Diana Mahoney

BOSTON — Alterations in circulating antiangiogenic protein levels in pregnant women with lupus and antiphospholipid antibody syndrome may predict preeclampsia, a pregnancy complication for which they are at increased risk, according to data presented at the annual meeting of the American College of Rheumatology.

The findings suggest that identification of angiogenic imbalances early in gestation and subsequent interventions targeting the inflammatory pathways that trigger the imbalances could potentially reduce the incidence of preeclampsia in women with these autoimmune conditions, reported Dr. Jane E. Salmon of the Hospital for Special Surgery in New York.

In a nested case-control study of pregnant women with systemic lupus erythematosus (SLE) and/or antiphospholipid antibody (APLA) syndrome, women with elevated levels of circulating soluble fms-like tyrosine kinase 1 (sFlt-1) and soluble endoglin (sEng) at midpregnancy were at significantly increased risk for preeclampsia later in pregnancy, compared with age- and ethnicity-matched disease control patients who had SLE and/or APLA but not preeclampsia, reported Dr. Salmon.

Subjects for the investigation were enrolled in the multicenter observational PROMISSE (Predictors of Pregnancy Outcome BioMarkers in Antiphospholipid Antibody Syndrome and Systemic Lupus Erythematosus) study. In the larger study, 211 women with SLE and/or APLA who were less than 12 weeks pregnant at enrollment were followed throughout their pregnancy to determine the association between alterations in antiangiogenic factors and the later development of preeclampsia. In the nested case-control study, each of the 16 women with SLE and/or APLA syndrome from the larger cohort who developed preeclampsia was matched to both another SLE woman and/or an APLA-positive woman who didn't develop preeclampsia and to a healthy control who had neither autoimmune disease or pregnancy complications, Dr. Salmon explained.

Compared with the healthy controls, elevations in levels of circulating sFlt-1 were observed in all of the autoimmune patients as early as 12–15 weeks' gestation. Additionally, the rate of increase in levels of that protein throughout pregnancy was significantly higher in patients who went on to develop preeclampsia, and it was higher in all patients with autoimmune disorders, compared with healthy controls, reported Dr. Salmon. Among the patients with autoimmune disorders, elevated levels of sFlt-1 and sEng at 20–23 weeks' gestation were independently associated with increased risk of developing preeclampsia, she noted.

The findings indicate that sFlt-1 and sEng are biomarkers predictive of preeclampsia in patients with lupus and/or APLA and that “imbalances [in the levels of these biomarkers] early in pregnancy increase the vulnerability of these patients to preeclampsia,” said Dr. Salmon. “Because inflammatory mediators trigger production of antiangiogenic factors, early intervention to block specific pathways of inflammation could prevent angiogenic imbalance in lupus pregnancies at risk for preeclampsia.”

Dr. Salmon reported having no financial disclosures relative to this presentation.

BOSTON — Alterations in circulating antiangiogenic protein levels in pregnant women with lupus and antiphospholipid antibody syndrome may predict preeclampsia, a pregnancy complication for which they are at increased risk, according to data presented at the annual meeting of the American College of Rheumatology.

The findings suggest that identification of angiogenic imbalances early in gestation and subsequent interventions targeting the inflammatory pathways that trigger the imbalances could potentially reduce the incidence of preeclampsia in women with these autoimmune conditions, reported Dr. Jane E. Salmon of the Hospital for Special Surgery in New York.

In a nested case-control study of pregnant women with systemic lupus erythematosus (SLE) and/or antiphospholipid antibody (APLA) syndrome, women with elevated levels of circulating soluble fms-like tyrosine kinase 1 (sFlt-1) and soluble endoglin (sEng) at midpregnancy were at significantly increased risk for preeclampsia later in pregnancy, compared with age- and ethnicity-matched disease control patients who had SLE and/or APLA but not preeclampsia, reported Dr. Salmon.

Subjects for the investigation were enrolled in the multicenter observational PROMISSE (Predictors of Pregnancy Outcome BioMarkers in Antiphospholipid Antibody Syndrome and Systemic Lupus Erythematosus) study. In the larger study, 211 women with SLE and/or APLA who were less than 12 weeks pregnant at enrollment were followed throughout their pregnancy to determine the association between alterations in antiangiogenic factors and the later development of preeclampsia. In the nested case-control study, each of the 16 women with SLE and/or APLA syndrome from the larger cohort who developed preeclampsia was matched to both another SLE woman and/or an APLA-positive woman who didn't develop preeclampsia and to a healthy control who had neither autoimmune disease or pregnancy complications, Dr. Salmon explained.

Compared with the healthy controls, elevations in levels of circulating sFlt-1 were observed in all of the autoimmune patients as early as 12–15 weeks' gestation. Additionally, the rate of increase in levels of that protein throughout pregnancy was significantly higher in patients who went on to develop preeclampsia, and it was higher in all patients with autoimmune disorders, compared with healthy controls, reported Dr. Salmon. Among the patients with autoimmune disorders, elevated levels of sFlt-1 and sEng at 20–23 weeks' gestation were independently associated with increased risk of developing preeclampsia, she noted.

The findings indicate that sFlt-1 and sEng are biomarkers predictive of preeclampsia in patients with lupus and/or APLA and that “imbalances [in the levels of these biomarkers] early in pregnancy increase the vulnerability of these patients to preeclampsia,” said Dr. Salmon. “Because inflammatory mediators trigger production of antiangiogenic factors, early intervention to block specific pathways of inflammation could prevent angiogenic imbalance in lupus pregnancies at risk for preeclampsia.”

Dr. Salmon reported having no financial disclosures relative to this presentation.

BOSTON — Alterations in circulating antiangiogenic protein levels in pregnant women with lupus and antiphospholipid antibody syndrome may predict preeclampsia, a pregnancy complication for which they are at increased risk, according to data presented at the annual meeting of the American College of Rheumatology.

The findings suggest that identification of angiogenic imbalances early in gestation and subsequent interventions targeting the inflammatory pathways that trigger the imbalances could potentially reduce the incidence of preeclampsia in women with these autoimmune conditions, reported Dr. Jane E. Salmon of the Hospital for Special Surgery in New York.

In a nested case-control study of pregnant women with systemic lupus erythematosus (SLE) and/or antiphospholipid antibody (APLA) syndrome, women with elevated levels of circulating soluble fms-like tyrosine kinase 1 (sFlt-1) and soluble endoglin (sEng) at midpregnancy were at significantly increased risk for preeclampsia later in pregnancy, compared with age- and ethnicity-matched disease control patients who had SLE and/or APLA but not preeclampsia, reported Dr. Salmon.

Subjects for the investigation were enrolled in the multicenter observational PROMISSE (Predictors of Pregnancy Outcome BioMarkers in Antiphospholipid Antibody Syndrome and Systemic Lupus Erythematosus) study. In the larger study, 211 women with SLE and/or APLA who were less than 12 weeks pregnant at enrollment were followed throughout their pregnancy to determine the association between alterations in antiangiogenic factors and the later development of preeclampsia. In the nested case-control study, each of the 16 women with SLE and/or APLA syndrome from the larger cohort who developed preeclampsia was matched to both another SLE woman and/or an APLA-positive woman who didn't develop preeclampsia and to a healthy control who had neither autoimmune disease or pregnancy complications, Dr. Salmon explained.

Compared with the healthy controls, elevations in levels of circulating sFlt-1 were observed in all of the autoimmune patients as early as 12–15 weeks' gestation. Additionally, the rate of increase in levels of that protein throughout pregnancy was significantly higher in patients who went on to develop preeclampsia, and it was higher in all patients with autoimmune disorders, compared with healthy controls, reported Dr. Salmon. Among the patients with autoimmune disorders, elevated levels of sFlt-1 and sEng at 20–23 weeks' gestation were independently associated with increased risk of developing preeclampsia, she noted.

The findings indicate that sFlt-1 and sEng are biomarkers predictive of preeclampsia in patients with lupus and/or APLA and that “imbalances [in the levels of these biomarkers] early in pregnancy increase the vulnerability of these patients to preeclampsia,” said Dr. Salmon. “Because inflammatory mediators trigger production of antiangiogenic factors, early intervention to block specific pathways of inflammation could prevent angiogenic imbalance in lupus pregnancies at risk for preeclampsia.”

Dr. Salmon reported having no financial disclosures relative to this presentation.

BOSTON — Preventing meniscal damage should be a top therapeutic priority in the fight against knee osteoarthritis, Dr. Martin Englund said at the annual meeting of the American College of Rheumatology.

The Multicenter Osteoarthritis study (MOST) demonstrated for the first time that meniscal damage without surgical resection is a risk factor for tibiofemoral radiographic knee osteoarthritis.

The onset of knee osteoarthritis (OA) after the surgical removal of all or part of a torn meniscus is common, and numerous longitudinal studies have identified meniscectomy as a significant risk factor for knee OA, according to Dr. Englund, of Boston University, and his colleagues. However, no studies have demonstrated that meniscal damage without surgical resection is associated with the development of incident radiographic knee OA (ROA), he said. To evaluate the effect of baseline meniscal damage on incident tibiofemoral radiographic OA, the researchers conducted a nested case-control investigation comprising patients enrolled in the MOST study, a prospective observational study of 3,026 individuals older than age 50 who have or are at high risk for knee OA. Prior knee surgery patients were excluded. Participants had standardized, weight-bearing fixed-flexion x-rays at baseline and at 30 months.

These x-rays were read paired by a musculoskeletal radiologist and rheumatologist, both blinded to clinical and MRI data, Dr. Englund explained.

For the current study, 52 knees with no tibiofemoral ROA at baseline but evidence of grade 2 or higher ROA on the Kellgren-Lawrence scale in the 30-month follow-up were cases; 130 knees drawn from the same source population but with no tibiofemoral ROA at follow-up were controls.

To assess the baseline meniscal status of the knees, two blinded musculoskeletal radiologists reviewed coronal and sagittal fast spin echo MRI images and evaluated each on a collapsed scale. Knees with no damage were grade 0, those with a minor tear were grade 1, and those with a nondisplaced tear, displaced tear, maceration, or destruction were considered grade 2.

The investigators analyzed the link between meniscal damage and ROA using two logistic regression models (one in which the meniscal score was entered as 0, 1, or 2, and one in which it was entered as meniscal damage or no damage) adjusted for age, sex, body mass index, physical activity, and mechanical knee alignment.

“Meniscal damage at baseline was significantly more common in cases than in controls,” Dr. Englund reported, evident in 52% of case knees, versus 18% of controls.

In a multivariable model, the odds ratio of incident tibiofemoral ROA increased as the meniscal score increased, Dr. Englund noted. When knees with meniscal damage were compared with knees that had a normal meniscus at baseline, the adjusted odds ratio for ROA at 30 months was 4.3 for knees with a meniscal score of 1 and 7.8 for those with a meniscal score of 2.

Dr. Englund disclosed no financial conflicts related to his presentation.

Meniscal damage at baseline was 52% more common in case knees versus 18% of controls. DR. ENGLUND

ELSEVIER GLOBAL MEDICAL NEWS

BOSTON — Preventing meniscal damage should be a top therapeutic priority in the fight against knee osteoarthritis, Dr. Martin Englund said at the annual meeting of the American College of Rheumatology.

The Multicenter Osteoarthritis study (MOST) demonstrated for the first time that meniscal damage without surgical resection is a risk factor for tibiofemoral radiographic knee osteoarthritis.

The onset of knee osteoarthritis (OA) after the surgical removal of all or part of a torn meniscus is common, and numerous longitudinal studies have identified meniscectomy as a significant risk factor for knee OA, according to Dr. Englund, of Boston University, and his colleagues. However, no studies have demonstrated that meniscal damage without surgical resection is associated with the development of incident radiographic knee OA (ROA), he said. To evaluate the effect of baseline meniscal damage on incident tibiofemoral radiographic OA, the researchers conducted a nested case-control investigation comprising patients enrolled in the MOST study, a prospective observational study of 3,026 individuals older than age 50 who have or are at high risk for knee OA. Prior knee surgery patients were excluded. Participants had standardized, weight-bearing fixed-flexion x-rays at baseline and at 30 months.

These x-rays were read paired by a musculoskeletal radiologist and rheumatologist, both blinded to clinical and MRI data, Dr. Englund explained.

For the current study, 52 knees with no tibiofemoral ROA at baseline but evidence of grade 2 or higher ROA on the Kellgren-Lawrence scale in the 30-month follow-up were cases; 130 knees drawn from the same source population but with no tibiofemoral ROA at follow-up were controls.

To assess the baseline meniscal status of the knees, two blinded musculoskeletal radiologists reviewed coronal and sagittal fast spin echo MRI images and evaluated each on a collapsed scale. Knees with no damage were grade 0, those with a minor tear were grade 1, and those with a nondisplaced tear, displaced tear, maceration, or destruction were considered grade 2.

The investigators analyzed the link between meniscal damage and ROA using two logistic regression models (one in which the meniscal score was entered as 0, 1, or 2, and one in which it was entered as meniscal damage or no damage) adjusted for age, sex, body mass index, physical activity, and mechanical knee alignment.

“Meniscal damage at baseline was significantly more common in cases than in controls,” Dr. Englund reported, evident in 52% of case knees, versus 18% of controls.

In a multivariable model, the odds ratio of incident tibiofemoral ROA increased as the meniscal score increased, Dr. Englund noted. When knees with meniscal damage were compared with knees that had a normal meniscus at baseline, the adjusted odds ratio for ROA at 30 months was 4.3 for knees with a meniscal score of 1 and 7.8 for those with a meniscal score of 2.

Dr. Englund disclosed no financial conflicts related to his presentation.

Meniscal damage at baseline was 52% more common in case knees versus 18% of controls. DR. ENGLUND

ELSEVIER GLOBAL MEDICAL NEWS

BOSTON — Preventing meniscal damage should be a top therapeutic priority in the fight against knee osteoarthritis, Dr. Martin Englund said at the annual meeting of the American College of Rheumatology.

The Multicenter Osteoarthritis study (MOST) demonstrated for the first time that meniscal damage without surgical resection is a risk factor for tibiofemoral radiographic knee osteoarthritis.

The onset of knee osteoarthritis (OA) after the surgical removal of all or part of a torn meniscus is common, and numerous longitudinal studies have identified meniscectomy as a significant risk factor for knee OA, according to Dr. Englund, of Boston University, and his colleagues. However, no studies have demonstrated that meniscal damage without surgical resection is associated with the development of incident radiographic knee OA (ROA), he said. To evaluate the effect of baseline meniscal damage on incident tibiofemoral radiographic OA, the researchers conducted a nested case-control investigation comprising patients enrolled in the MOST study, a prospective observational study of 3,026 individuals older than age 50 who have or are at high risk for knee OA. Prior knee surgery patients were excluded. Participants had standardized, weight-bearing fixed-flexion x-rays at baseline and at 30 months.

These x-rays were read paired by a musculoskeletal radiologist and rheumatologist, both blinded to clinical and MRI data, Dr. Englund explained.

For the current study, 52 knees with no tibiofemoral ROA at baseline but evidence of grade 2 or higher ROA on the Kellgren-Lawrence scale in the 30-month follow-up were cases; 130 knees drawn from the same source population but with no tibiofemoral ROA at follow-up were controls.

To assess the baseline meniscal status of the knees, two blinded musculoskeletal radiologists reviewed coronal and sagittal fast spin echo MRI images and evaluated each on a collapsed scale. Knees with no damage were grade 0, those with a minor tear were grade 1, and those with a nondisplaced tear, displaced tear, maceration, or destruction were considered grade 2.

The investigators analyzed the link between meniscal damage and ROA using two logistic regression models (one in which the meniscal score was entered as 0, 1, or 2, and one in which it was entered as meniscal damage or no damage) adjusted for age, sex, body mass index, physical activity, and mechanical knee alignment.

“Meniscal damage at baseline was significantly more common in cases than in controls,” Dr. Englund reported, evident in 52% of case knees, versus 18% of controls.

In a multivariable model, the odds ratio of incident tibiofemoral ROA increased as the meniscal score increased, Dr. Englund noted. When knees with meniscal damage were compared with knees that had a normal meniscus at baseline, the adjusted odds ratio for ROA at 30 months was 4.3 for knees with a meniscal score of 1 and 7.8 for those with a meniscal score of 2.

Dr. Englund disclosed no financial conflicts related to his presentation.

Meniscal damage at baseline was 52% more common in case knees versus 18% of controls. DR. ENGLUND

ELSEVIER GLOBAL MEDICAL NEWS

BOSTON — A new, long-acting interleukin-1 inhibitor being tested for multiple inflammatory conditions substantially decreased disease activity and pain associated with chronic active gout in a placebo-controlled pilot study.

If the findings are validated in larger investigations, the drug, rilonacept, may offer much-needed relief to patients with severe gouty arthritis who are refractory to other therapies, Dr. Robert Terkeltaub said in a late-breaking poster presentation at the annual meeting of the American College of Rheumatology.

Studies have shown that gout-associated uric acid crystals activate the NALP3 (cryopyrin) inflammasome, resulting in the production of active interleukin-1 (IL-1). Rilonacept, a fusion protein that is given by subcutaneous injection, attaches to and neutralizes IL-1 before the proinflammatory cytokine attaches to cell surface receptors and generates inflammation-triggering signals. Unlike some of the IL-1 blocking agents currently on the market, rilonacept is described as an IL-1-specific cytokine trap: Once the IL-1 attaches to rilonacept, it cannot bind to the cell surface receptors and is eliminated from the body with the rilonacept.

Based on data from preclinical studies and a clinical case series suggesting that blockade of the NALP3 inflammasome IL-1 pathway may be an effective treatment strategy for gout, as well as the promising results of a phase III trial of the drug in patients with cryopyrin-associated periodic syndrome (CAPS) arising from NALP3 mutations, Dr. Terkeltaub, professor of medicine at the University of California, San Diego, and colleagues, sought to assess the utility of the drug in chronic active gout in a multicenter, nonrandomized phase III trial.

The single-blind, placebo-controlled study enrolled 10 patients with severe chronic gout, mean age 62 years, with a mean disease duration of 13 years. Inclusion criteria were a diagnosis of chronic gouty arthritis for at least 6 months, at least one active joint for a minimum of 4 weeks, and a self-reported pain visual analog scale (VAS) of 3 or higher. The study protocol included a run-in period of 2 weekly subcutaneous injections of placebo, followed by 6 weekly injections of rilonacept. Gout activity was assessed using the Subject Pain VAS, Subject and Physician Global VAS, joint count, and serum levels of high-sensitivity C-reactive protein (hs-CRP).

At baseline, the mean and median Subject Pain VAS scores were 5.1 and 5.0, respectively. The mean and median changes in Subject Pain VAS from baseline to week 2 with placebo treatment were 0.25 and −0.25, respectively, and from week 2 to week 8 with rilonacept treatment were −3.2 and −2.25, respectively, Dr. Terkeltaub reported. During the active treatment period, 7 of the 10 subjects showed at least 50% improvement in Subject Pain VAS, and 6 of the 10 showed at least 75% improvement. By treatment week 8, serum CRP levels decreased by 59%, he said. At week 14, which was 6 weeks after the last dose of rilonacept, a trend toward baseline hs-CRP levels was observed.

Rilonacept treatment was not associated with deaths or severe adverse events. It generally was well tolerated with the most common adverse events being mild to moderate injection site reactions, Dr. Terkeltaub said.

The drug might be particularly useful in the treatment of “increasingly complex, refractory cases of gout,” said Dr. Terkeltaub. Advanced age, comorbidities such as chronic kidney disease, and concomitant medications complicate management decisions, he noted, as does the lack of new Food and Drug Administration-approved treatment options for “difficult gout.” The drug's ability to interfere with the IL-1 inflammatory process suggest it could be useful as an adjunct to uric acid-lowering drugs in gout, which sometimes lead to disease flares, he said.

Dr. Terkeltaub disclosed that he has had financial or other relationships with multiple companies, including TAP Pharmaceutical Products Inc., Savient Pharmaceuticals, ISIS Pharmaceuticals Inc., BioCryst Pharmaceuticals Inc., Novartis AG, and Regeneron Pharmaceuticals Inc., maker of rilonacept.

BOSTON — A new, long-acting interleukin-1 inhibitor being tested for multiple inflammatory conditions substantially decreased disease activity and pain associated with chronic active gout in a placebo-controlled pilot study.

If the findings are validated in larger investigations, the drug, rilonacept, may offer much-needed relief to patients with severe gouty arthritis who are refractory to other therapies, Dr. Robert Terkeltaub said in a late-breaking poster presentation at the annual meeting of the American College of Rheumatology.

Studies have shown that gout-associated uric acid crystals activate the NALP3 (cryopyrin) inflammasome, resulting in the production of active interleukin-1 (IL-1). Rilonacept, a fusion protein that is given by subcutaneous injection, attaches to and neutralizes IL-1 before the proinflammatory cytokine attaches to cell surface receptors and generates inflammation-triggering signals. Unlike some of the IL-1 blocking agents currently on the market, rilonacept is described as an IL-1-specific cytokine trap: Once the IL-1 attaches to rilonacept, it cannot bind to the cell surface receptors and is eliminated from the body with the rilonacept.

Based on data from preclinical studies and a clinical case series suggesting that blockade of the NALP3 inflammasome IL-1 pathway may be an effective treatment strategy for gout, as well as the promising results of a phase III trial of the drug in patients with cryopyrin-associated periodic syndrome (CAPS) arising from NALP3 mutations, Dr. Terkeltaub, professor of medicine at the University of California, San Diego, and colleagues, sought to assess the utility of the drug in chronic active gout in a multicenter, nonrandomized phase III trial.

The single-blind, placebo-controlled study enrolled 10 patients with severe chronic gout, mean age 62 years, with a mean disease duration of 13 years. Inclusion criteria were a diagnosis of chronic gouty arthritis for at least 6 months, at least one active joint for a minimum of 4 weeks, and a self-reported pain visual analog scale (VAS) of 3 or higher. The study protocol included a run-in period of 2 weekly subcutaneous injections of placebo, followed by 6 weekly injections of rilonacept. Gout activity was assessed using the Subject Pain VAS, Subject and Physician Global VAS, joint count, and serum levels of high-sensitivity C-reactive protein (hs-CRP).

At baseline, the mean and median Subject Pain VAS scores were 5.1 and 5.0, respectively. The mean and median changes in Subject Pain VAS from baseline to week 2 with placebo treatment were 0.25 and −0.25, respectively, and from week 2 to week 8 with rilonacept treatment were −3.2 and −2.25, respectively, Dr. Terkeltaub reported. During the active treatment period, 7 of the 10 subjects showed at least 50% improvement in Subject Pain VAS, and 6 of the 10 showed at least 75% improvement. By treatment week 8, serum CRP levels decreased by 59%, he said. At week 14, which was 6 weeks after the last dose of rilonacept, a trend toward baseline hs-CRP levels was observed.

Rilonacept treatment was not associated with deaths or severe adverse events. It generally was well tolerated with the most common adverse events being mild to moderate injection site reactions, Dr. Terkeltaub said.

The drug might be particularly useful in the treatment of “increasingly complex, refractory cases of gout,” said Dr. Terkeltaub. Advanced age, comorbidities such as chronic kidney disease, and concomitant medications complicate management decisions, he noted, as does the lack of new Food and Drug Administration-approved treatment options for “difficult gout.” The drug's ability to interfere with the IL-1 inflammatory process suggest it could be useful as an adjunct to uric acid-lowering drugs in gout, which sometimes lead to disease flares, he said.

Dr. Terkeltaub disclosed that he has had financial or other relationships with multiple companies, including TAP Pharmaceutical Products Inc., Savient Pharmaceuticals, ISIS Pharmaceuticals Inc., BioCryst Pharmaceuticals Inc., Novartis AG, and Regeneron Pharmaceuticals Inc., maker of rilonacept.

BOSTON — A new, long-acting interleukin-1 inhibitor being tested for multiple inflammatory conditions substantially decreased disease activity and pain associated with chronic active gout in a placebo-controlled pilot study.

If the findings are validated in larger investigations, the drug, rilonacept, may offer much-needed relief to patients with severe gouty arthritis who are refractory to other therapies, Dr. Robert Terkeltaub said in a late-breaking poster presentation at the annual meeting of the American College of Rheumatology.

Studies have shown that gout-associated uric acid crystals activate the NALP3 (cryopyrin) inflammasome, resulting in the production of active interleukin-1 (IL-1). Rilonacept, a fusion protein that is given by subcutaneous injection, attaches to and neutralizes IL-1 before the proinflammatory cytokine attaches to cell surface receptors and generates inflammation-triggering signals. Unlike some of the IL-1 blocking agents currently on the market, rilonacept is described as an IL-1-specific cytokine trap: Once the IL-1 attaches to rilonacept, it cannot bind to the cell surface receptors and is eliminated from the body with the rilonacept.

Based on data from preclinical studies and a clinical case series suggesting that blockade of the NALP3 inflammasome IL-1 pathway may be an effective treatment strategy for gout, as well as the promising results of a phase III trial of the drug in patients with cryopyrin-associated periodic syndrome (CAPS) arising from NALP3 mutations, Dr. Terkeltaub, professor of medicine at the University of California, San Diego, and colleagues, sought to assess the utility of the drug in chronic active gout in a multicenter, nonrandomized phase III trial.

The single-blind, placebo-controlled study enrolled 10 patients with severe chronic gout, mean age 62 years, with a mean disease duration of 13 years. Inclusion criteria were a diagnosis of chronic gouty arthritis for at least 6 months, at least one active joint for a minimum of 4 weeks, and a self-reported pain visual analog scale (VAS) of 3 or higher. The study protocol included a run-in period of 2 weekly subcutaneous injections of placebo, followed by 6 weekly injections of rilonacept. Gout activity was assessed using the Subject Pain VAS, Subject and Physician Global VAS, joint count, and serum levels of high-sensitivity C-reactive protein (hs-CRP).

At baseline, the mean and median Subject Pain VAS scores were 5.1 and 5.0, respectively. The mean and median changes in Subject Pain VAS from baseline to week 2 with placebo treatment were 0.25 and −0.25, respectively, and from week 2 to week 8 with rilonacept treatment were −3.2 and −2.25, respectively, Dr. Terkeltaub reported. During the active treatment period, 7 of the 10 subjects showed at least 50% improvement in Subject Pain VAS, and 6 of the 10 showed at least 75% improvement. By treatment week 8, serum CRP levels decreased by 59%, he said. At week 14, which was 6 weeks after the last dose of rilonacept, a trend toward baseline hs-CRP levels was observed.

Rilonacept treatment was not associated with deaths or severe adverse events. It generally was well tolerated with the most common adverse events being mild to moderate injection site reactions, Dr. Terkeltaub said.

The drug might be particularly useful in the treatment of “increasingly complex, refractory cases of gout,” said Dr. Terkeltaub. Advanced age, comorbidities such as chronic kidney disease, and concomitant medications complicate management decisions, he noted, as does the lack of new Food and Drug Administration-approved treatment options for “difficult gout.” The drug's ability to interfere with the IL-1 inflammatory process suggest it could be useful as an adjunct to uric acid-lowering drugs in gout, which sometimes lead to disease flares, he said.

Dr. Terkeltaub disclosed that he has had financial or other relationships with multiple companies, including TAP Pharmaceutical Products Inc., Savient Pharmaceuticals, ISIS Pharmaceuticals Inc., BioCryst Pharmaceuticals Inc., Novartis AG, and Regeneron Pharmaceuticals Inc., maker of rilonacept.

BOSTON — Preventing meniscal damage should be a top therapeutic priority in the fight against knee osteoarthritis, Dr. Martin Englund said at the annual meeting of the American College of Rheumatology.

Dr. Englund of Boston University and his colleagues in the Multicenter Osteoarthritis (MOST) study demonstrated for the first time that meniscal damage without surgical resection is a potent risk factor for the development of tibiofemoral radiographic knee osteoarthritis (OA).

No studies have demonstrated that meniscal damage without surgical resection is associated with the development of incident radiographic knee OA (ROA), he said.

The researchers conducted a nested case-control investigation comprising patients enrolled in the MOST study, which is a prospective observational study of 3,026 individuals older than age 50 who have or are at high risk of developing knee OA, excluding those who have had previous knee surgery. As per the MOST protocol, study participants underwent standardized, weight-bearing fixed-flexion x-rays at baseline and at 30 months, and these x-rays were read paired by a musculoskeletal radiologist and rheumatologist who were blinded to clinical and MRI data, Dr. Englund said.

For the current study, 52 knees that had no tibiofemoral ROA at baseline but had evidence of grade 2 or higher ROA on the Kellgren-Lawrence scale during the 30-month follow-up were case knees, and 130 knees drawn from the same source population but with no tibiofemoral ROA at follow-up served as controls.

To assess the baseline meniscal status of the knees included in the analysis, two musculoskeletal radiologists who were blinded to the case-control status of the knees reviewed coronal and sagittal fast spin echo MRI images and evaluated each for meniscal damage using a collapsed scale, whereby knees with no meniscal damage were graded as 0, those with a minor tear were considered grade 1, and those with a nondisplaced tear, displaced tear, maceration, or destruction were considered grade 2.

“Meniscal damage at baseline was significantly more common in cases than in controls,” Dr. Englund reported. Specifically, meniscal damage was evident in 52% of the case knees, compared with 18% of the control knees. When knees with meniscal damage were compared with knees that had a normal meniscus at baseline, the adjusted odds ratio for ROA at 30 months was 4.3 for knees with a meniscal score of 1 and 7.8 for those with a meniscal score of 2.

The findings highlight the need for better treatments and prevention of meniscal damage. Dr. Englund disclosed no financial conflicts related to his presentation.

BOSTON — Preventing meniscal damage should be a top therapeutic priority in the fight against knee osteoarthritis, Dr. Martin Englund said at the annual meeting of the American College of Rheumatology.

Dr. Englund of Boston University and his colleagues in the Multicenter Osteoarthritis (MOST) study demonstrated for the first time that meniscal damage without surgical resection is a potent risk factor for the development of tibiofemoral radiographic knee osteoarthritis (OA).

No studies have demonstrated that meniscal damage without surgical resection is associated with the development of incident radiographic knee OA (ROA), he said.

The researchers conducted a nested case-control investigation comprising patients enrolled in the MOST study, which is a prospective observational study of 3,026 individuals older than age 50 who have or are at high risk of developing knee OA, excluding those who have had previous knee surgery. As per the MOST protocol, study participants underwent standardized, weight-bearing fixed-flexion x-rays at baseline and at 30 months, and these x-rays were read paired by a musculoskeletal radiologist and rheumatologist who were blinded to clinical and MRI data, Dr. Englund said.

For the current study, 52 knees that had no tibiofemoral ROA at baseline but had evidence of grade 2 or higher ROA on the Kellgren-Lawrence scale during the 30-month follow-up were case knees, and 130 knees drawn from the same source population but with no tibiofemoral ROA at follow-up served as controls.

To assess the baseline meniscal status of the knees included in the analysis, two musculoskeletal radiologists who were blinded to the case-control status of the knees reviewed coronal and sagittal fast spin echo MRI images and evaluated each for meniscal damage using a collapsed scale, whereby knees with no meniscal damage were graded as 0, those with a minor tear were considered grade 1, and those with a nondisplaced tear, displaced tear, maceration, or destruction were considered grade 2.

“Meniscal damage at baseline was significantly more common in cases than in controls,” Dr. Englund reported. Specifically, meniscal damage was evident in 52% of the case knees, compared with 18% of the control knees. When knees with meniscal damage were compared with knees that had a normal meniscus at baseline, the adjusted odds ratio for ROA at 30 months was 4.3 for knees with a meniscal score of 1 and 7.8 for those with a meniscal score of 2.

The findings highlight the need for better treatments and prevention of meniscal damage. Dr. Englund disclosed no financial conflicts related to his presentation.

BOSTON — Preventing meniscal damage should be a top therapeutic priority in the fight against knee osteoarthritis, Dr. Martin Englund said at the annual meeting of the American College of Rheumatology.

Dr. Englund of Boston University and his colleagues in the Multicenter Osteoarthritis (MOST) study demonstrated for the first time that meniscal damage without surgical resection is a potent risk factor for the development of tibiofemoral radiographic knee osteoarthritis (OA).

No studies have demonstrated that meniscal damage without surgical resection is associated with the development of incident radiographic knee OA (ROA), he said.

The researchers conducted a nested case-control investigation comprising patients enrolled in the MOST study, which is a prospective observational study of 3,026 individuals older than age 50 who have or are at high risk of developing knee OA, excluding those who have had previous knee surgery. As per the MOST protocol, study participants underwent standardized, weight-bearing fixed-flexion x-rays at baseline and at 30 months, and these x-rays were read paired by a musculoskeletal radiologist and rheumatologist who were blinded to clinical and MRI data, Dr. Englund said.

For the current study, 52 knees that had no tibiofemoral ROA at baseline but had evidence of grade 2 or higher ROA on the Kellgren-Lawrence scale during the 30-month follow-up were case knees, and 130 knees drawn from the same source population but with no tibiofemoral ROA at follow-up served as controls.

To assess the baseline meniscal status of the knees included in the analysis, two musculoskeletal radiologists who were blinded to the case-control status of the knees reviewed coronal and sagittal fast spin echo MRI images and evaluated each for meniscal damage using a collapsed scale, whereby knees with no meniscal damage were graded as 0, those with a minor tear were considered grade 1, and those with a nondisplaced tear, displaced tear, maceration, or destruction were considered grade 2.

“Meniscal damage at baseline was significantly more common in cases than in controls,” Dr. Englund reported. Specifically, meniscal damage was evident in 52% of the case knees, compared with 18% of the control knees. When knees with meniscal damage were compared with knees that had a normal meniscus at baseline, the adjusted odds ratio for ROA at 30 months was 4.3 for knees with a meniscal score of 1 and 7.8 for those with a meniscal score of 2.

The findings highlight the need for better treatments and prevention of meniscal damage. Dr. Englund disclosed no financial conflicts related to his presentation.

BOSTON – The assumption that toddlers and preschoolers are not emotionally affected by traumatic grief in the same way as older children and adults are is not only wrong, it's dangerous, according to Chandra Ghosh Ippen, Ph.D.

Unaddressed traumatic grief in a very young child can manifest as vague but persistent fear and stress that threaten the child's core sense of safety and security, setting the stage for later behavioral problems and mental illness, Dr. Ippen said in a symposium at the annual meeting of the American Academy of Child and Adolescent Psychiatry.

Defined as a condition in which a child has lost a loved one under sudden or frightening circumstances that negatively affect the child's ability to negotiate the normal grieving process, childhood traumatic grief overlaps with, but is distinct from, uncomplicated bereavement in children and adult traumatic grief, according to symposium moderator Dr. Judith Cohen of Allegheny General Hospital in Pittsburgh.

“Children with traumatic grief get 'stuck' on the traumatic way their loved one died,” she said, so that efforts to remember happy, positive times with their loved one evoke only thoughts of how the person died. As a result, these children are, in effect, retraumatized each time they think or talk about their loved one, which impedes the normal course of a healthy grieving process–specifically the ability to reminisce about and preserve positive memories of the person who died and to reinvest in new relationships, she said.

“In very young children, the impact of the traumatic loss of a parent or caregiver is most evident through what they do versus what they say–how they interact, their body language,” said Dr. Ippen, clinical research coordinator of the Child Trauma Research Project (CTRP) at the University of California, San Francisco.

“In these kids,” she said, “the physical reaction is immediately evident when the loved one's name is brought up or the topic of the circumstances of the loss is introduced.”

Although efforts to accurately define and measure childhood traumatic grief are just emerging, effective intervention is possible. Within the CTRP, for example, Dr. Ippen and her colleagues have found child-parent psychotherapy (CPP) to be an effective tool.

An attachment-based intervention, CPP incorporates psychodynamic, relationship, and cognitive-behavioral principles for infants, toddlers, and preschool children who have experienced trauma. The treatment, which is delivered by a psychotherapist and typically lasts from 6 months to 1 year, is based on the premise that trauma-related problems in young children should be addressed within the context of the child's primary attachment relationships.

“In young children, their attachment system is the main organizer of emotional and behavioral responses, so the goal is to promote safety and growth in that relationship,” Dr. Ippen said. Doing so, she added, “will affect their entire developmental trajectory.”

Through free play with the parent and child, and the therapeutic use of developmental guidance and information, CPP targets and strengthens the caregiver-child relationship. The ultimate goal is the restoration of the child's sense of safety and trust in adult caretakers.

In a study published in 2005, CTRP investigators demonstrated the efficacy of child-parent psychotherapy in a randomized controlled trial of young trauma-exposed children. Dr. Ippen, along with lead author Alicia Lieberman, Ph.D., director of CTRP, and Patricia Van Horn, Ph.D., associate director, compared the impact of CPP with that of usual care in 75 children aged 3–5 years who had witnessed domestic violence (J. Am. Acad. Child Adolesc. Psychiatry 2005;44:1241–8).

The study population was not made up of children who had lost a parent or a loved one to death, but the trauma symptoms were similar, Dr. Ippen noted.

After treatment, the CPP children showed significantly greater reductions in total behavior problems and traumatic stress symptoms, compared with the usual care group. Additionally, CPP caregivers showed significantly greater reductions in avoidant symptoms.

In a 6-month follow-up study, the investigators observed that the improvements in both children's behavior and maternal symptoms continued after treatment had ended (J. Am. Acad. Child Adolesc. Psychiatry 2006;45:913–8).

“These findings suggest promise for childhood traumatic grief as well, where the goals are the same: to establish a safe and consistent environment and behavior, and to build empathetic relationships,” Dr. Ippen said.

“It's important to remember that where you have a child with trauma, you will generally have a caregiver with trauma.”

Therefore, using a relational approach simultaneously helps caregivers and children cope with their situations, she said. Also, promoting growth in the caregiver-child relationship “supports the healthy development of the child long after the intervention ends.”

BOSTON – The assumption that toddlers and preschoolers are not emotionally affected by traumatic grief in the same way as older children and adults are is not only wrong, it's dangerous, according to Chandra Ghosh Ippen, Ph.D.

Unaddressed traumatic grief in a very young child can manifest as vague but persistent fear and stress that threaten the child's core sense of safety and security, setting the stage for later behavioral problems and mental illness, Dr. Ippen said in a symposium at the annual meeting of the American Academy of Child and Adolescent Psychiatry.

Defined as a condition in which a child has lost a loved one under sudden or frightening circumstances that negatively affect the child's ability to negotiate the normal grieving process, childhood traumatic grief overlaps with, but is distinct from, uncomplicated bereavement in children and adult traumatic grief, according to symposium moderator Dr. Judith Cohen of Allegheny General Hospital in Pittsburgh.

“Children with traumatic grief get 'stuck' on the traumatic way their loved one died,” she said, so that efforts to remember happy, positive times with their loved one evoke only thoughts of how the person died. As a result, these children are, in effect, retraumatized each time they think or talk about their loved one, which impedes the normal course of a healthy grieving process–specifically the ability to reminisce about and preserve positive memories of the person who died and to reinvest in new relationships, she said.

“In very young children, the impact of the traumatic loss of a parent or caregiver is most evident through what they do versus what they say–how they interact, their body language,” said Dr. Ippen, clinical research coordinator of the Child Trauma Research Project (CTRP) at the University of California, San Francisco.

“In these kids,” she said, “the physical reaction is immediately evident when the loved one's name is brought up or the topic of the circumstances of the loss is introduced.”

Although efforts to accurately define and measure childhood traumatic grief are just emerging, effective intervention is possible. Within the CTRP, for example, Dr. Ippen and her colleagues have found child-parent psychotherapy (CPP) to be an effective tool.

An attachment-based intervention, CPP incorporates psychodynamic, relationship, and cognitive-behavioral principles for infants, toddlers, and preschool children who have experienced trauma. The treatment, which is delivered by a psychotherapist and typically lasts from 6 months to 1 year, is based on the premise that trauma-related problems in young children should be addressed within the context of the child's primary attachment relationships.

“In young children, their attachment system is the main organizer of emotional and behavioral responses, so the goal is to promote safety and growth in that relationship,” Dr. Ippen said. Doing so, she added, “will affect their entire developmental trajectory.”

Through free play with the parent and child, and the therapeutic use of developmental guidance and information, CPP targets and strengthens the caregiver-child relationship. The ultimate goal is the restoration of the child's sense of safety and trust in adult caretakers.

In a study published in 2005, CTRP investigators demonstrated the efficacy of child-parent psychotherapy in a randomized controlled trial of young trauma-exposed children. Dr. Ippen, along with lead author Alicia Lieberman, Ph.D., director of CTRP, and Patricia Van Horn, Ph.D., associate director, compared the impact of CPP with that of usual care in 75 children aged 3–5 years who had witnessed domestic violence (J. Am. Acad. Child Adolesc. Psychiatry 2005;44:1241–8).

The study population was not made up of children who had lost a parent or a loved one to death, but the trauma symptoms were similar, Dr. Ippen noted.

After treatment, the CPP children showed significantly greater reductions in total behavior problems and traumatic stress symptoms, compared with the usual care group. Additionally, CPP caregivers showed significantly greater reductions in avoidant symptoms.

In a 6-month follow-up study, the investigators observed that the improvements in both children's behavior and maternal symptoms continued after treatment had ended (J. Am. Acad. Child Adolesc. Psychiatry 2006;45:913–8).

“These findings suggest promise for childhood traumatic grief as well, where the goals are the same: to establish a safe and consistent environment and behavior, and to build empathetic relationships,” Dr. Ippen said.

“It's important to remember that where you have a child with trauma, you will generally have a caregiver with trauma.”

Therefore, using a relational approach simultaneously helps caregivers and children cope with their situations, she said. Also, promoting growth in the caregiver-child relationship “supports the healthy development of the child long after the intervention ends.”

BOSTON – The assumption that toddlers and preschoolers are not emotionally affected by traumatic grief in the same way as older children and adults are is not only wrong, it's dangerous, according to Chandra Ghosh Ippen, Ph.D.

Unaddressed traumatic grief in a very young child can manifest as vague but persistent fear and stress that threaten the child's core sense of safety and security, setting the stage for later behavioral problems and mental illness, Dr. Ippen said in a symposium at the annual meeting of the American Academy of Child and Adolescent Psychiatry.

Defined as a condition in which a child has lost a loved one under sudden or frightening circumstances that negatively affect the child's ability to negotiate the normal grieving process, childhood traumatic grief overlaps with, but is distinct from, uncomplicated bereavement in children and adult traumatic grief, according to symposium moderator Dr. Judith Cohen of Allegheny General Hospital in Pittsburgh.

“Children with traumatic grief get 'stuck' on the traumatic way their loved one died,” she said, so that efforts to remember happy, positive times with their loved one evoke only thoughts of how the person died. As a result, these children are, in effect, retraumatized each time they think or talk about their loved one, which impedes the normal course of a healthy grieving process–specifically the ability to reminisce about and preserve positive memories of the person who died and to reinvest in new relationships, she said.

“In very young children, the impact of the traumatic loss of a parent or caregiver is most evident through what they do versus what they say–how they interact, their body language,” said Dr. Ippen, clinical research coordinator of the Child Trauma Research Project (CTRP) at the University of California, San Francisco.

“In these kids,” she said, “the physical reaction is immediately evident when the loved one's name is brought up or the topic of the circumstances of the loss is introduced.”

Although efforts to accurately define and measure childhood traumatic grief are just emerging, effective intervention is possible. Within the CTRP, for example, Dr. Ippen and her colleagues have found child-parent psychotherapy (CPP) to be an effective tool.

An attachment-based intervention, CPP incorporates psychodynamic, relationship, and cognitive-behavioral principles for infants, toddlers, and preschool children who have experienced trauma. The treatment, which is delivered by a psychotherapist and typically lasts from 6 months to 1 year, is based on the premise that trauma-related problems in young children should be addressed within the context of the child's primary attachment relationships.

“In young children, their attachment system is the main organizer of emotional and behavioral responses, so the goal is to promote safety and growth in that relationship,” Dr. Ippen said. Doing so, she added, “will affect their entire developmental trajectory.”

Through free play with the parent and child, and the therapeutic use of developmental guidance and information, CPP targets and strengthens the caregiver-child relationship. The ultimate goal is the restoration of the child's sense of safety and trust in adult caretakers.

In a study published in 2005, CTRP investigators demonstrated the efficacy of child-parent psychotherapy in a randomized controlled trial of young trauma-exposed children. Dr. Ippen, along with lead author Alicia Lieberman, Ph.D., director of CTRP, and Patricia Van Horn, Ph.D., associate director, compared the impact of CPP with that of usual care in 75 children aged 3–5 years who had witnessed domestic violence (J. Am. Acad. Child Adolesc. Psychiatry 2005;44:1241–8).

The study population was not made up of children who had lost a parent or a loved one to death, but the trauma symptoms were similar, Dr. Ippen noted.

After treatment, the CPP children showed significantly greater reductions in total behavior problems and traumatic stress symptoms, compared with the usual care group. Additionally, CPP caregivers showed significantly greater reductions in avoidant symptoms.

In a 6-month follow-up study, the investigators observed that the improvements in both children's behavior and maternal symptoms continued after treatment had ended (J. Am. Acad. Child Adolesc. Psychiatry 2006;45:913–8).

“These findings suggest promise for childhood traumatic grief as well, where the goals are the same: to establish a safe and consistent environment and behavior, and to build empathetic relationships,” Dr. Ippen said.

“It's important to remember that where you have a child with trauma, you will generally have a caregiver with trauma.”

Therefore, using a relational approach simultaneously helps caregivers and children cope with their situations, she said. Also, promoting growth in the caregiver-child relationship “supports the healthy development of the child long after the intervention ends.”

BOSTON – Children and adolescents being treated for bipolar disorder and comorbid attention-deficit/hyperactivity disorder may benefit from the short-term use of adjunctive methylphenidate, a study has shown.

The findings add to the growing body of evidence supporting the concomitant treatment of both conditions. Using methylphenidate to treat patients with bipolar disorder has been the subject of controversy in light of concerns that the use of stimulant drugs in bipolar patients could exacerbate or trigger manic symptoms.

In fact, according to lead author Dr. Robert L. Findling of University Hospitals Case Medical Center, Cleveland, the addition of methylphenidate to monotherapy with either lithium or divalproex sodium (DVPX) or to combination therapy with both drugs “did not cause a destabilization of improved mood symptoms” in the 4-week, double-blind, placebo-controlled trial.

To examine the short-term efficacy of adjunctive methylphenidate in this patient population, Dr. Findling and his colleagues enrolled 20 young people aged 5–17 years who met DSM-IV criteria for bipolar disorder and ADHD. At the time of the investigation, all of the study participants were receiving a stable dose of at least one thymoleptic agent, and continued to have clinically significant symptoms of ADHD while euthymic.

As per study protocol, all of the patients received 1 week each of placebo, 5 mg of methylphenidate twice daily, 10 mg of methylphenidate twice daily, and 15 mg of methylphenidate twice daily using a crossover design, and were randomly assigned to receive one of six possible dosing orders.

The primary outcome measure for the study was the total score on the ADHD Rating Scale-IV (ARS-IV), which was completed by the parents. At the end of the study, before breaking the blind, the investigators determined a “best dose” week for each subject based on this measure.

A total of 16 patients, mean age 10.43 years, completed the trial. Of the 16, 12 were receiving combination therapy with DVPX and lithium, 3 were receiving DVPX monotherapy, and 1 was receiving lithium monotherapy.

To assess efficacy, the investigators compared psychometric ratings for the placebo week with those of the best dose week for each patient and observed significant differences for the ARS-IV Inattentive Subscale, the ARS-IV Impulsivity/Hyperactivity Subscale, and the ARS-IV total scores, indicating a therapeutic benefit, Dr. Findling reported in a poster presentation at the annual meeting of the American Academy of Child and Adolescent Psychiatry.

The investigators also used the Clinical Global Impression (CGI) severity scale to evaluate patient response to the therapy relative to the placebo week. The mean CGI-severity score was significantly lower at the best dose week, compared with the placebo week, “suggesting less psychiatric symptomatology,” said Dr. Findling, also of Case Western Reserve University.

The study was supported primarily by the Stanley Medical Research Institute. Study medications were provided, in part, by Abbott Laboratories, Dr. Findling disclosed.

BOSTON – Children and adolescents being treated for bipolar disorder and comorbid attention-deficit/hyperactivity disorder may benefit from the short-term use of adjunctive methylphenidate, a study has shown.

The findings add to the growing body of evidence supporting the concomitant treatment of both conditions. Using methylphenidate to treat patients with bipolar disorder has been the subject of controversy in light of concerns that the use of stimulant drugs in bipolar patients could exacerbate or trigger manic symptoms.

In fact, according to lead author Dr. Robert L. Findling of University Hospitals Case Medical Center, Cleveland, the addition of methylphenidate to monotherapy with either lithium or divalproex sodium (DVPX) or to combination therapy with both drugs “did not cause a destabilization of improved mood symptoms” in the 4-week, double-blind, placebo-controlled trial.

To examine the short-term efficacy of adjunctive methylphenidate in this patient population, Dr. Findling and his colleagues enrolled 20 young people aged 5–17 years who met DSM-IV criteria for bipolar disorder and ADHD. At the time of the investigation, all of the study participants were receiving a stable dose of at least one thymoleptic agent, and continued to have clinically significant symptoms of ADHD while euthymic.

As per study protocol, all of the patients received 1 week each of placebo, 5 mg of methylphenidate twice daily, 10 mg of methylphenidate twice daily, and 15 mg of methylphenidate twice daily using a crossover design, and were randomly assigned to receive one of six possible dosing orders.

The primary outcome measure for the study was the total score on the ADHD Rating Scale-IV (ARS-IV), which was completed by the parents. At the end of the study, before breaking the blind, the investigators determined a “best dose” week for each subject based on this measure.

A total of 16 patients, mean age 10.43 years, completed the trial. Of the 16, 12 were receiving combination therapy with DVPX and lithium, 3 were receiving DVPX monotherapy, and 1 was receiving lithium monotherapy.

To assess efficacy, the investigators compared psychometric ratings for the placebo week with those of the best dose week for each patient and observed significant differences for the ARS-IV Inattentive Subscale, the ARS-IV Impulsivity/Hyperactivity Subscale, and the ARS-IV total scores, indicating a therapeutic benefit, Dr. Findling reported in a poster presentation at the annual meeting of the American Academy of Child and Adolescent Psychiatry.

The investigators also used the Clinical Global Impression (CGI) severity scale to evaluate patient response to the therapy relative to the placebo week. The mean CGI-severity score was significantly lower at the best dose week, compared with the placebo week, “suggesting less psychiatric symptomatology,” said Dr. Findling, also of Case Western Reserve University.

The study was supported primarily by the Stanley Medical Research Institute. Study medications were provided, in part, by Abbott Laboratories, Dr. Findling disclosed.

BOSTON – Children and adolescents being treated for bipolar disorder and comorbid attention-deficit/hyperactivity disorder may benefit from the short-term use of adjunctive methylphenidate, a study has shown.

The findings add to the growing body of evidence supporting the concomitant treatment of both conditions. Using methylphenidate to treat patients with bipolar disorder has been the subject of controversy in light of concerns that the use of stimulant drugs in bipolar patients could exacerbate or trigger manic symptoms.

In fact, according to lead author Dr. Robert L. Findling of University Hospitals Case Medical Center, Cleveland, the addition of methylphenidate to monotherapy with either lithium or divalproex sodium (DVPX) or to combination therapy with both drugs “did not cause a destabilization of improved mood symptoms” in the 4-week, double-blind, placebo-controlled trial.

To examine the short-term efficacy of adjunctive methylphenidate in this patient population, Dr. Findling and his colleagues enrolled 20 young people aged 5–17 years who met DSM-IV criteria for bipolar disorder and ADHD. At the time of the investigation, all of the study participants were receiving a stable dose of at least one thymoleptic agent, and continued to have clinically significant symptoms of ADHD while euthymic.

As per study protocol, all of the patients received 1 week each of placebo, 5 mg of methylphenidate twice daily, 10 mg of methylphenidate twice daily, and 15 mg of methylphenidate twice daily using a crossover design, and were randomly assigned to receive one of six possible dosing orders.

The primary outcome measure for the study was the total score on the ADHD Rating Scale-IV (ARS-IV), which was completed by the parents. At the end of the study, before breaking the blind, the investigators determined a “best dose” week for each subject based on this measure.

A total of 16 patients, mean age 10.43 years, completed the trial. Of the 16, 12 were receiving combination therapy with DVPX and lithium, 3 were receiving DVPX monotherapy, and 1 was receiving lithium monotherapy.

To assess efficacy, the investigators compared psychometric ratings for the placebo week with those of the best dose week for each patient and observed significant differences for the ARS-IV Inattentive Subscale, the ARS-IV Impulsivity/Hyperactivity Subscale, and the ARS-IV total scores, indicating a therapeutic benefit, Dr. Findling reported in a poster presentation at the annual meeting of the American Academy of Child and Adolescent Psychiatry.

The investigators also used the Clinical Global Impression (CGI) severity scale to evaluate patient response to the therapy relative to the placebo week. The mean CGI-severity score was significantly lower at the best dose week, compared with the placebo week, “suggesting less psychiatric symptomatology,” said Dr. Findling, also of Case Western Reserve University.

The study was supported primarily by the Stanley Medical Research Institute. Study medications were provided, in part, by Abbott Laboratories, Dr. Findling disclosed.

BOSTON — A single botulinum toxin type A injection can decrease joint pain and improve function in patients with refractory shoulder osteoarthritis, Dr. Jasvinder Singh reported at the annual meeting of the American College of Rheumatology.

In a double-blind, randomized controlled trial involving 43 patients with moderate to severe shoulder arthritis pain, 21 patients were randomized to receive a single, intraarticular injection of botulinum toxin type A (Botox) and 22 patients were injected with a placebo.

Compared with baseline, the 28-day posttherapy pain levels in the treatment group were significantly lower than those reported in the placebo group, said Dr. Singh, staff physician at the Minneapolis VA Medical Center.

In particular, 38% of the patients who received the botulinum injection achieved a minimum 30% improvement in pain scores, compared with a 9% improvement among patients in the placebo group.

Preliminary animal and clincial studies have shown that neurotoxin injection for sustained analgesia is a promising approach to persistent joint pain, said Dr. Singh, noting that the agent may decrease pain by inhibiting vesicle release of neuropeptides—including substance P and calcitonin gene-related peptide—and by disrupting nociceptor function.

The current study assessed the efficacy of the neurotoxin in patients with chronic arthritis-associated shoulder pain who had failed to respond to corticosteroids or other pain medication and who were not candidates for shoulder arthroplasty.

All of the patients had a 6-month history of moderate to severe shoulder pain, which is categorized as greater than 4.5 (on a scale ranging from 0 to 10).

Patients randomized to the treatment intervention received a single injection of 100 units of botulinum toxin type A plus lidocaine, and patients in the placebo group received a single injection of saline plus lidocaine.

Patients were assessed using the Visual Analog Scale (VAS), a numeric rating scale (NRS) for day pain, and the Shoulder Pain and Disability Index (SPADI) pain subscale, said Dr. Singh.

Secondary outcomes included SPADI scores and the proportion of patients achieving clinically meaningful pain relief, defined as a minimum 30% improvement. At baseline, pain outcome variables between the intervention and placebo groups were comparable.

At day 28, the mean VAS pain score in the treatment group was 4.12, significantly lower than the mean 6.54 in the placebo group. Day pain, according to NRS and SPADI pain scores, was significantly improved in the treatment group.

The SPADI score was better at day 28 in the treatment group compared with that in the placebo group, with a trend toward significance, Dr. Singh said.

The investigators are analyzing the duration of the analgesic effect and the associated adverse effects.

The findings thus far provide “the initial proof of concept of effectiveness of botulinum toxin injection for relief of shoulder pain,” Dr. Singh said, adding they need to be replicated in a larger, multicenter, randomized trial before the treatment can be recommended.

Dr. Singh reported having received travel funds for previous research projects from Allergan Pharmaceuticals, maker of Botox. The current study was funded by the Arthritis Foundation, the Mayo Clinic, and the Minneapolis VA Medical Center.

BOSTON — A single botulinum toxin type A injection can decrease joint pain and improve function in patients with refractory shoulder osteoarthritis, Dr. Jasvinder Singh reported at the annual meeting of the American College of Rheumatology.

In a double-blind, randomized controlled trial involving 43 patients with moderate to severe shoulder arthritis pain, 21 patients were randomized to receive a single, intraarticular injection of botulinum toxin type A (Botox) and 22 patients were injected with a placebo.

Compared with baseline, the 28-day posttherapy pain levels in the treatment group were significantly lower than those reported in the placebo group, said Dr. Singh, staff physician at the Minneapolis VA Medical Center.

In particular, 38% of the patients who received the botulinum injection achieved a minimum 30% improvement in pain scores, compared with a 9% improvement among patients in the placebo group.

Preliminary animal and clincial studies have shown that neurotoxin injection for sustained analgesia is a promising approach to persistent joint pain, said Dr. Singh, noting that the agent may decrease pain by inhibiting vesicle release of neuropeptides—including substance P and calcitonin gene-related peptide—and by disrupting nociceptor function.

The current study assessed the efficacy of the neurotoxin in patients with chronic arthritis-associated shoulder pain who had failed to respond to corticosteroids or other pain medication and who were not candidates for shoulder arthroplasty.

All of the patients had a 6-month history of moderate to severe shoulder pain, which is categorized as greater than 4.5 (on a scale ranging from 0 to 10).

Patients randomized to the treatment intervention received a single injection of 100 units of botulinum toxin type A plus lidocaine, and patients in the placebo group received a single injection of saline plus lidocaine.

Patients were assessed using the Visual Analog Scale (VAS), a numeric rating scale (NRS) for day pain, and the Shoulder Pain and Disability Index (SPADI) pain subscale, said Dr. Singh.

Secondary outcomes included SPADI scores and the proportion of patients achieving clinically meaningful pain relief, defined as a minimum 30% improvement. At baseline, pain outcome variables between the intervention and placebo groups were comparable.

At day 28, the mean VAS pain score in the treatment group was 4.12, significantly lower than the mean 6.54 in the placebo group. Day pain, according to NRS and SPADI pain scores, was significantly improved in the treatment group.

The SPADI score was better at day 28 in the treatment group compared with that in the placebo group, with a trend toward significance, Dr. Singh said.

The investigators are analyzing the duration of the analgesic effect and the associated adverse effects.

The findings thus far provide “the initial proof of concept of effectiveness of botulinum toxin injection for relief of shoulder pain,” Dr. Singh said, adding they need to be replicated in a larger, multicenter, randomized trial before the treatment can be recommended.

Dr. Singh reported having received travel funds for previous research projects from Allergan Pharmaceuticals, maker of Botox. The current study was funded by the Arthritis Foundation, the Mayo Clinic, and the Minneapolis VA Medical Center.

BOSTON — A single botulinum toxin type A injection can decrease joint pain and improve function in patients with refractory shoulder osteoarthritis, Dr. Jasvinder Singh reported at the annual meeting of the American College of Rheumatology.

In a double-blind, randomized controlled trial involving 43 patients with moderate to severe shoulder arthritis pain, 21 patients were randomized to receive a single, intraarticular injection of botulinum toxin type A (Botox) and 22 patients were injected with a placebo.

Compared with baseline, the 28-day posttherapy pain levels in the treatment group were significantly lower than those reported in the placebo group, said Dr. Singh, staff physician at the Minneapolis VA Medical Center.

In particular, 38% of the patients who received the botulinum injection achieved a minimum 30% improvement in pain scores, compared with a 9% improvement among patients in the placebo group.

Preliminary animal and clincial studies have shown that neurotoxin injection for sustained analgesia is a promising approach to persistent joint pain, said Dr. Singh, noting that the agent may decrease pain by inhibiting vesicle release of neuropeptides—including substance P and calcitonin gene-related peptide—and by disrupting nociceptor function.

The current study assessed the efficacy of the neurotoxin in patients with chronic arthritis-associated shoulder pain who had failed to respond to corticosteroids or other pain medication and who were not candidates for shoulder arthroplasty.

All of the patients had a 6-month history of moderate to severe shoulder pain, which is categorized as greater than 4.5 (on a scale ranging from 0 to 10).

Patients randomized to the treatment intervention received a single injection of 100 units of botulinum toxin type A plus lidocaine, and patients in the placebo group received a single injection of saline plus lidocaine.

Patients were assessed using the Visual Analog Scale (VAS), a numeric rating scale (NRS) for day pain, and the Shoulder Pain and Disability Index (SPADI) pain subscale, said Dr. Singh.

Secondary outcomes included SPADI scores and the proportion of patients achieving clinically meaningful pain relief, defined as a minimum 30% improvement. At baseline, pain outcome variables between the intervention and placebo groups were comparable.

At day 28, the mean VAS pain score in the treatment group was 4.12, significantly lower than the mean 6.54 in the placebo group. Day pain, according to NRS and SPADI pain scores, was significantly improved in the treatment group.

The SPADI score was better at day 28 in the treatment group compared with that in the placebo group, with a trend toward significance, Dr. Singh said.

The investigators are analyzing the duration of the analgesic effect and the associated adverse effects.

The findings thus far provide “the initial proof of concept of effectiveness of botulinum toxin injection for relief of shoulder pain,” Dr. Singh said, adding they need to be replicated in a larger, multicenter, randomized trial before the treatment can be recommended.

Dr. Singh reported having received travel funds for previous research projects from Allergan Pharmaceuticals, maker of Botox. The current study was funded by the Arthritis Foundation, the Mayo Clinic, and the Minneapolis VA Medical Center.

BOSTON — When using triglycerides to identify insulin resistance, patient ethnicity must be taken into account.

An assessment of the relationship between insulin resistance and triglycerides in nearly 6,000 individuals representing four ethnic groups has shown that although a triglyceride level above 150 mg/dL is a reasonable predictor of insulin resistance in non-Hispanic white and Chinese individuals, it is a poor predictor in African Americans and Hispanic individuals, Dr. Preethi Srikanthan said at the Fifth Annual World Congress on the Insulin Resistance Syndrome.

Similarly, a triglyceride level lower than 150 mg/dL reasonably predicts the absence of insulin resistance in non-Hispanic whites and Chinese individuals. But the same is not seen in African Americans or Hispanic individuals.

Triglyceride levels are often used as a proxy measurement for identifying insulin resistance in the clinical setting, said Dr. Srikanthan of the University of California, Los Angeles. Elevated triglycerides—those over a threshold value of 150 mg/dL—are used as evidence of insulin resistance, and normal triglyceride levels are thought to indicate the absence of insulin resistance.

But because this assessment method does not take into consideration possible racial or ethnic differences in metabolic parameters, Dr. Srikanthan and colleagues sought to gauge its predictive accuracy across ethnic populations.

Using data from the Multi-Ethnic Study of Atherosclerosis (MESA), a multicenter investigation into the characteristics of subclinical cardiovascular disease and risk factors that predict progression to clinically overt cardiovascular disease, the researchers evaluated the relationship between insulin resistance and triglyceride levels above the 150 mg/dL threshold in four ethnic groups. The study included 5,997 nondiabetic participants of which 1,594 were African American (mean age 62 years), 1,239 were Hispanic (mean age 61 years), 2,463 were non-Hispanic whites (mean age 62 years), and 701 were Chinese (mean age 62 years).

They calculated the homeostasis model assessment of insulin resistance (HOMA-IR) using participants' fasting insulin and glucose values. Participants with HOMA-IR values in the upper quartile (greater than 2.32) were classified as having insulin resistance. Triglyceride levels were compared on a log scale by ethnicity using one-way analysis of variance with multiple comparison correction, Dr. Srikanthan said.

Of the full study population, 23% of the African American group, 56% of the Hispanic group, 55% of the non-Hispanic white group, and 66% of the Chinese group were insulin resistant with triglyceride levels greater than 150 mg/dL.

By comparison, insulin resistance with triglyceride levels at or below 150 mg/dL was noted in 18% of the African American group, 19% of the Hispanic group, 6% of the non-Hispanic white group, and 7% of the Chinese group, said Dr. Srikanthan.

To measure the accuracy of triglycerides as predictors of insulin resistance, the researchers computed area under receiver operating characteristic (ROC) curves. In the African American and Hispanic groups, the areas under ROC curves of insulin resistance by triglyceride level were 0.62 and 0.64, respectively, suggesting triglyceride status relative to the 150-mg/dL threshold is a poor predictor of insulin resistance status. In contrast, the areas under ROC curves of insulin resistance by triglyceride levels in the non-Hispanic white and Chinese participants were 0.73 and 0.75, respectively, indicating fair predictive accuracy.

ELSEVIER GLOBAL MEDICAL NEWS

BOSTON — When using triglycerides to identify insulin resistance, patient ethnicity must be taken into account.

An assessment of the relationship between insulin resistance and triglycerides in nearly 6,000 individuals representing four ethnic groups has shown that although a triglyceride level above 150 mg/dL is a reasonable predictor of insulin resistance in non-Hispanic white and Chinese individuals, it is a poor predictor in African Americans and Hispanic individuals, Dr. Preethi Srikanthan said at the Fifth Annual World Congress on the Insulin Resistance Syndrome.

Similarly, a triglyceride level lower than 150 mg/dL reasonably predicts the absence of insulin resistance in non-Hispanic whites and Chinese individuals. But the same is not seen in African Americans or Hispanic individuals.

Triglyceride levels are often used as a proxy measurement for identifying insulin resistance in the clinical setting, said Dr. Srikanthan of the University of California, Los Angeles. Elevated triglycerides—those over a threshold value of 150 mg/dL—are used as evidence of insulin resistance, and normal triglyceride levels are thought to indicate the absence of insulin resistance.

But because this assessment method does not take into consideration possible racial or ethnic differences in metabolic parameters, Dr. Srikanthan and colleagues sought to gauge its predictive accuracy across ethnic populations.

Using data from the Multi-Ethnic Study of Atherosclerosis (MESA), a multicenter investigation into the characteristics of subclinical cardiovascular disease and risk factors that predict progression to clinically overt cardiovascular disease, the researchers evaluated the relationship between insulin resistance and triglyceride levels above the 150 mg/dL threshold in four ethnic groups. The study included 5,997 nondiabetic participants of which 1,594 were African American (mean age 62 years), 1,239 were Hispanic (mean age 61 years), 2,463 were non-Hispanic whites (mean age 62 years), and 701 were Chinese (mean age 62 years).

They calculated the homeostasis model assessment of insulin resistance (HOMA-IR) using participants' fasting insulin and glucose values. Participants with HOMA-IR values in the upper quartile (greater than 2.32) were classified as having insulin resistance. Triglyceride levels were compared on a log scale by ethnicity using one-way analysis of variance with multiple comparison correction, Dr. Srikanthan said.

Of the full study population, 23% of the African American group, 56% of the Hispanic group, 55% of the non-Hispanic white group, and 66% of the Chinese group were insulin resistant with triglyceride levels greater than 150 mg/dL.

By comparison, insulin resistance with triglyceride levels at or below 150 mg/dL was noted in 18% of the African American group, 19% of the Hispanic group, 6% of the non-Hispanic white group, and 7% of the Chinese group, said Dr. Srikanthan.

To measure the accuracy of triglycerides as predictors of insulin resistance, the researchers computed area under receiver operating characteristic (ROC) curves. In the African American and Hispanic groups, the areas under ROC curves of insulin resistance by triglyceride level were 0.62 and 0.64, respectively, suggesting triglyceride status relative to the 150-mg/dL threshold is a poor predictor of insulin resistance status. In contrast, the areas under ROC curves of insulin resistance by triglyceride levels in the non-Hispanic white and Chinese participants were 0.73 and 0.75, respectively, indicating fair predictive accuracy.

ELSEVIER GLOBAL MEDICAL NEWS

BOSTON — When using triglycerides to identify insulin resistance, patient ethnicity must be taken into account.

An assessment of the relationship between insulin resistance and triglycerides in nearly 6,000 individuals representing four ethnic groups has shown that although a triglyceride level above 150 mg/dL is a reasonable predictor of insulin resistance in non-Hispanic white and Chinese individuals, it is a poor predictor in African Americans and Hispanic individuals, Dr. Preethi Srikanthan said at the Fifth Annual World Congress on the Insulin Resistance Syndrome.

Similarly, a triglyceride level lower than 150 mg/dL reasonably predicts the absence of insulin resistance in non-Hispanic whites and Chinese individuals. But the same is not seen in African Americans or Hispanic individuals.

Triglyceride levels are often used as a proxy measurement for identifying insulin resistance in the clinical setting, said Dr. Srikanthan of the University of California, Los Angeles. Elevated triglycerides—those over a threshold value of 150 mg/dL—are used as evidence of insulin resistance, and normal triglyceride levels are thought to indicate the absence of insulin resistance.

But because this assessment method does not take into consideration possible racial or ethnic differences in metabolic parameters, Dr. Srikanthan and colleagues sought to gauge its predictive accuracy across ethnic populations.

Using data from the Multi-Ethnic Study of Atherosclerosis (MESA), a multicenter investigation into the characteristics of subclinical cardiovascular disease and risk factors that predict progression to clinically overt cardiovascular disease, the researchers evaluated the relationship between insulin resistance and triglyceride levels above the 150 mg/dL threshold in four ethnic groups. The study included 5,997 nondiabetic participants of which 1,594 were African American (mean age 62 years), 1,239 were Hispanic (mean age 61 years), 2,463 were non-Hispanic whites (mean age 62 years), and 701 were Chinese (mean age 62 years).

They calculated the homeostasis model assessment of insulin resistance (HOMA-IR) using participants' fasting insulin and glucose values. Participants with HOMA-IR values in the upper quartile (greater than 2.32) were classified as having insulin resistance. Triglyceride levels were compared on a log scale by ethnicity using one-way analysis of variance with multiple comparison correction, Dr. Srikanthan said.

Of the full study population, 23% of the African American group, 56% of the Hispanic group, 55% of the non-Hispanic white group, and 66% of the Chinese group were insulin resistant with triglyceride levels greater than 150 mg/dL.

By comparison, insulin resistance with triglyceride levels at or below 150 mg/dL was noted in 18% of the African American group, 19% of the Hispanic group, 6% of the non-Hispanic white group, and 7% of the Chinese group, said Dr. Srikanthan.

To measure the accuracy of triglycerides as predictors of insulin resistance, the researchers computed area under receiver operating characteristic (ROC) curves. In the African American and Hispanic groups, the areas under ROC curves of insulin resistance by triglyceride level were 0.62 and 0.64, respectively, suggesting triglyceride status relative to the 150-mg/dL threshold is a poor predictor of insulin resistance status. In contrast, the areas under ROC curves of insulin resistance by triglyceride levels in the non-Hispanic white and Chinese participants were 0.73 and 0.75, respectively, indicating fair predictive accuracy.

ELSEVIER GLOBAL MEDICAL NEWS

BOSTON — Participation in a structured lifestyle and exercise intervention can significantly improve the metabolic parameters of obese children with high insulin sensitivity, according to findings of a study presented at the Fifth Annual World Congress on the Insulin Resistance Syndrome.

Dr. Radhika Purushothaman of the Infants' and Children's Hospital of Brooklyn (N.Y.) at Maimonides and her colleagues enrolled 128 healthy seventh-grade students into a 12-week randomized controlled trial: 24 of the students were randomized to a lifestyle-only intervention, which focused primarily on dietary modification; 58 were randomized to a lifestyle plus exercise intervention; and 46 were in a control group with no intervention. The lifestyle plus exercise group was further subdivided according to body mass index (BMI) percentile: 28 students were in the lean group (BMI less than 85%), 8 were in the overweight group (BMI between 85% and 95%), and 22 were in the obese group (BMI greater than 95%). The weight categories in this study differ from those of the Centers for Disease Control and Prevention.

Because of the small number of children in the overweight subgroup, they were not included in the final subgroup comparison.

The investigators measured clinical and biochemical parameters including height, weight, blood pressure, body fat percentage, waist circumference, lipid profile, glucose tolerance via intravenous glucose tolerance test, insulinlike growth factor binding protein-I (IGFBP-1), baseline adiponectin level, acute insulin response, quantitative insulin sensitivity check index (QUICKI), and glucose disposition index.

An assessment of the BMI subgroups of the lifestyle and exercise intervention group showed the most interesting findings. Post intervention, both subgroups demonstrated increased BMI and decreased blood pressure. Within the obese group, higher insulin sensitivity at baseline was associated with more significant loss of visceral fat, said Dr. Purushothaman.

The lean subgroup had—at baseline and post intervention—a lower percent body fat, waist circumference, systolic blood pressure, fasting insulin and acute insulin response, and a higher adiponectin level than the obese group. Relative to the obese group, the lean group showed improvements in body fat percentage, blood pressure, IGFBP-1, acute insulin response, and glucose disposition index.

The results showed a significant negative correlation between fasting insulin at baseline and change in waist circumference after intervention in the obese group, and a significant positive correlation between the change in waist circumference and adiponectin and IGFBP-1 in the lean group.

Given the variations in intervention response observed between lean and obese children, the investigators concluded that exercise and lifestyle interventions should be different in these subgroups of children, with obese children requiring more intensive intervention with specifically modified diet, Dr. Purushothaman reported.

The data also suggest that improvement in biochemical parameters can occur even before changes in BMI, and they may be associated with a decrease in body fat percentage, Dr. Purushothaman stated.

She noted that longer term follow-up is needed to determine if the metabolic changes are sustainable and whether obese children will start showing improvement with longer periods of intervention.

In terms of the larger groups, there was no difference at baseline across the three groups in BMI, percentage body fat, waist circumference, lipid profile, adiponectin, acute insulin response, IGFBP-1, QUICKI, and glucose disposition index, Dr. Purushothaman reported.

After 12 weeks, the glucose disposition index improved significantly in both intervention groups. The lifestyle plus exercise intervention was associated with increases in acute insulin response and BMI and decreases in body fat, while both intervention groups showed decreases in adiponectin and IGFBP-1.

BOSTON — Participation in a structured lifestyle and exercise intervention can significantly improve the metabolic parameters of obese children with high insulin sensitivity, according to findings of a study presented at the Fifth Annual World Congress on the Insulin Resistance Syndrome.

Dr. Radhika Purushothaman of the Infants' and Children's Hospital of Brooklyn (N.Y.) at Maimonides and her colleagues enrolled 128 healthy seventh-grade students into a 12-week randomized controlled trial: 24 of the students were randomized to a lifestyle-only intervention, which focused primarily on dietary modification; 58 were randomized to a lifestyle plus exercise intervention; and 46 were in a control group with no intervention. The lifestyle plus exercise group was further subdivided according to body mass index (BMI) percentile: 28 students were in the lean group (BMI less than 85%), 8 were in the overweight group (BMI between 85% and 95%), and 22 were in the obese group (BMI greater than 95%). The weight categories in this study differ from those of the Centers for Disease Control and Prevention.

Because of the small number of children in the overweight subgroup, they were not included in the final subgroup comparison.

The investigators measured clinical and biochemical parameters including height, weight, blood pressure, body fat percentage, waist circumference, lipid profile, glucose tolerance via intravenous glucose tolerance test, insulinlike growth factor binding protein-I (IGFBP-1), baseline adiponectin level, acute insulin response, quantitative insulin sensitivity check index (QUICKI), and glucose disposition index.

An assessment of the BMI subgroups of the lifestyle and exercise intervention group showed the most interesting findings. Post intervention, both subgroups demonstrated increased BMI and decreased blood pressure. Within the obese group, higher insulin sensitivity at baseline was associated with more significant loss of visceral fat, said Dr. Purushothaman.

The lean subgroup had—at baseline and post intervention—a lower percent body fat, waist circumference, systolic blood pressure, fasting insulin and acute insulin response, and a higher adiponectin level than the obese group. Relative to the obese group, the lean group showed improvements in body fat percentage, blood pressure, IGFBP-1, acute insulin response, and glucose disposition index.

The results showed a significant negative correlation between fasting insulin at baseline and change in waist circumference after intervention in the obese group, and a significant positive correlation between the change in waist circumference and adiponectin and IGFBP-1 in the lean group.

Given the variations in intervention response observed between lean and obese children, the investigators concluded that exercise and lifestyle interventions should be different in these subgroups of children, with obese children requiring more intensive intervention with specifically modified diet, Dr. Purushothaman reported.

The data also suggest that improvement in biochemical parameters can occur even before changes in BMI, and they may be associated with a decrease in body fat percentage, Dr. Purushothaman stated.

She noted that longer term follow-up is needed to determine if the metabolic changes are sustainable and whether obese children will start showing improvement with longer periods of intervention.

In terms of the larger groups, there was no difference at baseline across the three groups in BMI, percentage body fat, waist circumference, lipid profile, adiponectin, acute insulin response, IGFBP-1, QUICKI, and glucose disposition index, Dr. Purushothaman reported.

After 12 weeks, the glucose disposition index improved significantly in both intervention groups. The lifestyle plus exercise intervention was associated with increases in acute insulin response and BMI and decreases in body fat, while both intervention groups showed decreases in adiponectin and IGFBP-1.

BOSTON — Participation in a structured lifestyle and exercise intervention can significantly improve the metabolic parameters of obese children with high insulin sensitivity, according to findings of a study presented at the Fifth Annual World Congress on the Insulin Resistance Syndrome.

Dr. Radhika Purushothaman of the Infants' and Children's Hospital of Brooklyn (N.Y.) at Maimonides and her colleagues enrolled 128 healthy seventh-grade students into a 12-week randomized controlled trial: 24 of the students were randomized to a lifestyle-only intervention, which focused primarily on dietary modification; 58 were randomized to a lifestyle plus exercise intervention; and 46 were in a control group with no intervention. The lifestyle plus exercise group was further subdivided according to body mass index (BMI) percentile: 28 students were in the lean group (BMI less than 85%), 8 were in the overweight group (BMI between 85% and 95%), and 22 were in the obese group (BMI greater than 95%). The weight categories in this study differ from those of the Centers for Disease Control and Prevention.

Because of the small number of children in the overweight subgroup, they were not included in the final subgroup comparison.

The investigators measured clinical and biochemical parameters including height, weight, blood pressure, body fat percentage, waist circumference, lipid profile, glucose tolerance via intravenous glucose tolerance test, insulinlike growth factor binding protein-I (IGFBP-1), baseline adiponectin level, acute insulin response, quantitative insulin sensitivity check index (QUICKI), and glucose disposition index.

An assessment of the BMI subgroups of the lifestyle and exercise intervention group showed the most interesting findings. Post intervention, both subgroups demonstrated increased BMI and decreased blood pressure. Within the obese group, higher insulin sensitivity at baseline was associated with more significant loss of visceral fat, said Dr. Purushothaman.

The lean subgroup had—at baseline and post intervention—a lower percent body fat, waist circumference, systolic blood pressure, fasting insulin and acute insulin response, and a higher adiponectin level than the obese group. Relative to the obese group, the lean group showed improvements in body fat percentage, blood pressure, IGFBP-1, acute insulin response, and glucose disposition index.

The results showed a significant negative correlation between fasting insulin at baseline and change in waist circumference after intervention in the obese group, and a significant positive correlation between the change in waist circumference and adiponectin and IGFBP-1 in the lean group.

Given the variations in intervention response observed between lean and obese children, the investigators concluded that exercise and lifestyle interventions should be different in these subgroups of children, with obese children requiring more intensive intervention with specifically modified diet, Dr. Purushothaman reported.

The data also suggest that improvement in biochemical parameters can occur even before changes in BMI, and they may be associated with a decrease in body fat percentage, Dr. Purushothaman stated.

She noted that longer term follow-up is needed to determine if the metabolic changes are sustainable and whether obese children will start showing improvement with longer periods of intervention.

In terms of the larger groups, there was no difference at baseline across the three groups in BMI, percentage body fat, waist circumference, lipid profile, adiponectin, acute insulin response, IGFBP-1, QUICKI, and glucose disposition index, Dr. Purushothaman reported.

After 12 weeks, the glucose disposition index improved significantly in both intervention groups. The lifestyle plus exercise intervention was associated with increases in acute insulin response and BMI and decreases in body fat, while both intervention groups showed decreases in adiponectin and IGFBP-1.

BOSTON — Treatment with metformin significantly improves body mass index and other metabolic parameters in women with polycystic ovary syndrome and significantly decreases the prevalence of metabolic syndrome in this population, a retrospective study has shown.

The findings confirm the utility of metformin, coupled with diet and exercise, as a primary therapy for minimizing the long-term risks of developing metabolic syndrome-associated cardiovascular disease and diabetes in women with the hormonal disorder, Kai I. Cheang, Pharm.D., said at the Fifth Annual World Congress on the Insulin Resistance Syndrome.

To date, short-term studies have demonstrated beneficial metabolic effects associated with metformin in women with polycystic ovary syndrome (PCOS), but long-term data have been lacking, according to Dr. Cheang, of Virginia Commonwealth University, Richmond.

To assess the impact of long-term metformin use, Dr. Cheang and colleagues reviewed the charts of consecutive PCOS patients treated at the university-affiliated clinic from 2000 to 2005. Patients with more than 6 months of treatment with metformin were included in the final analysis if baseline and follow-up assessments of metabolic syndrome parameters were available. Those patients with diabetes at baseline and those taking other medications that would affect metabolic parameters, such as thiazolidinediones, weight-loss agents, antihypertensives, lipid-lowering agents, or antidiabetic agents, were excluded.

Of the nearly 250 PCOS patients treated with metformin during the study period, 71 met the inclusion criteria; their mean age was 31.2 years. For the purposes of the investigation, metabolic syndrome was defined by National Cholesterol Education Program Adult Treatment Panel III (ATP-III) criteria, with the exception of waist circumference; body mass index (BMI) was substituted for that criterion.

“This is because waist circumference was not available for most of the patients,” Dr. Cheang noted. “Based on correlation between BMI and waist circumference of local PCOS women with [that of] PCOS women who entered into our clinical studies, we determined the BMI cut-off value corresponding to a waist circumference of 88 cm was 32 kg/m

The average period from initiation of metformin therapy to the most recent assessment for the study population was 31 months. The data for those patients who began lipid-lowering or antihypertensive therapy during follow-up were analyzed up until the beginning of such therapy, according to Dr. Cheang.

The investigators assessed baseline and follow-up metabolic syndrome parameters using a two-sided student's paired t test and observed that, compared with baseline, follow-up values for BMI, diastolic blood pressure, and high-density lipoprotein were significantly improved with metformin therapy, Dr. Cheang reported. Additionally, metformin therapy also significantly decreased the overall prevalence of metabolic syndrome from 31% at baseline to 14% following 31 months of treatment. Observed improvements in systolic blood pressure, triglycerides, and fasting glucose measures did not reach statistical significance.

The findings were limited by the study's retrospective design, Dr. Cheang said. “As information was not being collected specifically for the study, certain data [were] not available for all patients.”

According to study coauthor Dr. John E. Nestler, chair of the university's division of endocrinology and metabolism, previous studies have shown that treatment with metformin, coupled with diet and exercise, improves ovulation and lowers androgens in PCOS women and possibly prevents or retards progression to glucose intolerance.

With this new data, “[metformin treatment] also appears to ameliorate several components of the metabolic syndrome,” he said in an interview.

The clinical significance of these findings is substantial, given the extremely high risk for the metabolic disorder in PCOS. “Among women with PCOS, approximately 20% of those younger than 20 years old have the metabolic syndrome and more than 50% of those 40 years and older have it,” he said.

No conflicts of interest were reported relative to this study.

BOSTON — Treatment with metformin significantly improves body mass index and other metabolic parameters in women with polycystic ovary syndrome and significantly decreases the prevalence of metabolic syndrome in this population, a retrospective study has shown.

The findings confirm the utility of metformin, coupled with diet and exercise, as a primary therapy for minimizing the long-term risks of developing metabolic syndrome-associated cardiovascular disease and diabetes in women with the hormonal disorder, Kai I. Cheang, Pharm.D., said at the Fifth Annual World Congress on the Insulin Resistance Syndrome.

To date, short-term studies have demonstrated beneficial metabolic effects associated with metformin in women with polycystic ovary syndrome (PCOS), but long-term data have been lacking, according to Dr. Cheang, of Virginia Commonwealth University, Richmond.

To assess the impact of long-term metformin use, Dr. Cheang and colleagues reviewed the charts of consecutive PCOS patients treated at the university-affiliated clinic from 2000 to 2005. Patients with more than 6 months of treatment with metformin were included in the final analysis if baseline and follow-up assessments of metabolic syndrome parameters were available. Those patients with diabetes at baseline and those taking other medications that would affect metabolic parameters, such as thiazolidinediones, weight-loss agents, antihypertensives, lipid-lowering agents, or antidiabetic agents, were excluded.

Of the nearly 250 PCOS patients treated with metformin during the study period, 71 met the inclusion criteria; their mean age was 31.2 years. For the purposes of the investigation, metabolic syndrome was defined by National Cholesterol Education Program Adult Treatment Panel III (ATP-III) criteria, with the exception of waist circumference; body mass index (BMI) was substituted for that criterion.

“This is because waist circumference was not available for most of the patients,” Dr. Cheang noted. “Based on correlation between BMI and waist circumference of local PCOS women with [that of] PCOS women who entered into our clinical studies, we determined the BMI cut-off value corresponding to a waist circumference of 88 cm was 32 kg/m

The average period from initiation of metformin therapy to the most recent assessment for the study population was 31 months. The data for those patients who began lipid-lowering or antihypertensive therapy during follow-up were analyzed up until the beginning of such therapy, according to Dr. Cheang.

The investigators assessed baseline and follow-up metabolic syndrome parameters using a two-sided student's paired t test and observed that, compared with baseline, follow-up values for BMI, diastolic blood pressure, and high-density lipoprotein were significantly improved with metformin therapy, Dr. Cheang reported. Additionally, metformin therapy also significantly decreased the overall prevalence of metabolic syndrome from 31% at baseline to 14% following 31 months of treatment. Observed improvements in systolic blood pressure, triglycerides, and fasting glucose measures did not reach statistical significance.

The findings were limited by the study's retrospective design, Dr. Cheang said. “As information was not being collected specifically for the study, certain data [were] not available for all patients.”

According to study coauthor Dr. John E. Nestler, chair of the university's division of endocrinology and metabolism, previous studies have shown that treatment with metformin, coupled with diet and exercise, improves ovulation and lowers androgens in PCOS women and possibly prevents or retards progression to glucose intolerance.

With this new data, “[metformin treatment] also appears to ameliorate several components of the metabolic syndrome,” he said in an interview.

The clinical significance of these findings is substantial, given the extremely high risk for the metabolic disorder in PCOS. “Among women with PCOS, approximately 20% of those younger than 20 years old have the metabolic syndrome and more than 50% of those 40 years and older have it,” he said.

No conflicts of interest were reported relative to this study.

BOSTON — Treatment with metformin significantly improves body mass index and other metabolic parameters in women with polycystic ovary syndrome and significantly decreases the prevalence of metabolic syndrome in this population, a retrospective study has shown.

The findings confirm the utility of metformin, coupled with diet and exercise, as a primary therapy for minimizing the long-term risks of developing metabolic syndrome-associated cardiovascular disease and diabetes in women with the hormonal disorder, Kai I. Cheang, Pharm.D., said at the Fifth Annual World Congress on the Insulin Resistance Syndrome.

To date, short-term studies have demonstrated beneficial metabolic effects associated with metformin in women with polycystic ovary syndrome (PCOS), but long-term data have been lacking, according to Dr. Cheang, of Virginia Commonwealth University, Richmond.

To assess the impact of long-term metformin use, Dr. Cheang and colleagues reviewed the charts of consecutive PCOS patients treated at the university-affiliated clinic from 2000 to 2005. Patients with more than 6 months of treatment with metformin were included in the final analysis if baseline and follow-up assessments of metabolic syndrome parameters were available. Those patients with diabetes at baseline and those taking other medications that would affect metabolic parameters, such as thiazolidinediones, weight-loss agents, antihypertensives, lipid-lowering agents, or antidiabetic agents, were excluded.

Of the nearly 250 PCOS patients treated with metformin during the study period, 71 met the inclusion criteria; their mean age was 31.2 years. For the purposes of the investigation, metabolic syndrome was defined by National Cholesterol Education Program Adult Treatment Panel III (ATP-III) criteria, with the exception of waist circumference; body mass index (BMI) was substituted for that criterion.

“This is because waist circumference was not available for most of the patients,” Dr. Cheang noted. “Based on correlation between BMI and waist circumference of local PCOS women with [that of] PCOS women who entered into our clinical studies, we determined the BMI cut-off value corresponding to a waist circumference of 88 cm was 32 kg/m

The average period from initiation of metformin therapy to the most recent assessment for the study population was 31 months. The data for those patients who began lipid-lowering or antihypertensive therapy during follow-up were analyzed up until the beginning of such therapy, according to Dr. Cheang.

The investigators assessed baseline and follow-up metabolic syndrome parameters using a two-sided student's paired t test and observed that, compared with baseline, follow-up values for BMI, diastolic blood pressure, and high-density lipoprotein were significantly improved with metformin therapy, Dr. Cheang reported. Additionally, metformin therapy also significantly decreased the overall prevalence of metabolic syndrome from 31% at baseline to 14% following 31 months of treatment. Observed improvements in systolic blood pressure, triglycerides, and fasting glucose measures did not reach statistical significance.

The findings were limited by the study's retrospective design, Dr. Cheang said. “As information was not being collected specifically for the study, certain data [were] not available for all patients.”

According to study coauthor Dr. John E. Nestler, chair of the university's division of endocrinology and metabolism, previous studies have shown that treatment with metformin, coupled with diet and exercise, improves ovulation and lowers androgens in PCOS women and possibly prevents or retards progression to glucose intolerance.

With this new data, “[metformin treatment] also appears to ameliorate several components of the metabolic syndrome,” he said in an interview.

The clinical significance of these findings is substantial, given the extremely high risk for the metabolic disorder in PCOS. “Among women with PCOS, approximately 20% of those younger than 20 years old have the metabolic syndrome and more than 50% of those 40 years and older have it,” he said.

No conflicts of interest were reported relative to this study.