries and one who had three primaries. Two of the thyroid cancers were in these patients, so one patient wound up with four tumors and one with three. Clearly, there is something different about them.”

The study findings also show that ultrasound was superior to CT in identifying nodules.

The correlation of thyroid nodule size that was seen on ultrasound with that found on pathology was excellent, and thyroid ultrasound should be considered essential if size is to be used as the criterion for determining which lesions to biopsy, Dr. Wilhelm emphasized.

An ultrasound shows a heterogenous thyroid nodule with very irregular borders. It turned out to be a papillary thyroid carcinoma on pathology. Courtesy Dr. Scott M. Wilhelm

CHICAGO — A high rate of malignancy was found in a retrospective review of incidentally discovered thyroid nodules among patients with a history of other cancers, Dr. Scott M. Wilhelm reported at the annual meeting of the Central Surgical Association.

Traditionally discovered palpable nodules reportedly have a 5% malignancy rate, but some studies have suggested that nonpalpable nodules found during other radiographic procedures carry malignancy rates ranging from 8% to 29%.

Office-based ultrasound confirmed the presence of a nodule 1 cm or more in diameter in 35 of 41 patients who were referred for evaluation after CT scans identified thyroid nodules, said Dr. Wilhelm, assistant professor, Case Western Reserve University, Cleveland.

Most (78%) of the patients were female. The primary site in 23 of the patients was gastrointestinal, including colon, pancreas, and small bowel, whereas the primary site was breast in 11 patients and prostate in 4. Three patients had lymphoma, and nine had various other tumors.

In some patients, there was more than one primary tumor, Dr. Wilhelm said.

The remaining six patients had nodules that were smaller than 1 cm or had no nodules, and were considered to represent false-positive CT scans.

Biopsy results were benign in 15 (42.8%) of the 35 patients, malignant in 2 (5.7%), indeterminate in 16 (45.7%), and nondiagnostic in 2 (5.7%). The malignancies were papillary thyroid cancers, whereas the indeterminate biopsies were classified as follicular neoplasms or suspicious, but not definitive, for papillary thyroid cancer.

A total of 20 patients had diagnoses that warranted surgical resection. One additional patient whose biopsy was benign was subsequently picked up on an OctreoScan study.

“At the time there was very little in the literature on this, so we offered her resection as well,” said Dr. Wilhelm.

Seventeen of the 21 patients underwent resection, with results including four papillary thyroid carcinomas, four micropapillary cancers ranging in size from 4 mm to 8 mm, and seven benign lesions.

Two thyroid metastases also were found, one from renal cell carcinoma and one from melanoma.

Three patients had a history of radiation exposure to the head and neck. In two of the three patients, the exposure had occurred 40 years earlier, during treatment for infantile thymus in one and for eczema in the other. Both patients had atypical biopsies and underwent surgery, but the pathologies were benign.

The third patient had been treated 10 years earlier for breast cancer, undergoing radiation therapy for a supraclavicular lymph node, and was found to have micropapillary thyroid cancer.

“The rate of malignancy in our incidental thyroid nodules was 24%, but we felt it appropriate to exclude the micropapillary cancers, so that left us with 15%, which is three times the rate of malignancy seen in traditionally discovered palpable nodules,” Dr. Wilhelm said at the meeting.

These microscopic foci are very common but pose little risk to patients. In autopsy studies that include these, up to 30% of the population will be found to have nodules, which is why they were excluded in this study, he said.

Some earlier studies did not specify whether micropapillary cancers were included, which may account for rates that were even higher than in this investigation.

The overall increase in thyroid cancer in recent years may be contributing to the high rates of malignancy: American Cancer Society data from 2002 show an actual number of 22,700 new cases and an estimated number of 33,550 for 2007.

“In this study, we also may have selected out patients with unusual genetics,” Dr. Wilhelm said. “We had nine patients who had two primaries and one who had three primaries. Two of the thyroid cancers were in these patients, so one patient wound up with four tumors and one with three. Clearly, there is something different about them.”

The study findings also show that ultrasound was superior to CT in identifying nodules.

The correlation of thyroid nodule size that was seen on ultrasound with that found on pathology was excellent, and thyroid ultrasound should be considered essential if size is to be used as the criterion for determining which lesions to biopsy, Dr. Wilhelm emphasized.

An ultrasound shows a heterogenous thyroid nodule with very irregular borders. It turned out to be a papillary thyroid carcinoma on pathology. Courtesy Dr. Scott M. Wilhelm

CHICAGO — A high rate of malignancy was found in a retrospective review of incidentally discovered thyroid nodules among patients with a history of other cancers, Dr. Scott M. Wilhelm reported at the annual meeting of the Central Surgical Association.

Traditionally discovered palpable nodules reportedly have a 5% malignancy rate, but some studies have suggested that nonpalpable nodules found during other radiographic procedures carry malignancy rates ranging from 8% to 29%.

Office-based ultrasound confirmed the presence of a nodule 1 cm or more in diameter in 35 of 41 patients who were referred for evaluation after CT scans identified thyroid nodules, said Dr. Wilhelm, assistant professor, Case Western Reserve University, Cleveland.

Most (78%) of the patients were female. The primary site in 23 of the patients was gastrointestinal, including colon, pancreas, and small bowel, whereas the primary site was breast in 11 patients and prostate in 4. Three patients had lymphoma, and nine had various other tumors.

In some patients, there was more than one primary tumor, Dr. Wilhelm said.

The remaining six patients had nodules that were smaller than 1 cm or had no nodules, and were considered to represent false-positive CT scans.

Biopsy results were benign in 15 (42.8%) of the 35 patients, malignant in 2 (5.7%), indeterminate in 16 (45.7%), and nondiagnostic in 2 (5.7%). The malignancies were papillary thyroid cancers, whereas the indeterminate biopsies were classified as follicular neoplasms or suspicious, but not definitive, for papillary thyroid cancer.

A total of 20 patients had diagnoses that warranted surgical resection. One additional patient whose biopsy was benign was subsequently picked up on an OctreoScan study.

“At the time there was very little in the literature on this, so we offered her resection as well,” said Dr. Wilhelm.

Seventeen of the 21 patients underwent resection, with results including four papillary thyroid carcinomas, four micropapillary cancers ranging in size from 4 mm to 8 mm, and seven benign lesions.

Two thyroid metastases also were found, one from renal cell carcinoma and one from melanoma.

Three patients had a history of radiation exposure to the head and neck. In two of the three patients, the exposure had occurred 40 years earlier, during treatment for infantile thymus in one and for eczema in the other. Both patients had atypical biopsies and underwent surgery, but the pathologies were benign.

The third patient had been treated 10 years earlier for breast cancer, undergoing radiation therapy for a supraclavicular lymph node, and was found to have micropapillary thyroid cancer.

“The rate of malignancy in our incidental thyroid nodules was 24%, but we felt it appropriate to exclude the micropapillary cancers, so that left us with 15%, which is three times the rate of malignancy seen in traditionally discovered palpable nodules,” Dr. Wilhelm said at the meeting.

These microscopic foci are very common but pose little risk to patients. In autopsy studies that include these, up to 30% of the population will be found to have nodules, which is why they were excluded in this study, he said.

Some earlier studies did not specify whether micropapillary cancers were included, which may account for rates that were even higher than in this investigation.

The overall increase in thyroid cancer in recent years may be contributing to the high rates of malignancy: American Cancer Society data from 2002 show an actual number of 22,700 new cases and an estimated number of 33,550 for 2007.

“In this study, we also may have selected out patients with unusual genetics,” Dr. Wilhelm said. “We had nine patients who had two primaries and one who had three primaries. Two of the thyroid cancers were in these patients, so one patient wound up with four tumors and one with three. Clearly, there is something different about them.”

The study findings also show that ultrasound was superior to CT in identifying nodules.

The correlation of thyroid nodule size that was seen on ultrasound with that found on pathology was excellent, and thyroid ultrasound should be considered essential if size is to be used as the criterion for determining which lesions to biopsy, Dr. Wilhelm emphasized.

An ultrasound shows a heterogenous thyroid nodule with very irregular borders. It turned out to be a papillary thyroid carcinoma on pathology. Courtesy Dr. Scott M. Wilhelm

CHICAGO — Mandatory screening for obstructive sleep apnea can significantly reduce the need for intensive care unit admission following bariatric surgery, Dr. Peter T. Hallowell said at the annual meeting of the Central Surgical Association.

“In our center, mandatory screening and aggressive preoperative treatment for sleep apnea has actually eliminated the need for respiratory-related ICU stay,” said Dr. Hallowell of the department of surgery, Case Western Reserve University, and the bariatric surgery program at University Hospitals Case Medical Center, both in Cleveland.

Previous studies have suggested that approximately 20% of patients have ICU stays following bariatric surgery, and sleep apnea—prevalent among the morbidly obese—is associated with increased postoperative complications such as respiratory distress.

“We have long suspected that sleep apnea is underdiagnosed in the bariatric population, so we did a retrospective review of our bariatric database from 1998 to 2005, comparing the era of selective screening with the era of mandatory screening,” Dr. Hallowell said.

Mandatory screening was implemented in 2004. All patients underwent an overnight polysomnogram and, if apnea was detected, continuous positive airway pressure therapy was instituted.

Before undergoing bariatric surgery, patients also are required to participate in an extensive education program, to stop smoking, and to begin exercising.

For a comparison of the effect of preoperative sleep apnea screening, patients were divided into two groups. Group 1 included the 572 patients who had gastric bypass between 1998 and December 2003; group 2 included the 318 who had the surgery between January 2004, when mandatory screening was instituted, and December 2005.

The groups were well matched in terms of demographics and comorbidities. Mean body mass index was 51.1 kg/m

Among the patients in group 1, there were 11 ICU admissions for respiratory problems and 21 for other complications such as leaks, bleeds, or obstruction either intraoperatively or postoperatively. In group 2, there were 11 ICU admissions in all, none of which were for respiratory complications, Dr. Hallowell said.

The difference in respiratory-related admissions between the two groups was statistically significant.

The average length of stay among patients admitted to the ICU was 12 days, compared with 2.8 days for those who did not require admission.

Multiple factors, including increased surgical experience, patient education, and the requirement for smoking cessation have led to a decrease in the need for ICU admission following bariatric surgery. “Our study shows that recognizing and treating occult sleep apnea further improves this quality metric,” Dr. Hallowell said.

Audience member Dr. Henry Buchwald of the University of Minnesota, Minneapolis, asked about patients who have had the procedure since the study cutoff in 2005. “At present, we now have 414 patients in group 2 and still have had no respiratory admissions,” Dr. Hallowell replied.

Dr. Buchwald also asked about the cost of sleep apnea screening. “The expense for evaluation and treatment of sleep apnea is approximately $5,000, while the cost for the ICU is about $3,000 a day without a ventilator or critical care consult,” Dr. Hallowell said.

CHICAGO — Mandatory screening for obstructive sleep apnea can significantly reduce the need for intensive care unit admission following bariatric surgery, Dr. Peter T. Hallowell said at the annual meeting of the Central Surgical Association.

“In our center, mandatory screening and aggressive preoperative treatment for sleep apnea has actually eliminated the need for respiratory-related ICU stay,” said Dr. Hallowell of the department of surgery, Case Western Reserve University, and the bariatric surgery program at University Hospitals Case Medical Center, both in Cleveland.

Previous studies have suggested that approximately 20% of patients have ICU stays following bariatric surgery, and sleep apnea—prevalent among the morbidly obese—is associated with increased postoperative complications such as respiratory distress.

“We have long suspected that sleep apnea is underdiagnosed in the bariatric population, so we did a retrospective review of our bariatric database from 1998 to 2005, comparing the era of selective screening with the era of mandatory screening,” Dr. Hallowell said.

Mandatory screening was implemented in 2004. All patients underwent an overnight polysomnogram and, if apnea was detected, continuous positive airway pressure therapy was instituted.

Before undergoing bariatric surgery, patients also are required to participate in an extensive education program, to stop smoking, and to begin exercising.

For a comparison of the effect of preoperative sleep apnea screening, patients were divided into two groups. Group 1 included the 572 patients who had gastric bypass between 1998 and December 2003; group 2 included the 318 who had the surgery between January 2004, when mandatory screening was instituted, and December 2005.

The groups were well matched in terms of demographics and comorbidities. Mean body mass index was 51.1 kg/m

Among the patients in group 1, there were 11 ICU admissions for respiratory problems and 21 for other complications such as leaks, bleeds, or obstruction either intraoperatively or postoperatively. In group 2, there were 11 ICU admissions in all, none of which were for respiratory complications, Dr. Hallowell said.

The difference in respiratory-related admissions between the two groups was statistically significant.

The average length of stay among patients admitted to the ICU was 12 days, compared with 2.8 days for those who did not require admission.

Multiple factors, including increased surgical experience, patient education, and the requirement for smoking cessation have led to a decrease in the need for ICU admission following bariatric surgery. “Our study shows that recognizing and treating occult sleep apnea further improves this quality metric,” Dr. Hallowell said.

Audience member Dr. Henry Buchwald of the University of Minnesota, Minneapolis, asked about patients who have had the procedure since the study cutoff in 2005. “At present, we now have 414 patients in group 2 and still have had no respiratory admissions,” Dr. Hallowell replied.

Dr. Buchwald also asked about the cost of sleep apnea screening. “The expense for evaluation and treatment of sleep apnea is approximately $5,000, while the cost for the ICU is about $3,000 a day without a ventilator or critical care consult,” Dr. Hallowell said.

CHICAGO — Mandatory screening for obstructive sleep apnea can significantly reduce the need for intensive care unit admission following bariatric surgery, Dr. Peter T. Hallowell said at the annual meeting of the Central Surgical Association.

“In our center, mandatory screening and aggressive preoperative treatment for sleep apnea has actually eliminated the need for respiratory-related ICU stay,” said Dr. Hallowell of the department of surgery, Case Western Reserve University, and the bariatric surgery program at University Hospitals Case Medical Center, both in Cleveland.

Previous studies have suggested that approximately 20% of patients have ICU stays following bariatric surgery, and sleep apnea—prevalent among the morbidly obese—is associated with increased postoperative complications such as respiratory distress.

“We have long suspected that sleep apnea is underdiagnosed in the bariatric population, so we did a retrospective review of our bariatric database from 1998 to 2005, comparing the era of selective screening with the era of mandatory screening,” Dr. Hallowell said.

Mandatory screening was implemented in 2004. All patients underwent an overnight polysomnogram and, if apnea was detected, continuous positive airway pressure therapy was instituted.

Before undergoing bariatric surgery, patients also are required to participate in an extensive education program, to stop smoking, and to begin exercising.

For a comparison of the effect of preoperative sleep apnea screening, patients were divided into two groups. Group 1 included the 572 patients who had gastric bypass between 1998 and December 2003; group 2 included the 318 who had the surgery between January 2004, when mandatory screening was instituted, and December 2005.

The groups were well matched in terms of demographics and comorbidities. Mean body mass index was 51.1 kg/m

Among the patients in group 1, there were 11 ICU admissions for respiratory problems and 21 for other complications such as leaks, bleeds, or obstruction either intraoperatively or postoperatively. In group 2, there were 11 ICU admissions in all, none of which were for respiratory complications, Dr. Hallowell said.

The difference in respiratory-related admissions between the two groups was statistically significant.

The average length of stay among patients admitted to the ICU was 12 days, compared with 2.8 days for those who did not require admission.

Multiple factors, including increased surgical experience, patient education, and the requirement for smoking cessation have led to a decrease in the need for ICU admission following bariatric surgery. “Our study shows that recognizing and treating occult sleep apnea further improves this quality metric,” Dr. Hallowell said.

Audience member Dr. Henry Buchwald of the University of Minnesota, Minneapolis, asked about patients who have had the procedure since the study cutoff in 2005. “At present, we now have 414 patients in group 2 and still have had no respiratory admissions,” Dr. Hallowell replied.

Dr. Buchwald also asked about the cost of sleep apnea screening. “The expense for evaluation and treatment of sleep apnea is approximately $5,000, while the cost for the ICU is about $3,000 a day without a ventilator or critical care consult,” Dr. Hallowell said.

NEW YORK — The process of inflammation—increasingly seen as a central component in a wide variety of chronic diseases—may prove to be the link between type 2 diabetes and cardiovascular disease, according to Dr. Vivian Fonseca.

This holds potential implications for the treatment of diabetes, with an old therapeutic approach being revisited. “In 1876, a report appeared in the German literature describing improvement in glucosuria in a patient with diabetes using high doses of sodium salicylate,” Dr. Fonseca said at a meeting sponsored by the American Diabetes Association.

It is now known that low-grade inflammation arises from adipose tissue, with adipocytes secreting many cytokines involved in the production of C-reactive protein, fibrinogen, and metalloproteinases, including tumor necrosis factor-α and interleukin-6 (IL-6).

“The master switch for inflammation is the [nuclear transcription factor] NF-B, which is normally present in the cytoplasm with [inhibitory protein] IB kinase,” said Dr. Fonseca, professor of medicine and pharmacology, Tulane University, New Orleans.

“When this NF-B/IB axis receives a signal, whether from a virus or from an adipocyte-derived cytokine, NF-B moves into the nucleus, where it serves as a transcription factor for a wide variety of genes involved in the inflammatory process,” he said.

Whether the use of anti-inflammatory agents to interrupt this NF-B axis may represent a new pharmacologic approach to the treatment of diabetes is now being evaluated in a multicenter study funded by the National Institutes of Health.

The agent being tested is salsalate, which is insoluble at acid pH and therefore does not cause stomach irritation. Salsalate also does not interfere with prostacyclin or cyclooxygenase-2, nor does it raise blood pressure, Dr. Fonseca said.

Preliminary studies with salsalate in a small number of patients have shown that, aside from suppressing inflammation, it also improves glucose utilization, increases insulin secretion, and increases energy expenditure.

Patients are now being recruited for the study; information is available at www.tinsal-t2d.org

Dr. Fonseca disclosed that he receives research support from the American Diabetes Association, the National Institutes of Health, and a number of pharmaceutical companies.

NEW YORK — The process of inflammation—increasingly seen as a central component in a wide variety of chronic diseases—may prove to be the link between type 2 diabetes and cardiovascular disease, according to Dr. Vivian Fonseca.

This holds potential implications for the treatment of diabetes, with an old therapeutic approach being revisited. “In 1876, a report appeared in the German literature describing improvement in glucosuria in a patient with diabetes using high doses of sodium salicylate,” Dr. Fonseca said at a meeting sponsored by the American Diabetes Association.

It is now known that low-grade inflammation arises from adipose tissue, with adipocytes secreting many cytokines involved in the production of C-reactive protein, fibrinogen, and metalloproteinases, including tumor necrosis factor-α and interleukin-6 (IL-6).

“The master switch for inflammation is the [nuclear transcription factor] NF-B, which is normally present in the cytoplasm with [inhibitory protein] IB kinase,” said Dr. Fonseca, professor of medicine and pharmacology, Tulane University, New Orleans.

“When this NF-B/IB axis receives a signal, whether from a virus or from an adipocyte-derived cytokine, NF-B moves into the nucleus, where it serves as a transcription factor for a wide variety of genes involved in the inflammatory process,” he said.

Whether the use of anti-inflammatory agents to interrupt this NF-B axis may represent a new pharmacologic approach to the treatment of diabetes is now being evaluated in a multicenter study funded by the National Institutes of Health.

The agent being tested is salsalate, which is insoluble at acid pH and therefore does not cause stomach irritation. Salsalate also does not interfere with prostacyclin or cyclooxygenase-2, nor does it raise blood pressure, Dr. Fonseca said.

Preliminary studies with salsalate in a small number of patients have shown that, aside from suppressing inflammation, it also improves glucose utilization, increases insulin secretion, and increases energy expenditure.

Patients are now being recruited for the study; information is available at www.tinsal-t2d.org

Dr. Fonseca disclosed that he receives research support from the American Diabetes Association, the National Institutes of Health, and a number of pharmaceutical companies.

NEW YORK — The process of inflammation—increasingly seen as a central component in a wide variety of chronic diseases—may prove to be the link between type 2 diabetes and cardiovascular disease, according to Dr. Vivian Fonseca.

This holds potential implications for the treatment of diabetes, with an old therapeutic approach being revisited. “In 1876, a report appeared in the German literature describing improvement in glucosuria in a patient with diabetes using high doses of sodium salicylate,” Dr. Fonseca said at a meeting sponsored by the American Diabetes Association.

It is now known that low-grade inflammation arises from adipose tissue, with adipocytes secreting many cytokines involved in the production of C-reactive protein, fibrinogen, and metalloproteinases, including tumor necrosis factor-α and interleukin-6 (IL-6).

“The master switch for inflammation is the [nuclear transcription factor] NF-B, which is normally present in the cytoplasm with [inhibitory protein] IB kinase,” said Dr. Fonseca, professor of medicine and pharmacology, Tulane University, New Orleans.

“When this NF-B/IB axis receives a signal, whether from a virus or from an adipocyte-derived cytokine, NF-B moves into the nucleus, where it serves as a transcription factor for a wide variety of genes involved in the inflammatory process,” he said.

Whether the use of anti-inflammatory agents to interrupt this NF-B axis may represent a new pharmacologic approach to the treatment of diabetes is now being evaluated in a multicenter study funded by the National Institutes of Health.

The agent being tested is salsalate, which is insoluble at acid pH and therefore does not cause stomach irritation. Salsalate also does not interfere with prostacyclin or cyclooxygenase-2, nor does it raise blood pressure, Dr. Fonseca said.

Preliminary studies with salsalate in a small number of patients have shown that, aside from suppressing inflammation, it also improves glucose utilization, increases insulin secretion, and increases energy expenditure.

Patients are now being recruited for the study; information is available at www.tinsal-t2d.org

Dr. Fonseca disclosed that he receives research support from the American Diabetes Association, the National Institutes of Health, and a number of pharmaceutical companies.

MONTREAL — Vardenafil is effective and well tolerated as a treatment for erectile dysfunction in men 65 and older, Patricia Stenger said at a congress sponsored by the Canadian Society for the Study of the Aging Male.

In a prospective postmarketing surveillance study conducted in 11 European countries, 12,063 patients with ED whose mean age was 70.2 years were followed for 2 months in routine practice. The duration of ED was longer than 3 years in one-third of patients, and more than half reported a moderate degree of dysfunction, according to Ms. Stenger of the pharmaceutical division of Bayer Corp. maker of Levitra (vardenafil), West Haven, Conn.

A 10-mg dose of vardenafil was prescribed for 69.2% of patients at the initial visit and for 54.3% of patients at the last follow-up visit. A 20-mg dose was prescribed for 23.6% initially and for 42.2% at the last follow-up visit. On average, patients took 1 tablet each week.

A total of 91% of patients reported an overall improvement in ED, with 66.9% noting an improvement after taking the first tablet, Ms. Stenger said in a moderated poster session at the meeting, which was cosponsored by the International Society for the Study of the Aging Male.

When asked by their physicians, 89.3% of patients said they were satisfied or very satisfied with the efficacy of treatment; patients exhibited a high response rate, regardless of the severity or duration of their ED.

Patients recorded successful penetration in 92.4% of attempts, and they maintained their erections until completion of intercourse in 81.2% of attempts.

Approximately 90% of patients had concomitant diseases, which were most commonly cardiac and vascular in nature. Concomitant drugs with the potential to interact with vardenafil, most commonly α-blockers, were prescribed to 10.3% of patients.

Despite the frequency of concomitant disease and patients' exposure to potentially interactive drugs, vardenafil was well tolerated; 97.5% of patients reported being satisfied or very satisfied with the overall tolerability.

MONTREAL — Vardenafil is effective and well tolerated as a treatment for erectile dysfunction in men 65 and older, Patricia Stenger said at a congress sponsored by the Canadian Society for the Study of the Aging Male.

In a prospective postmarketing surveillance study conducted in 11 European countries, 12,063 patients with ED whose mean age was 70.2 years were followed for 2 months in routine practice. The duration of ED was longer than 3 years in one-third of patients, and more than half reported a moderate degree of dysfunction, according to Ms. Stenger of the pharmaceutical division of Bayer Corp. maker of Levitra (vardenafil), West Haven, Conn.

A 10-mg dose of vardenafil was prescribed for 69.2% of patients at the initial visit and for 54.3% of patients at the last follow-up visit. A 20-mg dose was prescribed for 23.6% initially and for 42.2% at the last follow-up visit. On average, patients took 1 tablet each week.

A total of 91% of patients reported an overall improvement in ED, with 66.9% noting an improvement after taking the first tablet, Ms. Stenger said in a moderated poster session at the meeting, which was cosponsored by the International Society for the Study of the Aging Male.

When asked by their physicians, 89.3% of patients said they were satisfied or very satisfied with the efficacy of treatment; patients exhibited a high response rate, regardless of the severity or duration of their ED.

Patients recorded successful penetration in 92.4% of attempts, and they maintained their erections until completion of intercourse in 81.2% of attempts.

Approximately 90% of patients had concomitant diseases, which were most commonly cardiac and vascular in nature. Concomitant drugs with the potential to interact with vardenafil, most commonly α-blockers, were prescribed to 10.3% of patients.

Despite the frequency of concomitant disease and patients' exposure to potentially interactive drugs, vardenafil was well tolerated; 97.5% of patients reported being satisfied or very satisfied with the overall tolerability.

MONTREAL — Vardenafil is effective and well tolerated as a treatment for erectile dysfunction in men 65 and older, Patricia Stenger said at a congress sponsored by the Canadian Society for the Study of the Aging Male.

In a prospective postmarketing surveillance study conducted in 11 European countries, 12,063 patients with ED whose mean age was 70.2 years were followed for 2 months in routine practice. The duration of ED was longer than 3 years in one-third of patients, and more than half reported a moderate degree of dysfunction, according to Ms. Stenger of the pharmaceutical division of Bayer Corp. maker of Levitra (vardenafil), West Haven, Conn.

A 10-mg dose of vardenafil was prescribed for 69.2% of patients at the initial visit and for 54.3% of patients at the last follow-up visit. A 20-mg dose was prescribed for 23.6% initially and for 42.2% at the last follow-up visit. On average, patients took 1 tablet each week.

A total of 91% of patients reported an overall improvement in ED, with 66.9% noting an improvement after taking the first tablet, Ms. Stenger said in a moderated poster session at the meeting, which was cosponsored by the International Society for the Study of the Aging Male.

When asked by their physicians, 89.3% of patients said they were satisfied or very satisfied with the efficacy of treatment; patients exhibited a high response rate, regardless of the severity or duration of their ED.

Patients recorded successful penetration in 92.4% of attempts, and they maintained their erections until completion of intercourse in 81.2% of attempts.

Approximately 90% of patients had concomitant diseases, which were most commonly cardiac and vascular in nature. Concomitant drugs with the potential to interact with vardenafil, most commonly α-blockers, were prescribed to 10.3% of patients.

Despite the frequency of concomitant disease and patients' exposure to potentially interactive drugs, vardenafil was well tolerated; 97.5% of patients reported being satisfied or very satisfied with the overall tolerability.

NEW YORK — The safety of inhaled insulin is holding up at 2 years in an ongoing study, with adverse pulmonary effects being small, occurring early, and proving reversible on cessation of the drug, Dr. Jay S. Skyler said at a meeting sponsored by the American Diabetes Association.

An interim analysis of a 51/2-year multinational study that includes 441 patients with type 1 diabetes has found that declines in pulmonary function—most likely age related—were similar among patients randomized to receive either subcutaneous or inhaled insulin (Exubera, Pfizer) plus basal insulin.

The mean changes in forced expiratory volume in 1 second at 3 months for inhaled and subcutaneous insulin were-0.047 and −0.026, respectively, and at 24 months the mean changes from baseline were −0.104 and −0.082. Only at the 3-month time point was the difference between the groups statistically significant, and concerns that changes in pulmonary function would progress—which would have been a real worry—have not been borne out, said Dr. Skyler, professor in the division of endocrinology, diabetes, and metabolism at the University of Miami, and the study's lead investigator.

There also have been concerns that repetitive inhalation of insulin particles could result in cumulative insults and the long-term development of fibrosis or tumors. “But the statistical likelihood of a few drops of powder or liquid hitting the same spot on a repetitive basis is trivial to nonexistent,” he said, noting that the surface area of the adult human lung approximates that of a tennis court.

Among the 217 patients receiving inhaled insulin who completed the first 2 years of the trial, there was a 33% reduction in risk of severe hypoglycemia compared with those receiving the drug subcutaneously (Diabetes Care 2007; 30:579–85).

Patients receiving inhaled insulin did develop antibodies at an increased rate, said Dr. Skyler. Mean insulin antibody levels at baseline were 4.50 and 4.15 mcU/mL in the inhaled and subcutaneous groups, respectively. At 2 years, the respective levels were 64.5 and 3.85 mcU/mL. “When a substance is taken in through the lung, the immune system reacts in a Th2 fashion, favoring antibody formation,” he said. However, the antibodies do not appear to interfere with efficacy or to be associated with adverse effects, he added.

Researchers also looked at efficacy in the interim analysis, and found that glycemic control was sustained and similar in both groups. Decreases in fasting glucose were greater in the inhaled insulin group, and weight gain was significantly less.

“If it works and doesn't appear to have any major problems, and is priced not very differently from other insulins, why has it done so poorly in the marketplace?” Dr. Skyler said.

Since Exubera was approved in January 2006, marketing efforts have focused specifically on endocrinologists. “I would submit that endocrinologists are the wrong target audience. We are not the ones who encounter the patients who are reluctant to use insulin,” he said.

“By the time patients reach us, with our team of nurse practitioners and educators, we can get people onto injected insulin with ease,” Dr. Skyler continued. Primary care physicians are more likely to see patients unwilling to go on injected insulin, and whether the use of inhaled insulin will increase when marketing efforts begin to target them remains to be seen, he said.

NEW YORK — The safety of inhaled insulin is holding up at 2 years in an ongoing study, with adverse pulmonary effects being small, occurring early, and proving reversible on cessation of the drug, Dr. Jay S. Skyler said at a meeting sponsored by the American Diabetes Association.

An interim analysis of a 51/2-year multinational study that includes 441 patients with type 1 diabetes has found that declines in pulmonary function—most likely age related—were similar among patients randomized to receive either subcutaneous or inhaled insulin (Exubera, Pfizer) plus basal insulin.

The mean changes in forced expiratory volume in 1 second at 3 months for inhaled and subcutaneous insulin were-0.047 and −0.026, respectively, and at 24 months the mean changes from baseline were −0.104 and −0.082. Only at the 3-month time point was the difference between the groups statistically significant, and concerns that changes in pulmonary function would progress—which would have been a real worry—have not been borne out, said Dr. Skyler, professor in the division of endocrinology, diabetes, and metabolism at the University of Miami, and the study's lead investigator.

There also have been concerns that repetitive inhalation of insulin particles could result in cumulative insults and the long-term development of fibrosis or tumors. “But the statistical likelihood of a few drops of powder or liquid hitting the same spot on a repetitive basis is trivial to nonexistent,” he said, noting that the surface area of the adult human lung approximates that of a tennis court.

Among the 217 patients receiving inhaled insulin who completed the first 2 years of the trial, there was a 33% reduction in risk of severe hypoglycemia compared with those receiving the drug subcutaneously (Diabetes Care 2007; 30:579–85).

Patients receiving inhaled insulin did develop antibodies at an increased rate, said Dr. Skyler. Mean insulin antibody levels at baseline were 4.50 and 4.15 mcU/mL in the inhaled and subcutaneous groups, respectively. At 2 years, the respective levels were 64.5 and 3.85 mcU/mL. “When a substance is taken in through the lung, the immune system reacts in a Th2 fashion, favoring antibody formation,” he said. However, the antibodies do not appear to interfere with efficacy or to be associated with adverse effects, he added.

Researchers also looked at efficacy in the interim analysis, and found that glycemic control was sustained and similar in both groups. Decreases in fasting glucose were greater in the inhaled insulin group, and weight gain was significantly less.

“If it works and doesn't appear to have any major problems, and is priced not very differently from other insulins, why has it done so poorly in the marketplace?” Dr. Skyler said.

Since Exubera was approved in January 2006, marketing efforts have focused specifically on endocrinologists. “I would submit that endocrinologists are the wrong target audience. We are not the ones who encounter the patients who are reluctant to use insulin,” he said.

“By the time patients reach us, with our team of nurse practitioners and educators, we can get people onto injected insulin with ease,” Dr. Skyler continued. Primary care physicians are more likely to see patients unwilling to go on injected insulin, and whether the use of inhaled insulin will increase when marketing efforts begin to target them remains to be seen, he said.

NEW YORK — The safety of inhaled insulin is holding up at 2 years in an ongoing study, with adverse pulmonary effects being small, occurring early, and proving reversible on cessation of the drug, Dr. Jay S. Skyler said at a meeting sponsored by the American Diabetes Association.

An interim analysis of a 51/2-year multinational study that includes 441 patients with type 1 diabetes has found that declines in pulmonary function—most likely age related—were similar among patients randomized to receive either subcutaneous or inhaled insulin (Exubera, Pfizer) plus basal insulin.

The mean changes in forced expiratory volume in 1 second at 3 months for inhaled and subcutaneous insulin were-0.047 and −0.026, respectively, and at 24 months the mean changes from baseline were −0.104 and −0.082. Only at the 3-month time point was the difference between the groups statistically significant, and concerns that changes in pulmonary function would progress—which would have been a real worry—have not been borne out, said Dr. Skyler, professor in the division of endocrinology, diabetes, and metabolism at the University of Miami, and the study's lead investigator.

There also have been concerns that repetitive inhalation of insulin particles could result in cumulative insults and the long-term development of fibrosis or tumors. “But the statistical likelihood of a few drops of powder or liquid hitting the same spot on a repetitive basis is trivial to nonexistent,” he said, noting that the surface area of the adult human lung approximates that of a tennis court.

Among the 217 patients receiving inhaled insulin who completed the first 2 years of the trial, there was a 33% reduction in risk of severe hypoglycemia compared with those receiving the drug subcutaneously (Diabetes Care 2007; 30:579–85).

Patients receiving inhaled insulin did develop antibodies at an increased rate, said Dr. Skyler. Mean insulin antibody levels at baseline were 4.50 and 4.15 mcU/mL in the inhaled and subcutaneous groups, respectively. At 2 years, the respective levels were 64.5 and 3.85 mcU/mL. “When a substance is taken in through the lung, the immune system reacts in a Th2 fashion, favoring antibody formation,” he said. However, the antibodies do not appear to interfere with efficacy or to be associated with adverse effects, he added.

Researchers also looked at efficacy in the interim analysis, and found that glycemic control was sustained and similar in both groups. Decreases in fasting glucose were greater in the inhaled insulin group, and weight gain was significantly less.

“If it works and doesn't appear to have any major problems, and is priced not very differently from other insulins, why has it done so poorly in the marketplace?” Dr. Skyler said.

Since Exubera was approved in January 2006, marketing efforts have focused specifically on endocrinologists. “I would submit that endocrinologists are the wrong target audience. We are not the ones who encounter the patients who are reluctant to use insulin,” he said.

“By the time patients reach us, with our team of nurse practitioners and educators, we can get people onto injected insulin with ease,” Dr. Skyler continued. Primary care physicians are more likely to see patients unwilling to go on injected insulin, and whether the use of inhaled insulin will increase when marketing efforts begin to target them remains to be seen, he said.

Women who progress from normoglycemia to prediabetes have greater endothelial dysfunction than do men who similarly progress, a study has found.

It has previously been shown that women with impaired glucose tolerance have a more atherogenic risk profile than men, and that this is evident years before clinical diabetes develops—an observation that led to the “ticking clock” hypothesis that attributes diabetic patients' risk for coronary heart disease to a long-standing atherogenic state.

New data from patients enrolled in the Western New York Study, an epidemiologic case-control investigation that originally looked at alcohol intake and cardiovascular disease risk, now have demonstrated that emerging risk factors such as markers of endothelial dysfunction, inflammation, and fibrinolysis/thrombosis also are elevated early in women who develop prediabetes.

Among the study's 1,455 participants, 52 women and 39 men whose fasting serum glucose levels were below 100 mg/dL at baseline had levels between 100 and 125 mg/dL at a 6-year follow-up visit, according to Richard P. Donahue, Ph.D., of the department of social and preventive medicine, State University of New York at Buffalo, and colleagues (Diabetes Care 2007;30:354–9).

The women who progressed from normoglycemia to prediabetes were older than matched controls and had higher mean waist circumference, higher levels of triglycerides and fasting glucose, higher values on the homeostasis model assessment of insulin resistance (HOMA-IR), and a greater frequency of hypertension.

Aside from these conventional atherogenic risk factors, the women also had higher age-adjusted levels of biomarkers including human soluble intercellular adhesion molecule-1, E-selectin, and plasminogen activator inhibitor-1 (PAI-1).

In contrast, men who progressed from normoglycemia to prediabetes had higher levels of C-reactive protein and higher values on the HOMA-IR, compared with controls, without showing increased levels of the markers of endothelial dysfunction.

Dr. Donahue and his colleagues from Buffalo and from the University of North Carolina at Charlotte noted that previous studies have shown that elevations of E-selectin and PAI-1 are independent predictors of both type 2 diabetes and coronary heart disease. Elevated PAI-1, reflecting impaired fibrinolysis, is one of the most predictive of biomarkers, possibly working through a different pathway than do the cellular adhesion molecules, they said.

The markers of endothelial dysfunction that were elevated in women in this study and that predicted progression to prediabetes were independent of the effects of age or body mass index and HOMA-IR, according to the investigators.

Women who progress from normoglycemia to prediabetes have greater endothelial dysfunction than do men who similarly progress, a study has found.

It has previously been shown that women with impaired glucose tolerance have a more atherogenic risk profile than men, and that this is evident years before clinical diabetes develops—an observation that led to the “ticking clock” hypothesis that attributes diabetic patients' risk for coronary heart disease to a long-standing atherogenic state.

New data from patients enrolled in the Western New York Study, an epidemiologic case-control investigation that originally looked at alcohol intake and cardiovascular disease risk, now have demonstrated that emerging risk factors such as markers of endothelial dysfunction, inflammation, and fibrinolysis/thrombosis also are elevated early in women who develop prediabetes.

Among the study's 1,455 participants, 52 women and 39 men whose fasting serum glucose levels were below 100 mg/dL at baseline had levels between 100 and 125 mg/dL at a 6-year follow-up visit, according to Richard P. Donahue, Ph.D., of the department of social and preventive medicine, State University of New York at Buffalo, and colleagues (Diabetes Care 2007;30:354–9).

The women who progressed from normoglycemia to prediabetes were older than matched controls and had higher mean waist circumference, higher levels of triglycerides and fasting glucose, higher values on the homeostasis model assessment of insulin resistance (HOMA-IR), and a greater frequency of hypertension.

Aside from these conventional atherogenic risk factors, the women also had higher age-adjusted levels of biomarkers including human soluble intercellular adhesion molecule-1, E-selectin, and plasminogen activator inhibitor-1 (PAI-1).

In contrast, men who progressed from normoglycemia to prediabetes had higher levels of C-reactive protein and higher values on the HOMA-IR, compared with controls, without showing increased levels of the markers of endothelial dysfunction.

Dr. Donahue and his colleagues from Buffalo and from the University of North Carolina at Charlotte noted that previous studies have shown that elevations of E-selectin and PAI-1 are independent predictors of both type 2 diabetes and coronary heart disease. Elevated PAI-1, reflecting impaired fibrinolysis, is one of the most predictive of biomarkers, possibly working through a different pathway than do the cellular adhesion molecules, they said.

The markers of endothelial dysfunction that were elevated in women in this study and that predicted progression to prediabetes were independent of the effects of age or body mass index and HOMA-IR, according to the investigators.

Women who progress from normoglycemia to prediabetes have greater endothelial dysfunction than do men who similarly progress, a study has found.

It has previously been shown that women with impaired glucose tolerance have a more atherogenic risk profile than men, and that this is evident years before clinical diabetes develops—an observation that led to the “ticking clock” hypothesis that attributes diabetic patients' risk for coronary heart disease to a long-standing atherogenic state.

New data from patients enrolled in the Western New York Study, an epidemiologic case-control investigation that originally looked at alcohol intake and cardiovascular disease risk, now have demonstrated that emerging risk factors such as markers of endothelial dysfunction, inflammation, and fibrinolysis/thrombosis also are elevated early in women who develop prediabetes.

Among the study's 1,455 participants, 52 women and 39 men whose fasting serum glucose levels were below 100 mg/dL at baseline had levels between 100 and 125 mg/dL at a 6-year follow-up visit, according to Richard P. Donahue, Ph.D., of the department of social and preventive medicine, State University of New York at Buffalo, and colleagues (Diabetes Care 2007;30:354–9).

The women who progressed from normoglycemia to prediabetes were older than matched controls and had higher mean waist circumference, higher levels of triglycerides and fasting glucose, higher values on the homeostasis model assessment of insulin resistance (HOMA-IR), and a greater frequency of hypertension.

Aside from these conventional atherogenic risk factors, the women also had higher age-adjusted levels of biomarkers including human soluble intercellular adhesion molecule-1, E-selectin, and plasminogen activator inhibitor-1 (PAI-1).

In contrast, men who progressed from normoglycemia to prediabetes had higher levels of C-reactive protein and higher values on the HOMA-IR, compared with controls, without showing increased levels of the markers of endothelial dysfunction.

Dr. Donahue and his colleagues from Buffalo and from the University of North Carolina at Charlotte noted that previous studies have shown that elevations of E-selectin and PAI-1 are independent predictors of both type 2 diabetes and coronary heart disease. Elevated PAI-1, reflecting impaired fibrinolysis, is one of the most predictive of biomarkers, possibly working through a different pathway than do the cellular adhesion molecules, they said.

The markers of endothelial dysfunction that were elevated in women in this study and that predicted progression to prediabetes were independent of the effects of age or body mass index and HOMA-IR, according to the investigators.

NEW YORK — True brittle diabetes is a rarity, with characteristic blood glucose lability, frequent hospitalizations, and life disruption often reflecting underlying psychiatric or organic disease, according to Dr. Irl B. Hirsch.

Diagnosis and management of this potentially lethal condition present significant challenges, as was shown in several cases Dr. Hirsch presented at a meeting sponsored by the American Diabetes Association.

One case involved a 23-year-old woman who presented with a 15-year history of type 1 diabetes in 2000. She had been on an insulin pump for 5 years, and her hemoglobin A_1c (HbA_1c) levels ranged from 9% to 12%. As a teenager she had had an eating disorder and had multiple hospitalizations for diabetic ketoacidosis. In the previous 2 years she had been hospitalized twice for gastroparesis, and had developed severe peripheral neuropathy and osteoporosis.

By 2002 she developed nonproliferative retinopathy and proteinuria. “All those years of poor control were already catching up with her at age 25,” said Dr. Hirsch, professor of medicine in the division of metabolism, endocrinology, and nutrition at the University of Washington, Seattle.

In 2004 she had an unplanned pregnancy and was hospitalized for 4 months, delivering the child 3 months prematurely. Her glucose was well controlled while she was in the hospital, but subsequently HbA_1c became elevated once again, reaching 10.4%.

Finally, in the summer of 2006, she had a kidney-pancreas transplant. “So the question is, does she have brittle diabetes?” Dr. Hirsch asked.

A diagnostic work-up determined that she had underlying celiac disease, with an important clue being the osteoporosis. “When you see osteoporosis in a young person you have to think about calcium absorption,” he said. “Celiac disease often goes hand in hand with type 1 diabetes.”

These patients can have extremely irregular blood glucose patterns because their food absorption is so erratic, he added.

A further concern to keep in mind with a patient such as this is that between one-third and one-half of all teenage girls with type 1 diabetes will withhold insulin at some time for weight loss. “Unfortunately, this is a very effective and dangerous way to lose weight,” Dr. Hirsch said.

A second case involved a 30-year-old man who had nine hospitalizations during the first half of 2006 because of severe gastroparesis. “We solved this case with the help of our friends at the Mayo Clinic,” Dr. Hirsch said.

The patient was diagnosed with cannabis hyperemesis syndrome, a condition associated with long-term cannabis use that is characterized by cyclical episodes of vomiting in a susceptible patient.

“When he stopped smoking he also stopped coming to the hospital, but when he started smoking again the hospitalizations recurred,” he said.

The likely mechanism for this little-known phenomenon is a slowing of gastric emptying caused by the cannabis. “This patient does not have brittle diabetes when he's not smoking dope,” he said.

A third case involved a 29-year-old woman with a 20-year history of type 1 diabetes and an HbA_1c of 12% despite being on an insulin pump. She worked as a bank teller, and was not married.

This patient had frequent hospitalizations for pyelonephritis during the previous 10 years, although none for diabetic ketoacidosis.

“These patients are very good at taking just enough insulin to stay out of really bad ketoacidosis, even though they're ketotic most of the time,” Dr. Hirsch said.

In 2001 she switched from the insulin pump to glargine and lispro, with no change in HbA_1c.

She denied having depression and refused evaluation by a psychiatrist or psychologist.

In 2002 she developed mucormycosis and was hospitalized for 2 weeks and released on home intravenous antibiotics.

“One week after discharge the mother found the patient dead at home. The home antibiotics had never been opened,” he said.

Like many patients with uncontrolled or brittle diabetes, this patient had severe major depression. With no family support, she was totally incapable of taking care of the diabetes and too depressed and overwhelmed even to take the antibiotics. “This is as difficult a case as you can get,” he said.

It can be quite dramatic how poorly some of these patients do, Dr. Hirsch continued. In one series where 20 patients whose mean age was 19 were followed for 8 years, 2 of the patients died. In another series of 33 patients followed for a decade, 5 were lost, and of the remaining patients, 19% died from diabetic ketoacidosis, hypoglycemia, or end-stage renal disease.

“What you want to do when you present cases to a group like this is talk about really tough patients and how everybody lived happily ever after. That doesn't often happen with brittle diabetes,” he said.

NEW YORK — True brittle diabetes is a rarity, with characteristic blood glucose lability, frequent hospitalizations, and life disruption often reflecting underlying psychiatric or organic disease, according to Dr. Irl B. Hirsch.

Diagnosis and management of this potentially lethal condition present significant challenges, as was shown in several cases Dr. Hirsch presented at a meeting sponsored by the American Diabetes Association.

One case involved a 23-year-old woman who presented with a 15-year history of type 1 diabetes in 2000. She had been on an insulin pump for 5 years, and her hemoglobin A_1c (HbA_1c) levels ranged from 9% to 12%. As a teenager she had had an eating disorder and had multiple hospitalizations for diabetic ketoacidosis. In the previous 2 years she had been hospitalized twice for gastroparesis, and had developed severe peripheral neuropathy and osteoporosis.

By 2002 she developed nonproliferative retinopathy and proteinuria. “All those years of poor control were already catching up with her at age 25,” said Dr. Hirsch, professor of medicine in the division of metabolism, endocrinology, and nutrition at the University of Washington, Seattle.

In 2004 she had an unplanned pregnancy and was hospitalized for 4 months, delivering the child 3 months prematurely. Her glucose was well controlled while she was in the hospital, but subsequently HbA_1c became elevated once again, reaching 10.4%.

Finally, in the summer of 2006, she had a kidney-pancreas transplant. “So the question is, does she have brittle diabetes?” Dr. Hirsch asked.

A diagnostic work-up determined that she had underlying celiac disease, with an important clue being the osteoporosis. “When you see osteoporosis in a young person you have to think about calcium absorption,” he said. “Celiac disease often goes hand in hand with type 1 diabetes.”

These patients can have extremely irregular blood glucose patterns because their food absorption is so erratic, he added.

A further concern to keep in mind with a patient such as this is that between one-third and one-half of all teenage girls with type 1 diabetes will withhold insulin at some time for weight loss. “Unfortunately, this is a very effective and dangerous way to lose weight,” Dr. Hirsch said.

A second case involved a 30-year-old man who had nine hospitalizations during the first half of 2006 because of severe gastroparesis. “We solved this case with the help of our friends at the Mayo Clinic,” Dr. Hirsch said.

The patient was diagnosed with cannabis hyperemesis syndrome, a condition associated with long-term cannabis use that is characterized by cyclical episodes of vomiting in a susceptible patient.

“When he stopped smoking he also stopped coming to the hospital, but when he started smoking again the hospitalizations recurred,” he said.

The likely mechanism for this little-known phenomenon is a slowing of gastric emptying caused by the cannabis. “This patient does not have brittle diabetes when he's not smoking dope,” he said.

A third case involved a 29-year-old woman with a 20-year history of type 1 diabetes and an HbA_1c of 12% despite being on an insulin pump. She worked as a bank teller, and was not married.

This patient had frequent hospitalizations for pyelonephritis during the previous 10 years, although none for diabetic ketoacidosis.

“These patients are very good at taking just enough insulin to stay out of really bad ketoacidosis, even though they're ketotic most of the time,” Dr. Hirsch said.

In 2001 she switched from the insulin pump to glargine and lispro, with no change in HbA_1c.

She denied having depression and refused evaluation by a psychiatrist or psychologist.

In 2002 she developed mucormycosis and was hospitalized for 2 weeks and released on home intravenous antibiotics.

“One week after discharge the mother found the patient dead at home. The home antibiotics had never been opened,” he said.

Like many patients with uncontrolled or brittle diabetes, this patient had severe major depression. With no family support, she was totally incapable of taking care of the diabetes and too depressed and overwhelmed even to take the antibiotics. “This is as difficult a case as you can get,” he said.

It can be quite dramatic how poorly some of these patients do, Dr. Hirsch continued. In one series where 20 patients whose mean age was 19 were followed for 8 years, 2 of the patients died. In another series of 33 patients followed for a decade, 5 were lost, and of the remaining patients, 19% died from diabetic ketoacidosis, hypoglycemia, or end-stage renal disease.

“What you want to do when you present cases to a group like this is talk about really tough patients and how everybody lived happily ever after. That doesn't often happen with brittle diabetes,” he said.

NEW YORK — True brittle diabetes is a rarity, with characteristic blood glucose lability, frequent hospitalizations, and life disruption often reflecting underlying psychiatric or organic disease, according to Dr. Irl B. Hirsch.

Diagnosis and management of this potentially lethal condition present significant challenges, as was shown in several cases Dr. Hirsch presented at a meeting sponsored by the American Diabetes Association.

One case involved a 23-year-old woman who presented with a 15-year history of type 1 diabetes in 2000. She had been on an insulin pump for 5 years, and her hemoglobin A_1c (HbA_1c) levels ranged from 9% to 12%. As a teenager she had had an eating disorder and had multiple hospitalizations for diabetic ketoacidosis. In the previous 2 years she had been hospitalized twice for gastroparesis, and had developed severe peripheral neuropathy and osteoporosis.

By 2002 she developed nonproliferative retinopathy and proteinuria. “All those years of poor control were already catching up with her at age 25,” said Dr. Hirsch, professor of medicine in the division of metabolism, endocrinology, and nutrition at the University of Washington, Seattle.

In 2004 she had an unplanned pregnancy and was hospitalized for 4 months, delivering the child 3 months prematurely. Her glucose was well controlled while she was in the hospital, but subsequently HbA_1c became elevated once again, reaching 10.4%.

Finally, in the summer of 2006, she had a kidney-pancreas transplant. “So the question is, does she have brittle diabetes?” Dr. Hirsch asked.

A diagnostic work-up determined that she had underlying celiac disease, with an important clue being the osteoporosis. “When you see osteoporosis in a young person you have to think about calcium absorption,” he said. “Celiac disease often goes hand in hand with type 1 diabetes.”

These patients can have extremely irregular blood glucose patterns because their food absorption is so erratic, he added.

A further concern to keep in mind with a patient such as this is that between one-third and one-half of all teenage girls with type 1 diabetes will withhold insulin at some time for weight loss. “Unfortunately, this is a very effective and dangerous way to lose weight,” Dr. Hirsch said.

A second case involved a 30-year-old man who had nine hospitalizations during the first half of 2006 because of severe gastroparesis. “We solved this case with the help of our friends at the Mayo Clinic,” Dr. Hirsch said.

The patient was diagnosed with cannabis hyperemesis syndrome, a condition associated with long-term cannabis use that is characterized by cyclical episodes of vomiting in a susceptible patient.

“When he stopped smoking he also stopped coming to the hospital, but when he started smoking again the hospitalizations recurred,” he said.

The likely mechanism for this little-known phenomenon is a slowing of gastric emptying caused by the cannabis. “This patient does not have brittle diabetes when he's not smoking dope,” he said.

A third case involved a 29-year-old woman with a 20-year history of type 1 diabetes and an HbA_1c of 12% despite being on an insulin pump. She worked as a bank teller, and was not married.

This patient had frequent hospitalizations for pyelonephritis during the previous 10 years, although none for diabetic ketoacidosis.

“These patients are very good at taking just enough insulin to stay out of really bad ketoacidosis, even though they're ketotic most of the time,” Dr. Hirsch said.

In 2001 she switched from the insulin pump to glargine and lispro, with no change in HbA_1c.

She denied having depression and refused evaluation by a psychiatrist or psychologist.

In 2002 she developed mucormycosis and was hospitalized for 2 weeks and released on home intravenous antibiotics.

“One week after discharge the mother found the patient dead at home. The home antibiotics had never been opened,” he said.

Like many patients with uncontrolled or brittle diabetes, this patient had severe major depression. With no family support, she was totally incapable of taking care of the diabetes and too depressed and overwhelmed even to take the antibiotics. “This is as difficult a case as you can get,” he said.

It can be quite dramatic how poorly some of these patients do, Dr. Hirsch continued. In one series where 20 patients whose mean age was 19 were followed for 8 years, 2 of the patients died. In another series of 33 patients followed for a decade, 5 were lost, and of the remaining patients, 19% died from diabetic ketoacidosis, hypoglycemia, or end-stage renal disease.

“What you want to do when you present cases to a group like this is talk about really tough patients and how everybody lived happily ever after. That doesn't often happen with brittle diabetes,” he said.