Jennie Smith

BUENOS AIRES – A group of new studies on juvenile-onset systemic lupus erythematosus suggests that investigators are gaining a foothold on noninvasively monitoring renal disease, making more accurate diagnoses, and determining the prevalence of hippocampal atrophy in adolescents with the condition.

One of the three reports presented at the international congress on systemic lupus erythematosus (SLE) involved research from U.K. investigators on novel noninvasive biomarkers that can predict the course of renal disease in juvenile SLE, potentially allowing for earlier intervention, fewer kidney biopsies, and more accurate drug titration.

Researchers from Argentina revealed that new classification criteria for SLE, published in 2012, were more sensitive and specific in juvenile lupus patients than the widely used American College of Rheumatology criteria, which were last revised in 1997.

A third report from Brazil-based investigators found that atrophy of the hippocampus, the part of the brain associated with memory and learning, occurred in nearly two-thirds of a cohort of juvenile SLE patients.

Urine biomarkers for lupus nephritis

Dr. Louise Watson of Alder Hey Children’s NHS Hospital, Liverpool, England, presented findings on novel urine biomarkers from a multicenter, prospective cohort study of 64 SLE patients aged 16 years and younger. "We were keen to look for better ways to monitor the disease through biomarkers, and to move from a more reactive to a more proactive approach," Dr. Watson said at the meeting.

Rather than wait until the onset of proteinuria to start treatment, reliable noninvasive biomarkers "could allow disease to be detected at a much earlier time point, and hopefully help us try and prevent some of the irreversible kidney damage that we might see" associated with juvenile-onset SLE.

Dr. Watson and her colleagues looked at both standard and novel biomarkers in the cohort, and found that two novel ones – monocyte chemoattractant protein 1 (MCP1) and neutrophil gelatinase associated lipocalin (NGAL) – predicted changes in the course of renal disease over a 2-year period. MCP1 was highly predictive of disease improvement, and NGAL of disease progression.

MCP1 at a concentration of 343 pg/mL was a significant predictor of improvement in renal disease (P = .013; specificity 71%, sensitivity 70%), the researchers found. Meanwhile, NGAL at 30 ng/mL predicted worsening renal disease (P = .04; specificity 60%, sensitivity 61%).

Urine MCP1 and NGAL changed as subsequent renal disease changed (MCP1, P = .015; NGAL, P = .038), while standard biomarkers (erythrocyte sedimentation rate, anti-double stranded DNA, urine albumin to creatinine ratio, creatinine, complement 3, complement 4, and lymphocytes) did not predict disease activity changes. MCP1 and C3 were seen in a multivariate analysis as independent variables (P less than .001) for active renal disease (Lupus 2013;22 [Suppl.]:O13).

The fact that MCP1 and NGAL are so specific, Dr. Watson said, "may be because they’re expressed directly from the kidney cells. Perhaps we need to begin to validate some of these and move them towards commercialization so we can look towards earlier intervention and monitoring to try and improve the outcome in our patients."

New disease criteria perform better than old

In a separate talk at the congress (Lupus 2013;22[Suppl.]:O12), Dr. Marìa M. Katsicas of the Hospital de Pediatría Prof. Dr. Juan P. Garrahan, in Buenos Aires, presented results from a study comparing the Systemic Lupus International Collaborating Clinics (SLICC) classification criteria for SLE, published last year (Arthritis Rheum. 2012;64:2677-86), with the revised American College of Rheumatology criteria for SLE (Arthritis Rheum. 1997;40:1725) in a cohort of juvenile patients.

"The ACR criteria have not been completely evaluated in pediatric patients," Dr. Katsicas explained. "Only one publication describes sensitivity and specificity in Brazilian children" (Clin. Exp. Rheumatol. 1994;12:83-7).

For Dr. Katsicas and her colleagues’ study, experienced pediatric rheumatologists reviewed medical records and prospective data for 107 patients with juvenile-onset SLE, and 124 controls with juvenile idiopathic arthritis, juvenile dermatomyositis, autoimmune hepatitis, juvenile systemic sclerosis, ANCA-associated vasculitis, or Henoch-Schönlein purpura.

Using the SLICC SLE criteria, all of the SLE cases were correctly identified, while under the ACR 1997 criteria, six cases were missed. Sensitivity for the new criteria was 100%, compared with 86% for the ACR criteria, while specificity was 98% and 96% respectively. "It is very important to note that six patients were correctly identified by SLICC and not ACR," Dr. Katsicas said.

Many patients develop hippocampal atrophy

Dr. Simone Appenzeller of the State University of Campinas, São Paulo, Brazil, and her colleagues reported finding MRI evidence of hippocampal atrophy (in one or both lobes) in 24 of 40 juvenile SLE patients, compared with only 1 of 40 controls.

"Studies have suggested that in the hippocampus, which is the brain area important to memory and learning, [there] may be a specific target for some autoantibodies in neuropsychiatric SLE," Dr. Appenzeller told the congress.

"We have previously shown in adults that there is hippocampal atrophy associated with the total dose of corticosteroids," Dr. Appenzeller said (Ann. Rheum. Dis. 2006;65:1585-9), noting that the association was found once again in the current study (P = .019). Atrophy was also associated with anticardiolipin antibodies (P = .009), vasculitis (P = .042), disease duration (P = .001), cognitive impairment (P = .005), age of disease onset (P = .008) and current age (P = .013). However, disease activity and damage scores were not associated with hippocampal atrophy.

Patients that may have hippocampal atrophy should be followed more closely with MRI and cognitive evaluation, Dr. Appenzeller advised, adding that the findings "could allow us to develop strategies to prevent its occurrence" (Lupus 2013;22[Suppl.]:O15)

Neither Dr. Katsicas nor Dr. Appenzeller reported conflicts of interest. Dr. Watson disclosed that Abbott Laboratories provided the NGAL assay for her group’s study at no cost.

BUENOS AIRES – A group of new studies on juvenile-onset systemic lupus erythematosus suggests that investigators are gaining a foothold on noninvasively monitoring renal disease, making more accurate diagnoses, and determining the prevalence of hippocampal atrophy in adolescents with the condition.

One of the three reports presented at the international congress on systemic lupus erythematosus (SLE) involved research from U.K. investigators on novel noninvasive biomarkers that can predict the course of renal disease in juvenile SLE, potentially allowing for earlier intervention, fewer kidney biopsies, and more accurate drug titration.

Researchers from Argentina revealed that new classification criteria for SLE, published in 2012, were more sensitive and specific in juvenile lupus patients than the widely used American College of Rheumatology criteria, which were last revised in 1997.

A third report from Brazil-based investigators found that atrophy of the hippocampus, the part of the brain associated with memory and learning, occurred in nearly two-thirds of a cohort of juvenile SLE patients.

Urine biomarkers for lupus nephritis

Dr. Louise Watson of Alder Hey Children’s NHS Hospital, Liverpool, England, presented findings on novel urine biomarkers from a multicenter, prospective cohort study of 64 SLE patients aged 16 years and younger. "We were keen to look for better ways to monitor the disease through biomarkers, and to move from a more reactive to a more proactive approach," Dr. Watson said at the meeting.

Rather than wait until the onset of proteinuria to start treatment, reliable noninvasive biomarkers "could allow disease to be detected at a much earlier time point, and hopefully help us try and prevent some of the irreversible kidney damage that we might see" associated with juvenile-onset SLE.

Dr. Watson and her colleagues looked at both standard and novel biomarkers in the cohort, and found that two novel ones – monocyte chemoattractant protein 1 (MCP1) and neutrophil gelatinase associated lipocalin (NGAL) – predicted changes in the course of renal disease over a 2-year period. MCP1 was highly predictive of disease improvement, and NGAL of disease progression.

MCP1 at a concentration of 343 pg/mL was a significant predictor of improvement in renal disease (P = .013; specificity 71%, sensitivity 70%), the researchers found. Meanwhile, NGAL at 30 ng/mL predicted worsening renal disease (P = .04; specificity 60%, sensitivity 61%).

Urine MCP1 and NGAL changed as subsequent renal disease changed (MCP1, P = .015; NGAL, P = .038), while standard biomarkers (erythrocyte sedimentation rate, anti-double stranded DNA, urine albumin to creatinine ratio, creatinine, complement 3, complement 4, and lymphocytes) did not predict disease activity changes. MCP1 and C3 were seen in a multivariate analysis as independent variables (P less than .001) for active renal disease (Lupus 2013;22 [Suppl.]:O13).

The fact that MCP1 and NGAL are so specific, Dr. Watson said, "may be because they’re expressed directly from the kidney cells. Perhaps we need to begin to validate some of these and move them towards commercialization so we can look towards earlier intervention and monitoring to try and improve the outcome in our patients."

New disease criteria perform better than old

In a separate talk at the congress (Lupus 2013;22[Suppl.]:O12), Dr. Marìa M. Katsicas of the Hospital de Pediatría Prof. Dr. Juan P. Garrahan, in Buenos Aires, presented results from a study comparing the Systemic Lupus International Collaborating Clinics (SLICC) classification criteria for SLE, published last year (Arthritis Rheum. 2012;64:2677-86), with the revised American College of Rheumatology criteria for SLE (Arthritis Rheum. 1997;40:1725) in a cohort of juvenile patients.

"The ACR criteria have not been completely evaluated in pediatric patients," Dr. Katsicas explained. "Only one publication describes sensitivity and specificity in Brazilian children" (Clin. Exp. Rheumatol. 1994;12:83-7).

For Dr. Katsicas and her colleagues’ study, experienced pediatric rheumatologists reviewed medical records and prospective data for 107 patients with juvenile-onset SLE, and 124 controls with juvenile idiopathic arthritis, juvenile dermatomyositis, autoimmune hepatitis, juvenile systemic sclerosis, ANCA-associated vasculitis, or Henoch-Schönlein purpura.

Using the SLICC SLE criteria, all of the SLE cases were correctly identified, while under the ACR 1997 criteria, six cases were missed. Sensitivity for the new criteria was 100%, compared with 86% for the ACR criteria, while specificity was 98% and 96% respectively. "It is very important to note that six patients were correctly identified by SLICC and not ACR," Dr. Katsicas said.

Many patients develop hippocampal atrophy

Dr. Simone Appenzeller of the State University of Campinas, São Paulo, Brazil, and her colleagues reported finding MRI evidence of hippocampal atrophy (in one or both lobes) in 24 of 40 juvenile SLE patients, compared with only 1 of 40 controls.

"Studies have suggested that in the hippocampus, which is the brain area important to memory and learning, [there] may be a specific target for some autoantibodies in neuropsychiatric SLE," Dr. Appenzeller told the congress.

"We have previously shown in adults that there is hippocampal atrophy associated with the total dose of corticosteroids," Dr. Appenzeller said (Ann. Rheum. Dis. 2006;65:1585-9), noting that the association was found once again in the current study (P = .019). Atrophy was also associated with anticardiolipin antibodies (P = .009), vasculitis (P = .042), disease duration (P = .001), cognitive impairment (P = .005), age of disease onset (P = .008) and current age (P = .013). However, disease activity and damage scores were not associated with hippocampal atrophy.

Patients that may have hippocampal atrophy should be followed more closely with MRI and cognitive evaluation, Dr. Appenzeller advised, adding that the findings "could allow us to develop strategies to prevent its occurrence" (Lupus 2013;22[Suppl.]:O15)

Neither Dr. Katsicas nor Dr. Appenzeller reported conflicts of interest. Dr. Watson disclosed that Abbott Laboratories provided the NGAL assay for her group’s study at no cost.

BUENOS AIRES – A group of new studies on juvenile-onset systemic lupus erythematosus suggests that investigators are gaining a foothold on noninvasively monitoring renal disease, making more accurate diagnoses, and determining the prevalence of hippocampal atrophy in adolescents with the condition.

One of the three reports presented at the international congress on systemic lupus erythematosus (SLE) involved research from U.K. investigators on novel noninvasive biomarkers that can predict the course of renal disease in juvenile SLE, potentially allowing for earlier intervention, fewer kidney biopsies, and more accurate drug titration.

Researchers from Argentina revealed that new classification criteria for SLE, published in 2012, were more sensitive and specific in juvenile lupus patients than the widely used American College of Rheumatology criteria, which were last revised in 1997.

A third report from Brazil-based investigators found that atrophy of the hippocampus, the part of the brain associated with memory and learning, occurred in nearly two-thirds of a cohort of juvenile SLE patients.

Urine biomarkers for lupus nephritis

Dr. Louise Watson of Alder Hey Children’s NHS Hospital, Liverpool, England, presented findings on novel urine biomarkers from a multicenter, prospective cohort study of 64 SLE patients aged 16 years and younger. "We were keen to look for better ways to monitor the disease through biomarkers, and to move from a more reactive to a more proactive approach," Dr. Watson said at the meeting.

Rather than wait until the onset of proteinuria to start treatment, reliable noninvasive biomarkers "could allow disease to be detected at a much earlier time point, and hopefully help us try and prevent some of the irreversible kidney damage that we might see" associated with juvenile-onset SLE.

Dr. Watson and her colleagues looked at both standard and novel biomarkers in the cohort, and found that two novel ones – monocyte chemoattractant protein 1 (MCP1) and neutrophil gelatinase associated lipocalin (NGAL) – predicted changes in the course of renal disease over a 2-year period. MCP1 was highly predictive of disease improvement, and NGAL of disease progression.

MCP1 at a concentration of 343 pg/mL was a significant predictor of improvement in renal disease (P = .013; specificity 71%, sensitivity 70%), the researchers found. Meanwhile, NGAL at 30 ng/mL predicted worsening renal disease (P = .04; specificity 60%, sensitivity 61%).

Urine MCP1 and NGAL changed as subsequent renal disease changed (MCP1, P = .015; NGAL, P = .038), while standard biomarkers (erythrocyte sedimentation rate, anti-double stranded DNA, urine albumin to creatinine ratio, creatinine, complement 3, complement 4, and lymphocytes) did not predict disease activity changes. MCP1 and C3 were seen in a multivariate analysis as independent variables (P less than .001) for active renal disease (Lupus 2013;22 [Suppl.]:O13).

The fact that MCP1 and NGAL are so specific, Dr. Watson said, "may be because they’re expressed directly from the kidney cells. Perhaps we need to begin to validate some of these and move them towards commercialization so we can look towards earlier intervention and monitoring to try and improve the outcome in our patients."

New disease criteria perform better than old

In a separate talk at the congress (Lupus 2013;22[Suppl.]:O12), Dr. Marìa M. Katsicas of the Hospital de Pediatría Prof. Dr. Juan P. Garrahan, in Buenos Aires, presented results from a study comparing the Systemic Lupus International Collaborating Clinics (SLICC) classification criteria for SLE, published last year (Arthritis Rheum. 2012;64:2677-86), with the revised American College of Rheumatology criteria for SLE (Arthritis Rheum. 1997;40:1725) in a cohort of juvenile patients.

"The ACR criteria have not been completely evaluated in pediatric patients," Dr. Katsicas explained. "Only one publication describes sensitivity and specificity in Brazilian children" (Clin. Exp. Rheumatol. 1994;12:83-7).

For Dr. Katsicas and her colleagues’ study, experienced pediatric rheumatologists reviewed medical records and prospective data for 107 patients with juvenile-onset SLE, and 124 controls with juvenile idiopathic arthritis, juvenile dermatomyositis, autoimmune hepatitis, juvenile systemic sclerosis, ANCA-associated vasculitis, or Henoch-Schönlein purpura.

Using the SLICC SLE criteria, all of the SLE cases were correctly identified, while under the ACR 1997 criteria, six cases were missed. Sensitivity for the new criteria was 100%, compared with 86% for the ACR criteria, while specificity was 98% and 96% respectively. "It is very important to note that six patients were correctly identified by SLICC and not ACR," Dr. Katsicas said.

Many patients develop hippocampal atrophy

Dr. Simone Appenzeller of the State University of Campinas, São Paulo, Brazil, and her colleagues reported finding MRI evidence of hippocampal atrophy (in one or both lobes) in 24 of 40 juvenile SLE patients, compared with only 1 of 40 controls.

"Studies have suggested that in the hippocampus, which is the brain area important to memory and learning, [there] may be a specific target for some autoantibodies in neuropsychiatric SLE," Dr. Appenzeller told the congress.

"We have previously shown in adults that there is hippocampal atrophy associated with the total dose of corticosteroids," Dr. Appenzeller said (Ann. Rheum. Dis. 2006;65:1585-9), noting that the association was found once again in the current study (P = .019). Atrophy was also associated with anticardiolipin antibodies (P = .009), vasculitis (P = .042), disease duration (P = .001), cognitive impairment (P = .005), age of disease onset (P = .008) and current age (P = .013). However, disease activity and damage scores were not associated with hippocampal atrophy.

Patients that may have hippocampal atrophy should be followed more closely with MRI and cognitive evaluation, Dr. Appenzeller advised, adding that the findings "could allow us to develop strategies to prevent its occurrence" (Lupus 2013;22[Suppl.]:O15)

Neither Dr. Katsicas nor Dr. Appenzeller reported conflicts of interest. Dr. Watson disclosed that Abbott Laboratories provided the NGAL assay for her group’s study at no cost.

BUENOS AIRES – Traditional tools such as the Framingham risk score have long been known to underestimate cardiovascular risk in people with systemic lupus erythematosus.

At the international congress on systemic lupus erythematosus, Dr. Michelle Petri of Johns Hopkins University, Baltimore, presented data in support of a novel risk-assessment formula to calculate the 10-year risk of a cardiovascular event (CVE). The tool combines the traditional cardiovascular disease risk factors of age, sex, high blood pressure, high cholesterol, smoking, diabetes, and body mass index (BMI), with three lupus-specific factors: a SLEDAI (SLE Disease Activity Index) score of 2 or higher, lupus anticoagulant, and a low mean complement 3 (C3) level.

Under both this and the Framingham algorithms, a 50-year old woman with SLE with a BMI of 23 kg/m², systolic blood pressure of 150 mm Hg, and high cholesterol has about an 8% 10-year risk of a CVE. However, if she also has lupus anticoagulant, high disease activity, or a low C3 level, her risk rises to 15%-18% under the SLE-specific system, whereas her Framingham score, which does not measure these, would remain at 8%.

Courtesy of Keith Weller/Johns Hopkins Medicine

Dr. Petri told the conference that with rheumatoid arthritis, the advice has been to multiply an existing risk score by 1.5 when the patient has certain evidence of disease. "I thought we could do better than that in lupus, because we could derive a formula using actual data," she said.

"We know that traditional CV risk factors do predict actual events and also predict the progression of subclinical atherosclerosis. Even after we adjust, though, for every traditional cardiovascular risk factor, lupus patients still have a twofold increase in coronary calcium over controls – so obviously lupus-specific factors must be in the formula as well."

The data used to derive the new scoring system came from a cohort of 1,342 lupus patients (93% female) treated at the Johns Hopkins Lupus Center. None had a history of CVEs during the first 2 years of follow-up. Over the study period, 109 incident CVEs occurred in the cohort, including 52 strokes and 26 myocardial infarctions.

Dr. Petri and her colleagues used Cox proportional hazards models to determine the baseline variables affecting the risk of a subsequent CVE. Using the results, they derived a formula to calculate the 10-year risk of a CVE. For each of the risk factors, they investigators converted the hazard ratio into a simple integer score to simplify calculation in clinical practice. By adding up the integers and using a slide rule that stands in for the exponential equation, clinicians can translate the integer score into a risk percentage.

Dr. Petri acknowledged as limitations of the study its single-site design; the fact that the Johns Hopkins Lupus Center does not routinely perform cholesterol screening; and that the study reflects care from 1988 onward, where more recent data could reflect a better standard of care. "This needs to be independently validated," she said.

In another multivariate analysis of cardiovascular disease (CVD) risk factors in lupus, a cohort of 306 consecutive SLE patients at a clinic in Istanbul, Turkey, revealed pericarditis, lymphopenia, thrombocytopenia, and psychosis to be significantly associated with nonfatal CVD.

Dr. Murat Inanc of Istanbul University, the lead author of the study, said that 15.2% of the cohort (mean age, 40.2 years; 89% female) had clinical evidence of CVD. Many of them also had traditional risk factors. "The usual suspects are there – hypertension, high cholesterol, metabolic syndrome – but we also found disease-specific features more present in patients with CV involvement," Dr. Inanc said.

Patients with evidence of CVD were older and had longer disease duration, significantly more organ damage, and a higher number of American College of Rheumatology criteria for SLE. "We think disease severity takes almost equal importance with traditional risk factors in this population," he said. Treatment with cyclophosphamide was also seen as a risk factor, although it is likely related to disease severity, he told the congress.

Dr. Inanc noted that the conclusions that can be drawn from the study are limited by its single-site design and lack of data on subclinical CVD. Cumulative corticosteroid use was not investigated, and investigators did not have information on immunosuppressive use in the cohort.

Dr. Murray Urowitz, of the Toronto Western Research Institute, presented findings from an international, multicenter inception cohort of 1,401 SLE patients. The goal of the study was to determine factors at diagnosis that are predictive of the development of premature atherosclerosis. Dr. Urowitz and his colleagues looked at age, sex, diabetes, smoking, obesity, low-density lipoprotein cholesterol, and creatinine. A multivariate analysis showed that only age and male sex were significant risk factors for atherosclerotic vascular events after a mean 5 years’ follow-up. "The implication here is these risk factors take more time to have their maximum effect, and in the first decade it’s hard to have more than age and sex," Dr. Urowitz told the congress.

Also at the congress, Dr. Maureen McMahon of the University of California, Los Angeles, gave a presentation on a panel of biomarkers found to be predictive of current, progressive, or acquired carotid plaque in a cohort of SLE patients.

For their research, Dr. McMahon and her colleagues looked at 210 female SLE patients and 100 age-matched controls who underwent ultrasound imaging of their carotid arteries at baseline and after a mean 29 months of follow-up. Nearly a third of SLE patients had evidence of plaque on follow-up.

The researchers found that three or more of the following factors at baseline were 94% predictive of plaque: age 48 or older, evidence of proinflammatory high-density lipoprotein cholesterol, plasma leptin of 34 ng/dL or greater, homocysteine of 12 mmol/L or greater, and plasma levels of sTWEAK (soluble tumor necrosis factor–like weak inducer of apoptosis) of 373 pg/mL or greater. Any one of these factors plus diabetes was also predictive. Patients with at least three indicators (or one plus diabetes) saw a 28-fold increased odds for the longitudinal presence of carotid plaque (95% confidence interval, 10.6-72.7; P less than .001) and a significantly increased rate of progression of both plaque and intima-media thickness.

None of the investigators disclosed financial relationships related to these studies.

BUENOS AIRES – Traditional tools such as the Framingham risk score have long been known to underestimate cardiovascular risk in people with systemic lupus erythematosus.

At the international congress on systemic lupus erythematosus, Dr. Michelle Petri of Johns Hopkins University, Baltimore, presented data in support of a novel risk-assessment formula to calculate the 10-year risk of a cardiovascular event (CVE). The tool combines the traditional cardiovascular disease risk factors of age, sex, high blood pressure, high cholesterol, smoking, diabetes, and body mass index (BMI), with three lupus-specific factors: a SLEDAI (SLE Disease Activity Index) score of 2 or higher, lupus anticoagulant, and a low mean complement 3 (C3) level.

Under both this and the Framingham algorithms, a 50-year old woman with SLE with a BMI of 23 kg/m², systolic blood pressure of 150 mm Hg, and high cholesterol has about an 8% 10-year risk of a CVE. However, if she also has lupus anticoagulant, high disease activity, or a low C3 level, her risk rises to 15%-18% under the SLE-specific system, whereas her Framingham score, which does not measure these, would remain at 8%.

Courtesy of Keith Weller/Johns Hopkins Medicine

Dr. Petri told the conference that with rheumatoid arthritis, the advice has been to multiply an existing risk score by 1.5 when the patient has certain evidence of disease. "I thought we could do better than that in lupus, because we could derive a formula using actual data," she said.

"We know that traditional CV risk factors do predict actual events and also predict the progression of subclinical atherosclerosis. Even after we adjust, though, for every traditional cardiovascular risk factor, lupus patients still have a twofold increase in coronary calcium over controls – so obviously lupus-specific factors must be in the formula as well."

The data used to derive the new scoring system came from a cohort of 1,342 lupus patients (93% female) treated at the Johns Hopkins Lupus Center. None had a history of CVEs during the first 2 years of follow-up. Over the study period, 109 incident CVEs occurred in the cohort, including 52 strokes and 26 myocardial infarctions.

Dr. Petri and her colleagues used Cox proportional hazards models to determine the baseline variables affecting the risk of a subsequent CVE. Using the results, they derived a formula to calculate the 10-year risk of a CVE. For each of the risk factors, they investigators converted the hazard ratio into a simple integer score to simplify calculation in clinical practice. By adding up the integers and using a slide rule that stands in for the exponential equation, clinicians can translate the integer score into a risk percentage.

Dr. Petri acknowledged as limitations of the study its single-site design; the fact that the Johns Hopkins Lupus Center does not routinely perform cholesterol screening; and that the study reflects care from 1988 onward, where more recent data could reflect a better standard of care. "This needs to be independently validated," she said.

In another multivariate analysis of cardiovascular disease (CVD) risk factors in lupus, a cohort of 306 consecutive SLE patients at a clinic in Istanbul, Turkey, revealed pericarditis, lymphopenia, thrombocytopenia, and psychosis to be significantly associated with nonfatal CVD.

Dr. Murat Inanc of Istanbul University, the lead author of the study, said that 15.2% of the cohort (mean age, 40.2 years; 89% female) had clinical evidence of CVD. Many of them also had traditional risk factors. "The usual suspects are there – hypertension, high cholesterol, metabolic syndrome – but we also found disease-specific features more present in patients with CV involvement," Dr. Inanc said.

Patients with evidence of CVD were older and had longer disease duration, significantly more organ damage, and a higher number of American College of Rheumatology criteria for SLE. "We think disease severity takes almost equal importance with traditional risk factors in this population," he said. Treatment with cyclophosphamide was also seen as a risk factor, although it is likely related to disease severity, he told the congress.

Dr. Inanc noted that the conclusions that can be drawn from the study are limited by its single-site design and lack of data on subclinical CVD. Cumulative corticosteroid use was not investigated, and investigators did not have information on immunosuppressive use in the cohort.

Dr. Murray Urowitz, of the Toronto Western Research Institute, presented findings from an international, multicenter inception cohort of 1,401 SLE patients. The goal of the study was to determine factors at diagnosis that are predictive of the development of premature atherosclerosis. Dr. Urowitz and his colleagues looked at age, sex, diabetes, smoking, obesity, low-density lipoprotein cholesterol, and creatinine. A multivariate analysis showed that only age and male sex were significant risk factors for atherosclerotic vascular events after a mean 5 years’ follow-up. "The implication here is these risk factors take more time to have their maximum effect, and in the first decade it’s hard to have more than age and sex," Dr. Urowitz told the congress.

Also at the congress, Dr. Maureen McMahon of the University of California, Los Angeles, gave a presentation on a panel of biomarkers found to be predictive of current, progressive, or acquired carotid plaque in a cohort of SLE patients.

For their research, Dr. McMahon and her colleagues looked at 210 female SLE patients and 100 age-matched controls who underwent ultrasound imaging of their carotid arteries at baseline and after a mean 29 months of follow-up. Nearly a third of SLE patients had evidence of plaque on follow-up.

The researchers found that three or more of the following factors at baseline were 94% predictive of plaque: age 48 or older, evidence of proinflammatory high-density lipoprotein cholesterol, plasma leptin of 34 ng/dL or greater, homocysteine of 12 mmol/L or greater, and plasma levels of sTWEAK (soluble tumor necrosis factor–like weak inducer of apoptosis) of 373 pg/mL or greater. Any one of these factors plus diabetes was also predictive. Patients with at least three indicators (or one plus diabetes) saw a 28-fold increased odds for the longitudinal presence of carotid plaque (95% confidence interval, 10.6-72.7; P less than .001) and a significantly increased rate of progression of both plaque and intima-media thickness.

None of the investigators disclosed financial relationships related to these studies.

BUENOS AIRES – Traditional tools such as the Framingham risk score have long been known to underestimate cardiovascular risk in people with systemic lupus erythematosus.

At the international congress on systemic lupus erythematosus, Dr. Michelle Petri of Johns Hopkins University, Baltimore, presented data in support of a novel risk-assessment formula to calculate the 10-year risk of a cardiovascular event (CVE). The tool combines the traditional cardiovascular disease risk factors of age, sex, high blood pressure, high cholesterol, smoking, diabetes, and body mass index (BMI), with three lupus-specific factors: a SLEDAI (SLE Disease Activity Index) score of 2 or higher, lupus anticoagulant, and a low mean complement 3 (C3) level.

Under both this and the Framingham algorithms, a 50-year old woman with SLE with a BMI of 23 kg/m², systolic blood pressure of 150 mm Hg, and high cholesterol has about an 8% 10-year risk of a CVE. However, if she also has lupus anticoagulant, high disease activity, or a low C3 level, her risk rises to 15%-18% under the SLE-specific system, whereas her Framingham score, which does not measure these, would remain at 8%.

Courtesy of Keith Weller/Johns Hopkins Medicine

Dr. Petri told the conference that with rheumatoid arthritis, the advice has been to multiply an existing risk score by 1.5 when the patient has certain evidence of disease. "I thought we could do better than that in lupus, because we could derive a formula using actual data," she said.

"We know that traditional CV risk factors do predict actual events and also predict the progression of subclinical atherosclerosis. Even after we adjust, though, for every traditional cardiovascular risk factor, lupus patients still have a twofold increase in coronary calcium over controls – so obviously lupus-specific factors must be in the formula as well."

The data used to derive the new scoring system came from a cohort of 1,342 lupus patients (93% female) treated at the Johns Hopkins Lupus Center. None had a history of CVEs during the first 2 years of follow-up. Over the study period, 109 incident CVEs occurred in the cohort, including 52 strokes and 26 myocardial infarctions.

Dr. Petri and her colleagues used Cox proportional hazards models to determine the baseline variables affecting the risk of a subsequent CVE. Using the results, they derived a formula to calculate the 10-year risk of a CVE. For each of the risk factors, they investigators converted the hazard ratio into a simple integer score to simplify calculation in clinical practice. By adding up the integers and using a slide rule that stands in for the exponential equation, clinicians can translate the integer score into a risk percentage.

Dr. Petri acknowledged as limitations of the study its single-site design; the fact that the Johns Hopkins Lupus Center does not routinely perform cholesterol screening; and that the study reflects care from 1988 onward, where more recent data could reflect a better standard of care. "This needs to be independently validated," she said.

In another multivariate analysis of cardiovascular disease (CVD) risk factors in lupus, a cohort of 306 consecutive SLE patients at a clinic in Istanbul, Turkey, revealed pericarditis, lymphopenia, thrombocytopenia, and psychosis to be significantly associated with nonfatal CVD.

Dr. Murat Inanc of Istanbul University, the lead author of the study, said that 15.2% of the cohort (mean age, 40.2 years; 89% female) had clinical evidence of CVD. Many of them also had traditional risk factors. "The usual suspects are there – hypertension, high cholesterol, metabolic syndrome – but we also found disease-specific features more present in patients with CV involvement," Dr. Inanc said.

Patients with evidence of CVD were older and had longer disease duration, significantly more organ damage, and a higher number of American College of Rheumatology criteria for SLE. "We think disease severity takes almost equal importance with traditional risk factors in this population," he said. Treatment with cyclophosphamide was also seen as a risk factor, although it is likely related to disease severity, he told the congress.

Dr. Inanc noted that the conclusions that can be drawn from the study are limited by its single-site design and lack of data on subclinical CVD. Cumulative corticosteroid use was not investigated, and investigators did not have information on immunosuppressive use in the cohort.

Dr. Murray Urowitz, of the Toronto Western Research Institute, presented findings from an international, multicenter inception cohort of 1,401 SLE patients. The goal of the study was to determine factors at diagnosis that are predictive of the development of premature atherosclerosis. Dr. Urowitz and his colleagues looked at age, sex, diabetes, smoking, obesity, low-density lipoprotein cholesterol, and creatinine. A multivariate analysis showed that only age and male sex were significant risk factors for atherosclerotic vascular events after a mean 5 years’ follow-up. "The implication here is these risk factors take more time to have their maximum effect, and in the first decade it’s hard to have more than age and sex," Dr. Urowitz told the congress.

Also at the congress, Dr. Maureen McMahon of the University of California, Los Angeles, gave a presentation on a panel of biomarkers found to be predictive of current, progressive, or acquired carotid plaque in a cohort of SLE patients.

For their research, Dr. McMahon and her colleagues looked at 210 female SLE patients and 100 age-matched controls who underwent ultrasound imaging of their carotid arteries at baseline and after a mean 29 months of follow-up. Nearly a third of SLE patients had evidence of plaque on follow-up.

The researchers found that three or more of the following factors at baseline were 94% predictive of plaque: age 48 or older, evidence of proinflammatory high-density lipoprotein cholesterol, plasma leptin of 34 ng/dL or greater, homocysteine of 12 mmol/L or greater, and plasma levels of sTWEAK (soluble tumor necrosis factor–like weak inducer of apoptosis) of 373 pg/mL or greater. Any one of these factors plus diabetes was also predictive. Patients with at least three indicators (or one plus diabetes) saw a 28-fold increased odds for the longitudinal presence of carotid plaque (95% confidence interval, 10.6-72.7; P less than .001) and a significantly increased rate of progression of both plaque and intima-media thickness.

None of the investigators disclosed financial relationships related to these studies.

Only one in five adult Americans meets government guidelines for weekly aerobic and muscle-strengthening activities, the Centers for Disease Control and Prevention reported May 2.

Federal guidelines recommend that adults get 150 minutes of moderate-intensity aerobic activity, such as walking, or 75 minutes of vigorous-intensity activity, such as jogging, every week. They also advise adults to train major muscle groups, using weights or other forms of resistance, twice weekly. To see if these guidelines were being met, questions regarding exercise habits were added to the Behavioral Risk Factor Surveillance System in 2011.

Kristan Hutchison (Property of National Science Foundation)/ (Antarctic Photo Library via Wikimedia Commons)

Of more than 400,000 BRFSS respondents, just more than half (52%) reported that they met guidelines for aerobic activity, while under a third (29%) said they met guidelines for muscle-strengthening activity. One-fifth (20%) were classified as meeting both the aerobic and muscle-strengthening guidelines (MMWR 2013;62:326-30).

Women were less likely to meet the guidelines than men, with only 18% reporting compliance, compared with 23% of men. Whites and blacks reported similar habits, with about 21% meeting guidelines; Hispanics had somewhat lower compliance at 18%, and other races 23%.

Younger adults were more likely to meet fitness guidelines, with 31% of 18-to-24-year-olds compliant, compared with only 16% of people aged 65 years and older.

The CDC noted a few limitations to its findings. Data from the survey were self-reported, "and might be overestimated because of social-desirability bias, recall limitations, or other factors."

Only half of those called responded, and the survey was not designed to capture aerobic or muscle-strengthening activities that are a component of job duties.

Only one in five adult Americans meets government guidelines for weekly aerobic and muscle-strengthening activities, the Centers for Disease Control and Prevention reported May 2.

Federal guidelines recommend that adults get 150 minutes of moderate-intensity aerobic activity, such as walking, or 75 minutes of vigorous-intensity activity, such as jogging, every week. They also advise adults to train major muscle groups, using weights or other forms of resistance, twice weekly. To see if these guidelines were being met, questions regarding exercise habits were added to the Behavioral Risk Factor Surveillance System in 2011.

Kristan Hutchison (Property of National Science Foundation)/ (Antarctic Photo Library via Wikimedia Commons)

Of more than 400,000 BRFSS respondents, just more than half (52%) reported that they met guidelines for aerobic activity, while under a third (29%) said they met guidelines for muscle-strengthening activity. One-fifth (20%) were classified as meeting both the aerobic and muscle-strengthening guidelines (MMWR 2013;62:326-30).

Women were less likely to meet the guidelines than men, with only 18% reporting compliance, compared with 23% of men. Whites and blacks reported similar habits, with about 21% meeting guidelines; Hispanics had somewhat lower compliance at 18%, and other races 23%.

Younger adults were more likely to meet fitness guidelines, with 31% of 18-to-24-year-olds compliant, compared with only 16% of people aged 65 years and older.

The CDC noted a few limitations to its findings. Data from the survey were self-reported, "and might be overestimated because of social-desirability bias, recall limitations, or other factors."

Only half of those called responded, and the survey was not designed to capture aerobic or muscle-strengthening activities that are a component of job duties.

Only one in five adult Americans meets government guidelines for weekly aerobic and muscle-strengthening activities, the Centers for Disease Control and Prevention reported May 2.

Federal guidelines recommend that adults get 150 minutes of moderate-intensity aerobic activity, such as walking, or 75 minutes of vigorous-intensity activity, such as jogging, every week. They also advise adults to train major muscle groups, using weights or other forms of resistance, twice weekly. To see if these guidelines were being met, questions regarding exercise habits were added to the Behavioral Risk Factor Surveillance System in 2011.

Kristan Hutchison (Property of National Science Foundation)/ (Antarctic Photo Library via Wikimedia Commons)

Of more than 400,000 BRFSS respondents, just more than half (52%) reported that they met guidelines for aerobic activity, while under a third (29%) said they met guidelines for muscle-strengthening activity. One-fifth (20%) were classified as meeting both the aerobic and muscle-strengthening guidelines (MMWR 2013;62:326-30).

Women were less likely to meet the guidelines than men, with only 18% reporting compliance, compared with 23% of men. Whites and blacks reported similar habits, with about 21% meeting guidelines; Hispanics had somewhat lower compliance at 18%, and other races 23%.

Younger adults were more likely to meet fitness guidelines, with 31% of 18-to-24-year-olds compliant, compared with only 16% of people aged 65 years and older.

The CDC noted a few limitations to its findings. Data from the survey were self-reported, "and might be overestimated because of social-desirability bias, recall limitations, or other factors."

Only half of those called responded, and the survey was not designed to capture aerobic or muscle-strengthening activities that are a component of job duties.

BUENOS AIRES – Incidences of certain cancers, particularly lymphomas, have been shown to be higher in people with systemic lupus erythematosus, while hormone-influenced breast, ovarian, and endometrial cancers have recently been found to occur less often in SLE patients than in the general population.

At the 10th International Congress on SLE, the researchers responsible for these findings discussed their implications for clinical practice.

Dr. Ann Clarke of McGill University, Montreal, coauthor of a large case-cohort study that found neither immunosuppressant drug use nor disease activity correlated with lymphoma risk as hypothesized (Ann. Rheum. Dis. 2013 Jan. 8 [doi:10.1136/annrheumdis-2012-202099]), said that clinicians should nonetheless consider a history of malignancies when deciding whether to prescribe immunosuppressants.

The study by Dr. Clarke and her colleagues, led by Dr. Sasha Bernatsky of McGill, enrolled 75 SLE patients with lymphoma and 4,961 cancer-free controls with SLE, seeking to determine associations between lymphoma risk and exposures to cyclophosphamide, azathioprine, methotrexate, mycophenolate, antimalarials, or steroids. The team also looked at Sjögren’s syndrome, disease duration, and disease activity as potential indicators of risk.

Although cyclophosphamide use was seen more frequently among the lymphoma cases (20%) than in the controls (16.8%), this difference did not reach statistical significance. "There isn’t a strong signal that the drugs are responsible," Dr. Clarke said, but she nonetheless argued for caution in the clinic.

"If there is a remote history of malignancy – more than 5 years, certainly more than 10 – I would proceed [with immunosuppressants]," she said. "If there is a recent history, I would try to avoid them, using rituximab or belimumab as appropriate."

Dr. Clarke’s team, again led by Dr. Bernatsky, also conducted research that examined the incidence of specific cancers in an international cohort of 16,409 patients with SLE (J. Autoimmun. 2013 Feb. 11 [doi:10.1016/j.jaut.2012.12.009]).

This study showed that lupus patients had a threefold higher risk for hematological cancers, especially non-Hodgkin’s lymphoma, and a slightly elevated risk for cancer overall, but saw fewer hormone-sensitive cancers than expected, with the standardized incidence ratio of 0.73 for breast cancers (95% confidence interval [CI], 0.61-0.88), 0.44 for endometrial cancers (95% CI, 0.23-0.77), and 0.64 for ovarian cancers (95% CI, 0.34-1.10).

"There certainly seems to be a convincing signal that female hormone-sensitive cancers appear to be decreased in patients with lupus," said Dr. Clarke, who is also codirector of the lupus clinic at Montreal General Hospital. She said that there are various hypotheses as to why, including animal models that suggest that anti-DNA antibodies could have antitumor effects against certain cancer cell lines (Sci. Transl. Med. 2012;4:157ra142).

"I don’t think this should give us a false sense of reassurance," Dr. Clarke said of the findings, noting that vulvar cancers, likely resulting from HPV infection, were seen as increased in lupus patients and that cervical dysplasia was known to be increased as well.

"I think we still have to screen for breast cancer. And I think that this risk for dysplasia calls us to be even more vigilant than current recommendations," she said.

In a related talk, Dr. Murray B. Urowitz, director of the Centre for Prognosis Studies in the Rheumatic Diseases at Toronto Western Research Institute and a coauthor on both studies, praised Dr. Clarke and colleagues’ malignancy findings as "very important."

"The expected numbers of malignancy in this tremendous number of patients was 561," Dr. Urowitz said at the meeting, referring to the large cohort study. "And the observed number was 644, with the driver being hematologic malignancies." He noted that only age and male gender were found to be predictive factors.

The lower-than expected incidence of hormone-sensitive cancers in the same cohort study, Dr. Urowitz said, was yet another mystery. "Is there a hormonal factor favoring the lupus patient – less total estrogen over her lifetime, less likely to get hormone replacement? Maybe, but the decreased risk seen in SLE is evident in both pre- and postmenopausal lupus. Could it be genetic? It’s unclear. There [are] some very exciting data that anti-DNA antibody may actually be protective, but that’s still in the very early phases."

Dr. Urowitz, Dr. Clarke, and Dr. Bernatsky did not disclose financial relationships bearing on their studies.

BUENOS AIRES – Incidences of certain cancers, particularly lymphomas, have been shown to be higher in people with systemic lupus erythematosus, while hormone-influenced breast, ovarian, and endometrial cancers have recently been found to occur less often in SLE patients than in the general population.

At the 10th International Congress on SLE, the researchers responsible for these findings discussed their implications for clinical practice.

Dr. Ann Clarke of McGill University, Montreal, coauthor of a large case-cohort study that found neither immunosuppressant drug use nor disease activity correlated with lymphoma risk as hypothesized (Ann. Rheum. Dis. 2013 Jan. 8 [doi:10.1136/annrheumdis-2012-202099]), said that clinicians should nonetheless consider a history of malignancies when deciding whether to prescribe immunosuppressants.

The study by Dr. Clarke and her colleagues, led by Dr. Sasha Bernatsky of McGill, enrolled 75 SLE patients with lymphoma and 4,961 cancer-free controls with SLE, seeking to determine associations between lymphoma risk and exposures to cyclophosphamide, azathioprine, methotrexate, mycophenolate, antimalarials, or steroids. The team also looked at Sjögren’s syndrome, disease duration, and disease activity as potential indicators of risk.

Although cyclophosphamide use was seen more frequently among the lymphoma cases (20%) than in the controls (16.8%), this difference did not reach statistical significance. "There isn’t a strong signal that the drugs are responsible," Dr. Clarke said, but she nonetheless argued for caution in the clinic.

"If there is a remote history of malignancy – more than 5 years, certainly more than 10 – I would proceed [with immunosuppressants]," she said. "If there is a recent history, I would try to avoid them, using rituximab or belimumab as appropriate."

Dr. Clarke’s team, again led by Dr. Bernatsky, also conducted research that examined the incidence of specific cancers in an international cohort of 16,409 patients with SLE (J. Autoimmun. 2013 Feb. 11 [doi:10.1016/j.jaut.2012.12.009]).

This study showed that lupus patients had a threefold higher risk for hematological cancers, especially non-Hodgkin’s lymphoma, and a slightly elevated risk for cancer overall, but saw fewer hormone-sensitive cancers than expected, with the standardized incidence ratio of 0.73 for breast cancers (95% confidence interval [CI], 0.61-0.88), 0.44 for endometrial cancers (95% CI, 0.23-0.77), and 0.64 for ovarian cancers (95% CI, 0.34-1.10).

"There certainly seems to be a convincing signal that female hormone-sensitive cancers appear to be decreased in patients with lupus," said Dr. Clarke, who is also codirector of the lupus clinic at Montreal General Hospital. She said that there are various hypotheses as to why, including animal models that suggest that anti-DNA antibodies could have antitumor effects against certain cancer cell lines (Sci. Transl. Med. 2012;4:157ra142).

"I don’t think this should give us a false sense of reassurance," Dr. Clarke said of the findings, noting that vulvar cancers, likely resulting from HPV infection, were seen as increased in lupus patients and that cervical dysplasia was known to be increased as well.

"I think we still have to screen for breast cancer. And I think that this risk for dysplasia calls us to be even more vigilant than current recommendations," she said.

In a related talk, Dr. Murray B. Urowitz, director of the Centre for Prognosis Studies in the Rheumatic Diseases at Toronto Western Research Institute and a coauthor on both studies, praised Dr. Clarke and colleagues’ malignancy findings as "very important."

"The expected numbers of malignancy in this tremendous number of patients was 561," Dr. Urowitz said at the meeting, referring to the large cohort study. "And the observed number was 644, with the driver being hematologic malignancies." He noted that only age and male gender were found to be predictive factors.

The lower-than expected incidence of hormone-sensitive cancers in the same cohort study, Dr. Urowitz said, was yet another mystery. "Is there a hormonal factor favoring the lupus patient – less total estrogen over her lifetime, less likely to get hormone replacement? Maybe, but the decreased risk seen in SLE is evident in both pre- and postmenopausal lupus. Could it be genetic? It’s unclear. There [are] some very exciting data that anti-DNA antibody may actually be protective, but that’s still in the very early phases."

Dr. Urowitz, Dr. Clarke, and Dr. Bernatsky did not disclose financial relationships bearing on their studies.

BUENOS AIRES – Incidences of certain cancers, particularly lymphomas, have been shown to be higher in people with systemic lupus erythematosus, while hormone-influenced breast, ovarian, and endometrial cancers have recently been found to occur less often in SLE patients than in the general population.

At the 10th International Congress on SLE, the researchers responsible for these findings discussed their implications for clinical practice.

Dr. Ann Clarke of McGill University, Montreal, coauthor of a large case-cohort study that found neither immunosuppressant drug use nor disease activity correlated with lymphoma risk as hypothesized (Ann. Rheum. Dis. 2013 Jan. 8 [doi:10.1136/annrheumdis-2012-202099]), said that clinicians should nonetheless consider a history of malignancies when deciding whether to prescribe immunosuppressants.

The study by Dr. Clarke and her colleagues, led by Dr. Sasha Bernatsky of McGill, enrolled 75 SLE patients with lymphoma and 4,961 cancer-free controls with SLE, seeking to determine associations between lymphoma risk and exposures to cyclophosphamide, azathioprine, methotrexate, mycophenolate, antimalarials, or steroids. The team also looked at Sjögren’s syndrome, disease duration, and disease activity as potential indicators of risk.

Although cyclophosphamide use was seen more frequently among the lymphoma cases (20%) than in the controls (16.8%), this difference did not reach statistical significance. "There isn’t a strong signal that the drugs are responsible," Dr. Clarke said, but she nonetheless argued for caution in the clinic.

"If there is a remote history of malignancy – more than 5 years, certainly more than 10 – I would proceed [with immunosuppressants]," she said. "If there is a recent history, I would try to avoid them, using rituximab or belimumab as appropriate."

Dr. Clarke’s team, again led by Dr. Bernatsky, also conducted research that examined the incidence of specific cancers in an international cohort of 16,409 patients with SLE (J. Autoimmun. 2013 Feb. 11 [doi:10.1016/j.jaut.2012.12.009]).

This study showed that lupus patients had a threefold higher risk for hematological cancers, especially non-Hodgkin’s lymphoma, and a slightly elevated risk for cancer overall, but saw fewer hormone-sensitive cancers than expected, with the standardized incidence ratio of 0.73 for breast cancers (95% confidence interval [CI], 0.61-0.88), 0.44 for endometrial cancers (95% CI, 0.23-0.77), and 0.64 for ovarian cancers (95% CI, 0.34-1.10).

"There certainly seems to be a convincing signal that female hormone-sensitive cancers appear to be decreased in patients with lupus," said Dr. Clarke, who is also codirector of the lupus clinic at Montreal General Hospital. She said that there are various hypotheses as to why, including animal models that suggest that anti-DNA antibodies could have antitumor effects against certain cancer cell lines (Sci. Transl. Med. 2012;4:157ra142).

"I don’t think this should give us a false sense of reassurance," Dr. Clarke said of the findings, noting that vulvar cancers, likely resulting from HPV infection, were seen as increased in lupus patients and that cervical dysplasia was known to be increased as well.

"I think we still have to screen for breast cancer. And I think that this risk for dysplasia calls us to be even more vigilant than current recommendations," she said.

In a related talk, Dr. Murray B. Urowitz, director of the Centre for Prognosis Studies in the Rheumatic Diseases at Toronto Western Research Institute and a coauthor on both studies, praised Dr. Clarke and colleagues’ malignancy findings as "very important."

"The expected numbers of malignancy in this tremendous number of patients was 561," Dr. Urowitz said at the meeting, referring to the large cohort study. "And the observed number was 644, with the driver being hematologic malignancies." He noted that only age and male gender were found to be predictive factors.

The lower-than expected incidence of hormone-sensitive cancers in the same cohort study, Dr. Urowitz said, was yet another mystery. "Is there a hormonal factor favoring the lupus patient – less total estrogen over her lifetime, less likely to get hormone replacement? Maybe, but the decreased risk seen in SLE is evident in both pre- and postmenopausal lupus. Could it be genetic? It’s unclear. There [are] some very exciting data that anti-DNA antibody may actually be protective, but that’s still in the very early phases."

Dr. Urowitz, Dr. Clarke, and Dr. Bernatsky did not disclose financial relationships bearing on their studies.

BUENOS AIRES – Despite some early letdowns in clinical trials, biologic therapies targeting nearly every point in the pathway of the known pathogenesis of systemic lupus erythematosus are currently in the pipeline.

At the International Congress on Systemic Lupus Erythematosus, investigators presented promising new data on several experimental biologics. And in the shadow of some costly failures, they also discussed ways to refine endpoints, inclusion criteria, and the use of background medicines to make trial results for these agents clearer.

Biomarker-driven response to rontalizumab

Rontalizumab, a humanized antibody against anti-interferon-alpha, was shown in a phase II randomized controlled trial of 159 patients with moderate to severe SLE to improve signs and symptoms, flare rates, and need for steroids at 24 weeks in the subset of patients who had low interferon signature gene expression metric (ISM), an emerging biomarker in SLE, at baseline.

Although whether patients are classified as ISM high or low makes little difference in terms of measurable disease activity, it does appear to affect how treatments work. "No matter what drug you look at, the impact differs depending on whether the patients are ISM high or low," said Dr. Joan T. Merrill, one of the coauthors of the rontalizumab study, which was presented at the meeting by Dr. William Kennedy, senior medical director of Genentech.

Rontalizumab was associated with improvement in the ISM-low subgroup in the trial, which compared both intravenous and subcutaneous forms of rontalizumab with placebo. In ISM-low patients, a quarter of the total enrolled, IV rontalizumab vs. placebo SLE Responder Index (SRI) response rates were 75% vs. 18%. Treatment groups saw a nearly 40% reduced risk of disease flare based on SELENA-SLEDAI (Safety of Estrogens in Lupus Erythematosus National Assessment-SLE Disease Activity Index) flare rates, compared with placebo (hazard ratio 0.61 [90% confidence interval 0.46-0.81; P = .0040]), driven by ISM-low patients. Also, 91% of ISM-low patients in the treatment groups achieved prednisone reduction (10 mg/day) by week 24, compared with 67% of placebo subjects (Lupus 2013;22[Suppl.]:O22).

Limiting background medications in trials

Background immunosuppressants were not used in the rontalizumab study, and steroids were limited. Dr. Merrill, of the University of Oklahoma Health Sciences Center, Oklahoma City, discussed some of the thinking behind this. Limiting background medications "can lead to more interpretable results," she said. While many investigators have argued that only the sickest and most refractory patients should be enrolled in SLE clinical trials as a way to discern a clearer differences between treatment and placebo, Dr. Merrill instead championed recruiting less-sick patients for whom it is safer to withdraw or minimize background medicines.

Patients without severe disease will still die early and accumulate increasing damage over time, Dr. Merrill said. "They represent a huge unmet need. So if we could do trials with these patients and limit the background noise caused by their medications, perhaps we could also see a difference between treatment and placebo. Trials would be easier to recruit, we would see fewer infections, and most importantly, there would be a bigger market for pharma companies to pursue."

Targeting CD22 antigen on B cells

Two randomized, placebo-controlled trials of epratuzumab, a monoclonal antibody targeting CD22 antigen on B cells, had to be terminated when drug supply was interrupted. However, the early findings had shown clinically meaningful improvements in disease activity and corticosteroid sparing. Final results from an open-label extension study for SLE patients previously enrolled in these trials (n = 429), sponsored by UCB Pharma, showed that continued administration of epratuzumab resulted in sustained improvements after a mean four years of treatment, with no new safety signals (Lupus 2013;22[Suppl.]:O25).

Phase II data on blisibimod

Blisibimod, a biologic injected subcutaneously that inhibits B-cell activating factor, or BAFF, was investigated in a phase IIb manufacturer-sponsored trial of 547 patients with anti-dsDNA or anti-nuclear antibodies and SELENA-SLEDAI score of 6 or higher at baseline. Dr. Morton Scheinberg of Rheumatology Hospital Abreu Sodre Pesquisa Clínica, São Paulo, Brazil, led the trial, sponsored by Anthera Pharmaceuticals, in which patients were randomized to one of three doses or placebo. The composite primary endpoint, SRI-5 (defined as a 5-point improvement in SELENA-SLEDAI, no new BILAG A or 2B organ domain scores, and no worsening in Physician’s Global Assessment) was not met because efficacy was not shown in the lower doses. However, more subjects who received the highest dose (200 mg once weekly) met the response criteria starting in week 16 (8%, P = .14), through week 24 (8.2%, P = .15), reaching statistical significance at week 20 (Lupus 2013;22[Suppl.]:O21).

Improving on past trial missteps

One of the coinvestigators on the blisibimod trial, Dr. Richard A. Furie, discussed missteps in the design of earlier studies. "Trials of new biologic therapies have taught us to be humble and logical, and to persevere – we’ve made a lot of mistakes over last 20 years," he told the conference, pointing to a handful of trials in which subjects did not have serologic evidence of disease at baseline. "In my book, if someone is clinically active they should have autoantibodies," he said. "So the rules for entry were changed for all trials."

Dr. Furie, chief of the division of rheumatology and allergy-clinical immunology in the North Shore–LIJ Health System and professor of medicine at Hofstra University, Hempstead, N.Y., said that while inclusion criteria had improved, investigators of biologic agents still had far to go in refining SLE trial endpoints. "No two endpoints are the same – we’ve customized the endpoints and are struggling with extrarenal trials whether it should be a single or composite endpoint, whether it should be based on SLEDAI or BILAG alone or should we use SRI – there is no consensus." Echoing Dr. Merrill, he stressed that background medications were another area in need of increased scrutiny and consensus. "Each trial has handled steroids and immunosuppressants differently," he said.

Dr. Merrill has received support from Genentech. Dr. Furie has received support from Anthera, Genentech, and UCB Pharma. Both rheumatologists have received support from many other companies involved in lupus research and therapy.

BUENOS AIRES – Despite some early letdowns in clinical trials, biologic therapies targeting nearly every point in the pathway of the known pathogenesis of systemic lupus erythematosus are currently in the pipeline.

At the International Congress on Systemic Lupus Erythematosus, investigators presented promising new data on several experimental biologics. And in the shadow of some costly failures, they also discussed ways to refine endpoints, inclusion criteria, and the use of background medicines to make trial results for these agents clearer.

Biomarker-driven response to rontalizumab

Rontalizumab, a humanized antibody against anti-interferon-alpha, was shown in a phase II randomized controlled trial of 159 patients with moderate to severe SLE to improve signs and symptoms, flare rates, and need for steroids at 24 weeks in the subset of patients who had low interferon signature gene expression metric (ISM), an emerging biomarker in SLE, at baseline.

Although whether patients are classified as ISM high or low makes little difference in terms of measurable disease activity, it does appear to affect how treatments work. "No matter what drug you look at, the impact differs depending on whether the patients are ISM high or low," said Dr. Joan T. Merrill, one of the coauthors of the rontalizumab study, which was presented at the meeting by Dr. William Kennedy, senior medical director of Genentech.

Rontalizumab was associated with improvement in the ISM-low subgroup in the trial, which compared both intravenous and subcutaneous forms of rontalizumab with placebo. In ISM-low patients, a quarter of the total enrolled, IV rontalizumab vs. placebo SLE Responder Index (SRI) response rates were 75% vs. 18%. Treatment groups saw a nearly 40% reduced risk of disease flare based on SELENA-SLEDAI (Safety of Estrogens in Lupus Erythematosus National Assessment-SLE Disease Activity Index) flare rates, compared with placebo (hazard ratio 0.61 [90% confidence interval 0.46-0.81; P = .0040]), driven by ISM-low patients. Also, 91% of ISM-low patients in the treatment groups achieved prednisone reduction (10 mg/day) by week 24, compared with 67% of placebo subjects (Lupus 2013;22[Suppl.]:O22).

Limiting background medications in trials

Background immunosuppressants were not used in the rontalizumab study, and steroids were limited. Dr. Merrill, of the University of Oklahoma Health Sciences Center, Oklahoma City, discussed some of the thinking behind this. Limiting background medications "can lead to more interpretable results," she said. While many investigators have argued that only the sickest and most refractory patients should be enrolled in SLE clinical trials as a way to discern a clearer differences between treatment and placebo, Dr. Merrill instead championed recruiting less-sick patients for whom it is safer to withdraw or minimize background medicines.

Patients without severe disease will still die early and accumulate increasing damage over time, Dr. Merrill said. "They represent a huge unmet need. So if we could do trials with these patients and limit the background noise caused by their medications, perhaps we could also see a difference between treatment and placebo. Trials would be easier to recruit, we would see fewer infections, and most importantly, there would be a bigger market for pharma companies to pursue."

Targeting CD22 antigen on B cells

Two randomized, placebo-controlled trials of epratuzumab, a monoclonal antibody targeting CD22 antigen on B cells, had to be terminated when drug supply was interrupted. However, the early findings had shown clinically meaningful improvements in disease activity and corticosteroid sparing. Final results from an open-label extension study for SLE patients previously enrolled in these trials (n = 429), sponsored by UCB Pharma, showed that continued administration of epratuzumab resulted in sustained improvements after a mean four years of treatment, with no new safety signals (Lupus 2013;22[Suppl.]:O25).

Phase II data on blisibimod

Blisibimod, a biologic injected subcutaneously that inhibits B-cell activating factor, or BAFF, was investigated in a phase IIb manufacturer-sponsored trial of 547 patients with anti-dsDNA or anti-nuclear antibodies and SELENA-SLEDAI score of 6 or higher at baseline. Dr. Morton Scheinberg of Rheumatology Hospital Abreu Sodre Pesquisa Clínica, São Paulo, Brazil, led the trial, sponsored by Anthera Pharmaceuticals, in which patients were randomized to one of three doses or placebo. The composite primary endpoint, SRI-5 (defined as a 5-point improvement in SELENA-SLEDAI, no new BILAG A or 2B organ domain scores, and no worsening in Physician’s Global Assessment) was not met because efficacy was not shown in the lower doses. However, more subjects who received the highest dose (200 mg once weekly) met the response criteria starting in week 16 (8%, P = .14), through week 24 (8.2%, P = .15), reaching statistical significance at week 20 (Lupus 2013;22[Suppl.]:O21).

Improving on past trial missteps

One of the coinvestigators on the blisibimod trial, Dr. Richard A. Furie, discussed missteps in the design of earlier studies. "Trials of new biologic therapies have taught us to be humble and logical, and to persevere – we’ve made a lot of mistakes over last 20 years," he told the conference, pointing to a handful of trials in which subjects did not have serologic evidence of disease at baseline. "In my book, if someone is clinically active they should have autoantibodies," he said. "So the rules for entry were changed for all trials."

Dr. Furie, chief of the division of rheumatology and allergy-clinical immunology in the North Shore–LIJ Health System and professor of medicine at Hofstra University, Hempstead, N.Y., said that while inclusion criteria had improved, investigators of biologic agents still had far to go in refining SLE trial endpoints. "No two endpoints are the same – we’ve customized the endpoints and are struggling with extrarenal trials whether it should be a single or composite endpoint, whether it should be based on SLEDAI or BILAG alone or should we use SRI – there is no consensus." Echoing Dr. Merrill, he stressed that background medications were another area in need of increased scrutiny and consensus. "Each trial has handled steroids and immunosuppressants differently," he said.

Dr. Merrill has received support from Genentech. Dr. Furie has received support from Anthera, Genentech, and UCB Pharma. Both rheumatologists have received support from many other companies involved in lupus research and therapy.

BUENOS AIRES – Despite some early letdowns in clinical trials, biologic therapies targeting nearly every point in the pathway of the known pathogenesis of systemic lupus erythematosus are currently in the pipeline.

At the International Congress on Systemic Lupus Erythematosus, investigators presented promising new data on several experimental biologics. And in the shadow of some costly failures, they also discussed ways to refine endpoints, inclusion criteria, and the use of background medicines to make trial results for these agents clearer.

Biomarker-driven response to rontalizumab

Rontalizumab, a humanized antibody against anti-interferon-alpha, was shown in a phase II randomized controlled trial of 159 patients with moderate to severe SLE to improve signs and symptoms, flare rates, and need for steroids at 24 weeks in the subset of patients who had low interferon signature gene expression metric (ISM), an emerging biomarker in SLE, at baseline.

Although whether patients are classified as ISM high or low makes little difference in terms of measurable disease activity, it does appear to affect how treatments work. "No matter what drug you look at, the impact differs depending on whether the patients are ISM high or low," said Dr. Joan T. Merrill, one of the coauthors of the rontalizumab study, which was presented at the meeting by Dr. William Kennedy, senior medical director of Genentech.

Rontalizumab was associated with improvement in the ISM-low subgroup in the trial, which compared both intravenous and subcutaneous forms of rontalizumab with placebo. In ISM-low patients, a quarter of the total enrolled, IV rontalizumab vs. placebo SLE Responder Index (SRI) response rates were 75% vs. 18%. Treatment groups saw a nearly 40% reduced risk of disease flare based on SELENA-SLEDAI (Safety of Estrogens in Lupus Erythematosus National Assessment-SLE Disease Activity Index) flare rates, compared with placebo (hazard ratio 0.61 [90% confidence interval 0.46-0.81; P = .0040]), driven by ISM-low patients. Also, 91% of ISM-low patients in the treatment groups achieved prednisone reduction (10 mg/day) by week 24, compared with 67% of placebo subjects (Lupus 2013;22[Suppl.]:O22).

Limiting background medications in trials

Background immunosuppressants were not used in the rontalizumab study, and steroids were limited. Dr. Merrill, of the University of Oklahoma Health Sciences Center, Oklahoma City, discussed some of the thinking behind this. Limiting background medications "can lead to more interpretable results," she said. While many investigators have argued that only the sickest and most refractory patients should be enrolled in SLE clinical trials as a way to discern a clearer differences between treatment and placebo, Dr. Merrill instead championed recruiting less-sick patients for whom it is safer to withdraw or minimize background medicines.

Patients without severe disease will still die early and accumulate increasing damage over time, Dr. Merrill said. "They represent a huge unmet need. So if we could do trials with these patients and limit the background noise caused by their medications, perhaps we could also see a difference between treatment and placebo. Trials would be easier to recruit, we would see fewer infections, and most importantly, there would be a bigger market for pharma companies to pursue."

Targeting CD22 antigen on B cells

Two randomized, placebo-controlled trials of epratuzumab, a monoclonal antibody targeting CD22 antigen on B cells, had to be terminated when drug supply was interrupted. However, the early findings had shown clinically meaningful improvements in disease activity and corticosteroid sparing. Final results from an open-label extension study for SLE patients previously enrolled in these trials (n = 429), sponsored by UCB Pharma, showed that continued administration of epratuzumab resulted in sustained improvements after a mean four years of treatment, with no new safety signals (Lupus 2013;22[Suppl.]:O25).

Phase II data on blisibimod

Blisibimod, a biologic injected subcutaneously that inhibits B-cell activating factor, or BAFF, was investigated in a phase IIb manufacturer-sponsored trial of 547 patients with anti-dsDNA or anti-nuclear antibodies and SELENA-SLEDAI score of 6 or higher at baseline. Dr. Morton Scheinberg of Rheumatology Hospital Abreu Sodre Pesquisa Clínica, São Paulo, Brazil, led the trial, sponsored by Anthera Pharmaceuticals, in which patients were randomized to one of three doses or placebo. The composite primary endpoint, SRI-5 (defined as a 5-point improvement in SELENA-SLEDAI, no new BILAG A or 2B organ domain scores, and no worsening in Physician’s Global Assessment) was not met because efficacy was not shown in the lower doses. However, more subjects who received the highest dose (200 mg once weekly) met the response criteria starting in week 16 (8%, P = .14), through week 24 (8.2%, P = .15), reaching statistical significance at week 20 (Lupus 2013;22[Suppl.]:O21).

Improving on past trial missteps

One of the coinvestigators on the blisibimod trial, Dr. Richard A. Furie, discussed missteps in the design of earlier studies. "Trials of new biologic therapies have taught us to be humble and logical, and to persevere – we’ve made a lot of mistakes over last 20 years," he told the conference, pointing to a handful of trials in which subjects did not have serologic evidence of disease at baseline. "In my book, if someone is clinically active they should have autoantibodies," he said. "So the rules for entry were changed for all trials."

Dr. Furie, chief of the division of rheumatology and allergy-clinical immunology in the North Shore–LIJ Health System and professor of medicine at Hofstra University, Hempstead, N.Y., said that while inclusion criteria had improved, investigators of biologic agents still had far to go in refining SLE trial endpoints. "No two endpoints are the same – we’ve customized the endpoints and are struggling with extrarenal trials whether it should be a single or composite endpoint, whether it should be based on SLEDAI or BILAG alone or should we use SRI – there is no consensus." Echoing Dr. Merrill, he stressed that background medications were another area in need of increased scrutiny and consensus. "Each trial has handled steroids and immunosuppressants differently," he said.

Dr. Merrill has received support from Genentech. Dr. Furie has received support from Anthera, Genentech, and UCB Pharma. Both rheumatologists have received support from many other companies involved in lupus research and therapy.

BUENOS AIRES – Approved biologic therapies for systematic lupus erythematosus have so far been limited to belimumab, and there has been little compelling trial evidence to date for the effectiveness of abatacept or rituximab in either SLE or lupus nephritis.

Nonetheless, investigators presenting at an international congress on systemic lupus erythematosus gave clinicians reasons to be optimistic about these three biologics currently in clinical use, both on and off label.

Reinterpretation of randomized controlled trial data even from trials that did not meet their primary or secondary endpoints, new registry data, clinical observation, and ongoing trials with better-defined endpoints are producing insights into how and which SLE and lupus nephritis patients might benefit from rituximab, abatacept, or belimumab.

Dr. Ronald F. van Vollenhoven of the Karolinska Institute in Stockholm discussed findings from a yet-unpublished registry study of biologics in lupus, to be presented in June at the EULAR annual meeting in Madrid. Dr. van Vollenhoven and colleagues found that rituximab, which had not succeeded in the 2012 LUNAR trial in lupus nephritis patients (Arthritis Rheum. 2012;64:1215-26), was the most frequently used off-label biologic being used in lupus in European countries, with about 1% of lupus patients receiving it. "These are more severe disease patients with more damage who have failed other therapies – it seems to be an option of last resort," Dr. van Vollenhoven said.

Dr. Elizabeth Lightstone, a nephrologist at Imperial College London, argued for a role for rituximab beyond rescue therapy in lupus nephritis. "I think most of us think that rituximab does work," Dr. Lightstone told the conference, and described soon-to-be published results from an observational cohort study (n = 50) of new or relapsed lupus nephritis patients receiving rituximab as a first-line treatment protocol along with mycophenolate mofetil (MMF), with a median follow-up of 163 weeks.

By 12 weeks, 18% of patients saw a complete renal response, which increased to 32% at 26 weeks and 50% at 52 weeks, Dr. Lightstone said. Remarkably, 43 patients who started on this regimen have been managed successfully without oral steroids. Dr. Lightstone said that her U.K.-based nephrology group was about to begin recruiting for a randomized, controlled trial that would compare this rituximab-based regimen with MMF and steroids in 252 lupus nephritis patients.

Dr. Lightstone described the failed LUNAR study as having set the bar too high in its definition of complete renal remission, and having gone too short at only 1 year. "There were a lot of positives in that trial," she said. "The serology normalized significantly; in the exploratory endpoints there was at least a 50% reduction in proteinuria significant in the rituximab group at 78 weeks, so there was divergence beyond one year. The need for immunosuppression was significantly different in week 52 and week 78, and there was a reduction in steroids. And black patients responded better – the trial wasn’t powered to show that as significant, but it looks tantalizing."

She also pointed to a randomized, controlled trial of rituximab vs. standard of care, led by Dr. Frédéric Houssiau of the Université Catholique de Louvain in Brussels that may better define the role of rituximab in lupus nephritis. This trial, which aims to recruit 194 patients and is scheduled to end in 2016, is double the duration of the LUNAR trial, at 104 weeks, and defines complete response as a protein/creatinine ratio of 0.5 or less (compared with 0.2 or less in the LUNAR trial).

Dr. van Vollenhoven told the conference that abatacept was being used very rarely in clinical practice in Europe in either SLE or lupus nephritis. He noted, however, that in a negative trial of abatacept in SLE (Arthritis Rheum. 2010;62:3077-87), patients with polyarthritis were seen to benefit most, and though this did not reach statistical significance, it indicated that abatacept might be appropriate for off-label use in such patients. A post hoc analysis of one failed trial of abatacept in lupus nephritis argued that better-defined response criteria would have shown significant differences between the control and placebo groups (Arthritis Rheum. 2012;64:3660-5); company report PDF. "And there are several interesting trials going on with abatacept suggesting that it could work in combination with cyclophosphamide for lupus nephritis," Dr. van Vollenhoven said. "I don’t think the book is completely closed on this."

While belimumab has been the success story among biologics in SLE, as the first biologic developed and licensed to treat the disease, Dr. van Vollenhoven argued that even belimumab may be given short shrift. In the phase III trial of belimumab in SLE (n = 867), belimumab at 10 mg/kg was associated with significant improvement over placebo in standard lupus disease activity scores (Lancet 2011;377:721-31).

"But with just a 10% difference effect size between the two arms, people say this is a weak effect, making all patients a little better," Dr. van Vollenhoven said. "But there could be at least two other explanations. One is that this is a very good medication, but only for some patients. In practice we would have to figure out who these patients are and that they should be getting this treatment. Another is that in these huge trials there is a lot of static – if you’re measuring with an instrument that’s not very good, you won’t get a strong signal."

Dr. van Vollenhoven said that in his clinical practice, "we have found that the patient who has low complement and anti-DNA antibodies plus active disease and are on steroids have a pretty good likelihood of benefiting from belimumab, and that’s how we have been using it in our practice. And we are seeing good results."

Dr. van Vollenhoven has served as an adviser or consultant for Abbott, Bristol-Myers Squibb, GlaxoSmithKline, Merck Sharp & Dohme, Pfizer, Roche, and UCB Pharma. Dr. Lightstone has received support from Genentech, Roche, Biogen Idec, Aspreva, and GlaxoSmithKline.

BUENOS AIRES – Approved biologic therapies for systematic lupus erythematosus have so far been limited to belimumab, and there has been little compelling trial evidence to date for the effectiveness of abatacept or rituximab in either SLE or lupus nephritis.

Nonetheless, investigators presenting at an international congress on systemic lupus erythematosus gave clinicians reasons to be optimistic about these three biologics currently in clinical use, both on and off label.

Reinterpretation of randomized controlled trial data even from trials that did not meet their primary or secondary endpoints, new registry data, clinical observation, and ongoing trials with better-defined endpoints are producing insights into how and which SLE and lupus nephritis patients might benefit from rituximab, abatacept, or belimumab.

Dr. Ronald F. van Vollenhoven of the Karolinska Institute in Stockholm discussed findings from a yet-unpublished registry study of biologics in lupus, to be presented in June at the EULAR annual meeting in Madrid. Dr. van Vollenhoven and colleagues found that rituximab, which had not succeeded in the 2012 LUNAR trial in lupus nephritis patients (Arthritis Rheum. 2012;64:1215-26), was the most frequently used off-label biologic being used in lupus in European countries, with about 1% of lupus patients receiving it. "These are more severe disease patients with more damage who have failed other therapies – it seems to be an option of last resort," Dr. van Vollenhoven said.

Dr. Elizabeth Lightstone, a nephrologist at Imperial College London, argued for a role for rituximab beyond rescue therapy in lupus nephritis. "I think most of us think that rituximab does work," Dr. Lightstone told the conference, and described soon-to-be published results from an observational cohort study (n = 50) of new or relapsed lupus nephritis patients receiving rituximab as a first-line treatment protocol along with mycophenolate mofetil (MMF), with a median follow-up of 163 weeks.

By 12 weeks, 18% of patients saw a complete renal response, which increased to 32% at 26 weeks and 50% at 52 weeks, Dr. Lightstone said. Remarkably, 43 patients who started on this regimen have been managed successfully without oral steroids. Dr. Lightstone said that her U.K.-based nephrology group was about to begin recruiting for a randomized, controlled trial that would compare this rituximab-based regimen with MMF and steroids in 252 lupus nephritis patients.

Dr. Lightstone described the failed LUNAR study as having set the bar too high in its definition of complete renal remission, and having gone too short at only 1 year. "There were a lot of positives in that trial," she said. "The serology normalized significantly; in the exploratory endpoints there was at least a 50% reduction in proteinuria significant in the rituximab group at 78 weeks, so there was divergence beyond one year. The need for immunosuppression was significantly different in week 52 and week 78, and there was a reduction in steroids. And black patients responded better – the trial wasn’t powered to show that as significant, but it looks tantalizing."

She also pointed to a randomized, controlled trial of rituximab vs. standard of care, led by Dr. Frédéric Houssiau of the Université Catholique de Louvain in Brussels that may better define the role of rituximab in lupus nephritis. This trial, which aims to recruit 194 patients and is scheduled to end in 2016, is double the duration of the LUNAR trial, at 104 weeks, and defines complete response as a protein/creatinine ratio of 0.5 or less (compared with 0.2 or less in the LUNAR trial).

Dr. van Vollenhoven told the conference that abatacept was being used very rarely in clinical practice in Europe in either SLE or lupus nephritis. He noted, however, that in a negative trial of abatacept in SLE (Arthritis Rheum. 2010;62:3077-87), patients with polyarthritis were seen to benefit most, and though this did not reach statistical significance, it indicated that abatacept might be appropriate for off-label use in such patients. A post hoc analysis of one failed trial of abatacept in lupus nephritis argued that better-defined response criteria would have shown significant differences between the control and placebo groups (Arthritis Rheum. 2012;64:3660-5); company report PDF. "And there are several interesting trials going on with abatacept suggesting that it could work in combination with cyclophosphamide for lupus nephritis," Dr. van Vollenhoven said. "I don’t think the book is completely closed on this."

While belimumab has been the success story among biologics in SLE, as the first biologic developed and licensed to treat the disease, Dr. van Vollenhoven argued that even belimumab may be given short shrift. In the phase III trial of belimumab in SLE (n = 867), belimumab at 10 mg/kg was associated with significant improvement over placebo in standard lupus disease activity scores (Lancet 2011;377:721-31).

"But with just a 10% difference effect size between the two arms, people say this is a weak effect, making all patients a little better," Dr. van Vollenhoven said. "But there could be at least two other explanations. One is that this is a very good medication, but only for some patients. In practice we would have to figure out who these patients are and that they should be getting this treatment. Another is that in these huge trials there is a lot of static – if you’re measuring with an instrument that’s not very good, you won’t get a strong signal."

Dr. van Vollenhoven said that in his clinical practice, "we have found that the patient who has low complement and anti-DNA antibodies plus active disease and are on steroids have a pretty good likelihood of benefiting from belimumab, and that’s how we have been using it in our practice. And we are seeing good results."

Dr. van Vollenhoven has served as an adviser or consultant for Abbott, Bristol-Myers Squibb, GlaxoSmithKline, Merck Sharp & Dohme, Pfizer, Roche, and UCB Pharma. Dr. Lightstone has received support from Genentech, Roche, Biogen Idec, Aspreva, and GlaxoSmithKline.

BUENOS AIRES – Approved biologic therapies for systematic lupus erythematosus have so far been limited to belimumab, and there has been little compelling trial evidence to date for the effectiveness of abatacept or rituximab in either SLE or lupus nephritis.

Nonetheless, investigators presenting at an international congress on systemic lupus erythematosus gave clinicians reasons to be optimistic about these three biologics currently in clinical use, both on and off label.

Reinterpretation of randomized controlled trial data even from trials that did not meet their primary or secondary endpoints, new registry data, clinical observation, and ongoing trials with better-defined endpoints are producing insights into how and which SLE and lupus nephritis patients might benefit from rituximab, abatacept, or belimumab.

Dr. Ronald F. van Vollenhoven of the Karolinska Institute in Stockholm discussed findings from a yet-unpublished registry study of biologics in lupus, to be presented in June at the EULAR annual meeting in Madrid. Dr. van Vollenhoven and colleagues found that rituximab, which had not succeeded in the 2012 LUNAR trial in lupus nephritis patients (Arthritis Rheum. 2012;64:1215-26), was the most frequently used off-label biologic being used in lupus in European countries, with about 1% of lupus patients receiving it. "These are more severe disease patients with more damage who have failed other therapies – it seems to be an option of last resort," Dr. van Vollenhoven said.

Dr. Elizabeth Lightstone, a nephrologist at Imperial College London, argued for a role for rituximab beyond rescue therapy in lupus nephritis. "I think most of us think that rituximab does work," Dr. Lightstone told the conference, and described soon-to-be published results from an observational cohort study (n = 50) of new or relapsed lupus nephritis patients receiving rituximab as a first-line treatment protocol along with mycophenolate mofetil (MMF), with a median follow-up of 163 weeks.

By 12 weeks, 18% of patients saw a complete renal response, which increased to 32% at 26 weeks and 50% at 52 weeks, Dr. Lightstone said. Remarkably, 43 patients who started on this regimen have been managed successfully without oral steroids. Dr. Lightstone said that her U.K.-based nephrology group was about to begin recruiting for a randomized, controlled trial that would compare this rituximab-based regimen with MMF and steroids in 252 lupus nephritis patients.

Dr. Lightstone described the failed LUNAR study as having set the bar too high in its definition of complete renal remission, and having gone too short at only 1 year. "There were a lot of positives in that trial," she said. "The serology normalized significantly; in the exploratory endpoints there was at least a 50% reduction in proteinuria significant in the rituximab group at 78 weeks, so there was divergence beyond one year. The need for immunosuppression was significantly different in week 52 and week 78, and there was a reduction in steroids. And black patients responded better – the trial wasn’t powered to show that as significant, but it looks tantalizing."

She also pointed to a randomized, controlled trial of rituximab vs. standard of care, led by Dr. Frédéric Houssiau of the Université Catholique de Louvain in Brussels that may better define the role of rituximab in lupus nephritis. This trial, which aims to recruit 194 patients and is scheduled to end in 2016, is double the duration of the LUNAR trial, at 104 weeks, and defines complete response as a protein/creatinine ratio of 0.5 or less (compared with 0.2 or less in the LUNAR trial).

Dr. van Vollenhoven told the conference that abatacept was being used very rarely in clinical practice in Europe in either SLE or lupus nephritis. He noted, however, that in a negative trial of abatacept in SLE (Arthritis Rheum. 2010;62:3077-87), patients with polyarthritis were seen to benefit most, and though this did not reach statistical significance, it indicated that abatacept might be appropriate for off-label use in such patients. A post hoc analysis of one failed trial of abatacept in lupus nephritis argued that better-defined response criteria would have shown significant differences between the control and placebo groups (Arthritis Rheum. 2012;64:3660-5); company report PDF. "And there are several interesting trials going on with abatacept suggesting that it could work in combination with cyclophosphamide for lupus nephritis," Dr. van Vollenhoven said. "I don’t think the book is completely closed on this."

While belimumab has been the success story among biologics in SLE, as the first biologic developed and licensed to treat the disease, Dr. van Vollenhoven argued that even belimumab may be given short shrift. In the phase III trial of belimumab in SLE (n = 867), belimumab at 10 mg/kg was associated with significant improvement over placebo in standard lupus disease activity scores (Lancet 2011;377:721-31).

"But with just a 10% difference effect size between the two arms, people say this is a weak effect, making all patients a little better," Dr. van Vollenhoven said. "But there could be at least two other explanations. One is that this is a very good medication, but only for some patients. In practice we would have to figure out who these patients are and that they should be getting this treatment. Another is that in these huge trials there is a lot of static – if you’re measuring with an instrument that’s not very good, you won’t get a strong signal."

Dr. van Vollenhoven said that in his clinical practice, "we have found that the patient who has low complement and anti-DNA antibodies plus active disease and are on steroids have a pretty good likelihood of benefiting from belimumab, and that’s how we have been using it in our practice. And we are seeing good results."

Dr. van Vollenhoven has served as an adviser or consultant for Abbott, Bristol-Myers Squibb, GlaxoSmithKline, Merck Sharp & Dohme, Pfizer, Roche, and UCB Pharma. Dr. Lightstone has received support from Genentech, Roche, Biogen Idec, Aspreva, and GlaxoSmithKline.

Preterm infants with two types of dysbiosis, or an imbalance of gut microbiota, are more likely to develop necrotizing enterocolitis, and within distinct time frames, based on the results of a small prospective cohort study.

Necrotizing enterocolitis (NEC) is an intestinal disorder that affects 10% of infants born before the 29th week and is fatal in about 30% of those affected. It has long been thought to be related to intestinal colonization, as preterm infants are known to have fewer beneficial organisms, lower bacterial diversity, and more pathogens, than healthy term infants. However, a clear understanding of the pathogenesis of NEC and the timing of its onset has thus far eluded investigators.

For their research, epidemiologist Ardythe L. Morrow, Ph.D., of Cincinnati Children’s Hospital Medical Center, and colleagues, examined the early microbial community of 11 preterm infants who later developed NEC and that of 21 controls matched for gestational age, birth weight, and other factors who did not develop NEC. The researchers used gene sequencing of stool samples taken between 4 and 16 days after birth to identify microbial community signatures, and urine samples to identify bacteria-derived metabolites of NEC (Microbiome 2013 [doi:10.1186/2049-2618-1-13]).

Infants whose microbial communities were dominated by gram-positive Firmicutes (class Bacilli, with the dominant genera Staphylococcus and Enterococcus) between 4 and 9 days of life had a significantly higher risk of developing NEC by 21 days compared with matched controls, Dr. Morrow and colleagues found. Infants with evidence of gram-negative Proteobacteria (Enterobacteriaceae, with the dominant genera Enterobacter and Escherichia) at 10-16 days had an increased risk of developing NEC later – between 19 and 39 days of life – compared with controls.

The absence of Propionibacterium organisms in stool samples taken in the first week after birth was associated with a significantly higher risk of developing NEC, and this factor combined with evidence of dysbiosis in the first 2 weeks of life was highly predictive of NEC. A high urinary alanine to histidine ratio also was highly predictive of NEC (82% of infants with NEC vs. 25% of controls). Propionibacterium occurred in more than half of the healthy controls and none of the infants who went on to develop NEC.

Dr. Morrow and colleagues’ study is the first to identify the role and timing of early gram-positive and gram-negative forms of dysbiosis in the development of NEC. It also underscored the potential beneficial role of Propionibacterium in the intestinal health of preterm infants.

The study was funded by grants from the National Institutes of Health and the Department of Health and Human Services. None of the authors disclosed relevant financial conflicts.

Preterm infants with two types of dysbiosis, or an imbalance of gut microbiota, are more likely to develop necrotizing enterocolitis, and within distinct time frames, based on the results of a small prospective cohort study.

Necrotizing enterocolitis (NEC) is an intestinal disorder that affects 10% of infants born before the 29th week and is fatal in about 30% of those affected. It has long been thought to be related to intestinal colonization, as preterm infants are known to have fewer beneficial organisms, lower bacterial diversity, and more pathogens, than healthy term infants. However, a clear understanding of the pathogenesis of NEC and the timing of its onset has thus far eluded investigators.

For their research, epidemiologist Ardythe L. Morrow, Ph.D., of Cincinnati Children’s Hospital Medical Center, and colleagues, examined the early microbial community of 11 preterm infants who later developed NEC and that of 21 controls matched for gestational age, birth weight, and other factors who did not develop NEC. The researchers used gene sequencing of stool samples taken between 4 and 16 days after birth to identify microbial community signatures, and urine samples to identify bacteria-derived metabolites of NEC (Microbiome 2013 [doi:10.1186/2049-2618-1-13]).

Infants whose microbial communities were dominated by gram-positive Firmicutes (class Bacilli, with the dominant genera Staphylococcus and Enterococcus) between 4 and 9 days of life had a significantly higher risk of developing NEC by 21 days compared with matched controls, Dr. Morrow and colleagues found. Infants with evidence of gram-negative Proteobacteria (Enterobacteriaceae, with the dominant genera Enterobacter and Escherichia) at 10-16 days had an increased risk of developing NEC later – between 19 and 39 days of life – compared with controls.

The absence of Propionibacterium organisms in stool samples taken in the first week after birth was associated with a significantly higher risk of developing NEC, and this factor combined with evidence of dysbiosis in the first 2 weeks of life was highly predictive of NEC. A high urinary alanine to histidine ratio also was highly predictive of NEC (82% of infants with NEC vs. 25% of controls). Propionibacterium occurred in more than half of the healthy controls and none of the infants who went on to develop NEC.

Dr. Morrow and colleagues’ study is the first to identify the role and timing of early gram-positive and gram-negative forms of dysbiosis in the development of NEC. It also underscored the potential beneficial role of Propionibacterium in the intestinal health of preterm infants.

The study was funded by grants from the National Institutes of Health and the Department of Health and Human Services. None of the authors disclosed relevant financial conflicts.

Preterm infants with two types of dysbiosis, or an imbalance of gut microbiota, are more likely to develop necrotizing enterocolitis, and within distinct time frames, based on the results of a small prospective cohort study.

Necrotizing enterocolitis (NEC) is an intestinal disorder that affects 10% of infants born before the 29th week and is fatal in about 30% of those affected. It has long been thought to be related to intestinal colonization, as preterm infants are known to have fewer beneficial organisms, lower bacterial diversity, and more pathogens, than healthy term infants. However, a clear understanding of the pathogenesis of NEC and the timing of its onset has thus far eluded investigators.

For their research, epidemiologist Ardythe L. Morrow, Ph.D., of Cincinnati Children’s Hospital Medical Center, and colleagues, examined the early microbial community of 11 preterm infants who later developed NEC and that of 21 controls matched for gestational age, birth weight, and other factors who did not develop NEC. The researchers used gene sequencing of stool samples taken between 4 and 16 days after birth to identify microbial community signatures, and urine samples to identify bacteria-derived metabolites of NEC (Microbiome 2013 [doi:10.1186/2049-2618-1-13]).

Infants whose microbial communities were dominated by gram-positive Firmicutes (class Bacilli, with the dominant genera Staphylococcus and Enterococcus) between 4 and 9 days of life had a significantly higher risk of developing NEC by 21 days compared with matched controls, Dr. Morrow and colleagues found. Infants with evidence of gram-negative Proteobacteria (Enterobacteriaceae, with the dominant genera Enterobacter and Escherichia) at 10-16 days had an increased risk of developing NEC later – between 19 and 39 days of life – compared with controls.

The absence of Propionibacterium organisms in stool samples taken in the first week after birth was associated with a significantly higher risk of developing NEC, and this factor combined with evidence of dysbiosis in the first 2 weeks of life was highly predictive of NEC. A high urinary alanine to histidine ratio also was highly predictive of NEC (82% of infants with NEC vs. 25% of controls). Propionibacterium occurred in more than half of the healthy controls and none of the infants who went on to develop NEC.

Dr. Morrow and colleagues’ study is the first to identify the role and timing of early gram-positive and gram-negative forms of dysbiosis in the development of NEC. It also underscored the potential beneficial role of Propionibacterium in the intestinal health of preterm infants.

The study was funded by grants from the National Institutes of Health and the Department of Health and Human Services. None of the authors disclosed relevant financial conflicts.

Nearly 3 years after tasking themselves with overhauling the nation’s publicly funded cancer clinical trials system, which had been criticized as sluggish and unwieldy, researchers working for and with the National Cancer Institute are reporting a number of important successes.

The time between concept and activation of phase II trials sponsored by NCI has shrunk by more than a third, the researchers revealed at a 2-day workshop held this month in Washington. Time to activation for phase III trials has been halved since the overhaul process began.

Dr. James H. Doroshow of the NCI’s Division of Cancer Treatment and Diagnosis in Bethesda, Md., said that trial opening times would continue to shrink, with an ideal lag of between 6 and 7 months for early phase trials, compared to more than 2 years in the past.

But Dr. Doroshow and other presenters also acknowledged that the overhaul is a work in progress, with serious challenges remaining. Prominent among these, said workshop chair Monica Bertagnolli of the Dana-Farber Cancer Institute in Boston, is "maintaining the integration of the community centers into the research network" as NCI’s scientific emphasis shifts quickly from large phase III trials to smaller, biomarker-driven phase II trials. The trials cannot succeed without broad participation in cutting-edge trials at the community level.

The workshop was sponsored by the American Society for Clinical Oncology and presented by the Institute of Medicine, which had commissioned a 2010 report demanding critical changes to the NCI’s clinical trials cooperative group program. The report described the program as "approaching a state of crisis," and recommended that it streamline its bureaucracy, speed activation and improve completion rates of its trials, emphasize innovative biomarker-driven science, and increase reimbursement per patient for trial participation.

The program has since undergone a restructuring to reduce its 10 cooperative groups to 5, including 1 pediatric group. It has created common enrollment and data management systems to be used by all 3,100 affiliated community and research institutions. It standardized its agreements for industry collaborations, launched a review process for grading the quality of its trials, and is in the process of creating integrated biospecimen banks, among other accomplishments reported by NCI’s Dr. Doroshow.

The conviction that innovative, molecular phase II studies were the key to a more responsive and effective trials system was shared widely at the conference. "We need to rethink clinical trials, not just fund 7,000 patients in toothpaste A vs. toothpaste B," commented Dr. George Sledge of Stanford (Calif.) University. Presenters discussed a number of novel phase II trial designs, including "basket trials," or series of simultaneous single-arm trials matching biomarkers to target agents.

In a presentation on designing cutting-edge trials using genomic profiling for eligibility, Dr. Levi Garraway pointed to both the extraordinary possibilities and challenges of the new, nimble trial ideal.

"This is the first time that we can say for the major cancer signaling pathways, there are multiple drugs targeting multiple alterations in those pathways," said Dr. Garraway, a researcher at Dana Farber Cancer Institute in Boston, noting that in 40%-60% of tumors, there is a genetically-determined actionable target for which there is either an approved agent, an experimental agent, or an agent to avoid. Yet while genomics-driven "precision medicine," is exciting, it is"very hard, daunting even to the most advanced cancer centers," Dr. Garraway said.

Encouraging broad participation in these cutting-edge trials at the community level may prove a daunting task, however.

"The No. 1 job is to get these trials done and, without the community programs, they’re not going to get done fast enough," Dr. Steven Grubbs of Christiana Care Health System's Helen F. Graham Cancer Center in Newark, Del., told the conference. Nonacademic community oncology sites, both hospitals and private practices, are responsible for accruing between half and two-thirds of the patients currently taking part in the network’s trials, Dr. Grubbs pointed out, with most cancer patients receiving their first diagnosis outside a research center.

Dr. Robert Comis of Drexel University, Philadelphia, the cooperative groups’ chairman, commented that while the novel phase II trials "are essential to drive the process forward," many community sites hesitate to participate because these trials tend to be small, end quickly, and can be more complicated than are large phase IIIs.

As other participants noted throughout the conference, cancer trials increasingly require tissue submissions to enroll, a financial and logistical burden that falls on hospital pathology departments. Molecular research also means exponentially more data points and requires close collaboration with genetics labs – all at a time in which many of the NCI’s community-based research affiliates are plagued with tightening budgets and looming cuts.

Meanwhile, a broad new NCI initiative to consolidate the institute’s community research programs into one, whose agenda also includes parallel nonclinical research on cancer care delivery, had several of the workshop participants concerned about the potential for added financial and logistical strain on community affiliates.

"We don’t want to stress private practices," said Dr. Robin Zon of the Northern Indiana Cancer Research Consortium and Memorial Hospital in South Bend, Ind., of NCI’s added research focus on care delivery. "There has to be a streamlining, otherwise they will opt out."

Dr. Zon also cautioned that researchers on the community level face the "real issue of payers not covering clinical trial participation," at least until January 2014, when federal law will require that insurers not deny patients participation in clinical trials or limit coverage of routine patient costs stemming from a trial. "Let’s try to lobby to make sure that this becomes imperative," Dr. Zon said.

The trials network’s total funding for fiscal year 2014 was $152 million, Dr. Comis said, adding that he was hoping to increase that to $178 million. One of the stated goals of the overhaul was to increase reimbursement per patient enrolled from $2,000 to $6,000, but increases have not yet been universally adopted. The 2010 IOM report also recommended other incentives to increase accrual, such as reimbursing physicians for offering patients the option of enrolling in a trial, even if the patient ultimately chooses not to. This recommendation has not yet been adopted.

The United Kingdom’s experience overhauling its own trials network offered valuable perspective on what was happening in the United States, despite major structural differences between the countries’ health care systems. In 2001, the U.K.’s cancer trials network was reorganized out of a similar "sense of crisis and national purpose," said presenter Dr. Richard Kaplan of University College London Hospital and the U.K. National Cancer Research Network. Prior to 2001, Dr. Kaplan told the conference, research was not considered part of the National Health Service’s cancer care agenda. Now, it is understood that NHS exists partly to do clinical research, "a view that has become ever more firmly embedded in constitution of NHS."

Some of the key changes that allowed the NHS to manage clinical trials included the hiring of dedicated research staff, particularly research nurses, who cannot perform nonresearch-related duties within the hospitals. The NHS also covers costs for all patients enrolled in a trial. Currently, Dr. Kaplan said, 23% of cancer patients in the United Kingdom are enrolled in trials, and 7.5% in randomized trials. All in all 19,000 patients are currently taking part in trials, making the U.K. network comparable in size to the U.S. network, despite a vastly smaller national population. It is also comparable in terms of annual budget, Dr. Kaplan said, with the NCI trials network, with funding coming from government, charity, and industry sources.

One important difference between the United States and the United Kingdom is that novel agents are available only within license in the U.K., providing a powerful motive to both patients and providers to enroll. "The clinical oncology community within the NHS – there’s very little private oncology – were frustrated with the fact that they had limited ability to provide new agents or move forward and so, when it was given to them, they embraced it," Dr. Kaplan said.

Clinicians in the NHS system get an annual review, Dr. Kaplan said, "and nowadays they get asked how much they are participating in clinical trials. They lose face if they haven’t – people pay attention to the fact that if you’re an oncologist and don’t participate, it doesn’t look good."

Still, the U.K. trials system is not leading the way in phase II or biomarker-driven trials at the community level, Dr. Kaplan acknowledged. It has thus far emphasized phase III trials, though 4 years ago, it began to prioritize phase IIs, which have increased as a share of trials underway. Dr. Kaplan said many local NHS networks have tended to "avoid more complex studies, favoring easier studies."

Dr. Bertagnolli said in an interview following the conference that she was confident that cutting-edge science could be conducted well beyond the bounds of dedicated cancer centers in the United States.

"We need to make it possible for these types of studies to be done in our community oncology sites. I don’t think we can effectively accomplish even those goals in this era where we’re looking at smaller and smaller patient populations without engaging the community oncology sites."

Fortunately, Dr. Bertagnolli said, "we have a very experienced community oncology network in the United States, and I have no doubt whatsoever that they are capable, if properly resourced, of doing any of these studies."

[email protected]

Nearly 3 years after tasking themselves with overhauling the nation’s publicly funded cancer clinical trials system, which had been criticized as sluggish and unwieldy, researchers working for and with the National Cancer Institute are reporting a number of important successes.

The time between concept and activation of phase II trials sponsored by NCI has shrunk by more than a third, the researchers revealed at a 2-day workshop held this month in Washington. Time to activation for phase III trials has been halved since the overhaul process began.

Dr. James H. Doroshow of the NCI’s Division of Cancer Treatment and Diagnosis in Bethesda, Md., said that trial opening times would continue to shrink, with an ideal lag of between 6 and 7 months for early phase trials, compared to more than 2 years in the past.

But Dr. Doroshow and other presenters also acknowledged that the overhaul is a work in progress, with serious challenges remaining. Prominent among these, said workshop chair Monica Bertagnolli of the Dana-Farber Cancer Institute in Boston, is "maintaining the integration of the community centers into the research network" as NCI’s scientific emphasis shifts quickly from large phase III trials to smaller, biomarker-driven phase II trials. The trials cannot succeed without broad participation in cutting-edge trials at the community level.

The workshop was sponsored by the American Society for Clinical Oncology and presented by the Institute of Medicine, which had commissioned a 2010 report demanding critical changes to the NCI’s clinical trials cooperative group program. The report described the program as "approaching a state of crisis," and recommended that it streamline its bureaucracy, speed activation and improve completion rates of its trials, emphasize innovative biomarker-driven science, and increase reimbursement per patient for trial participation.

The program has since undergone a restructuring to reduce its 10 cooperative groups to 5, including 1 pediatric group. It has created common enrollment and data management systems to be used by all 3,100 affiliated community and research institutions. It standardized its agreements for industry collaborations, launched a review process for grading the quality of its trials, and is in the process of creating integrated biospecimen banks, among other accomplishments reported by NCI’s Dr. Doroshow.

The conviction that innovative, molecular phase II studies were the key to a more responsive and effective trials system was shared widely at the conference. "We need to rethink clinical trials, not just fund 7,000 patients in toothpaste A vs. toothpaste B," commented Dr. George Sledge of Stanford (Calif.) University. Presenters discussed a number of novel phase II trial designs, including "basket trials," or series of simultaneous single-arm trials matching biomarkers to target agents.

In a presentation on designing cutting-edge trials using genomic profiling for eligibility, Dr. Levi Garraway pointed to both the extraordinary possibilities and challenges of the new, nimble trial ideal.

"This is the first time that we can say for the major cancer signaling pathways, there are multiple drugs targeting multiple alterations in those pathways," said Dr. Garraway, a researcher at Dana Farber Cancer Institute in Boston, noting that in 40%-60% of tumors, there is a genetically-determined actionable target for which there is either an approved agent, an experimental agent, or an agent to avoid. Yet while genomics-driven "precision medicine," is exciting, it is"very hard, daunting even to the most advanced cancer centers," Dr. Garraway said.

Encouraging broad participation in these cutting-edge trials at the community level may prove a daunting task, however.

"The No. 1 job is to get these trials done and, without the community programs, they’re not going to get done fast enough," Dr. Steven Grubbs of Christiana Care Health System's Helen F. Graham Cancer Center in Newark, Del., told the conference. Nonacademic community oncology sites, both hospitals and private practices, are responsible for accruing between half and two-thirds of the patients currently taking part in the network’s trials, Dr. Grubbs pointed out, with most cancer patients receiving their first diagnosis outside a research center.

Dr. Robert Comis of Drexel University, Philadelphia, the cooperative groups’ chairman, commented that while the novel phase II trials "are essential to drive the process forward," many community sites hesitate to participate because these trials tend to be small, end quickly, and can be more complicated than are large phase IIIs.

As other participants noted throughout the conference, cancer trials increasingly require tissue submissions to enroll, a financial and logistical burden that falls on hospital pathology departments. Molecular research also means exponentially more data points and requires close collaboration with genetics labs – all at a time in which many of the NCI’s community-based research affiliates are plagued with tightening budgets and looming cuts.

Meanwhile, a broad new NCI initiative to consolidate the institute’s community research programs into one, whose agenda also includes parallel nonclinical research on cancer care delivery, had several of the workshop participants concerned about the potential for added financial and logistical strain on community affiliates.

"We don’t want to stress private practices," said Dr. Robin Zon of the Northern Indiana Cancer Research Consortium and Memorial Hospital in South Bend, Ind., of NCI’s added research focus on care delivery. "There has to be a streamlining, otherwise they will opt out."

Dr. Zon also cautioned that researchers on the community level face the "real issue of payers not covering clinical trial participation," at least until January 2014, when federal law will require that insurers not deny patients participation in clinical trials or limit coverage of routine patient costs stemming from a trial. "Let’s try to lobby to make sure that this becomes imperative," Dr. Zon said.

The trials network’s total funding for fiscal year 2014 was $152 million, Dr. Comis said, adding that he was hoping to increase that to $178 million. One of the stated goals of the overhaul was to increase reimbursement per patient enrolled from $2,000 to $6,000, but increases have not yet been universally adopted. The 2010 IOM report also recommended other incentives to increase accrual, such as reimbursing physicians for offering patients the option of enrolling in a trial, even if the patient ultimately chooses not to. This recommendation has not yet been adopted.

The United Kingdom’s experience overhauling its own trials network offered valuable perspective on what was happening in the United States, despite major structural differences between the countries’ health care systems. In 2001, the U.K.’s cancer trials network was reorganized out of a similar "sense of crisis and national purpose," said presenter Dr. Richard Kaplan of University College London Hospital and the U.K. National Cancer Research Network. Prior to 2001, Dr. Kaplan told the conference, research was not considered part of the National Health Service’s cancer care agenda. Now, it is understood that NHS exists partly to do clinical research, "a view that has become ever more firmly embedded in constitution of NHS."

Some of the key changes that allowed the NHS to manage clinical trials included the hiring of dedicated research staff, particularly research nurses, who cannot perform nonresearch-related duties within the hospitals. The NHS also covers costs for all patients enrolled in a trial. Currently, Dr. Kaplan said, 23% of cancer patients in the United Kingdom are enrolled in trials, and 7.5% in randomized trials. All in all 19,000 patients are currently taking part in trials, making the U.K. network comparable in size to the U.S. network, despite a vastly smaller national population. It is also comparable in terms of annual budget, Dr. Kaplan said, with the NCI trials network, with funding coming from government, charity, and industry sources.

One important difference between the United States and the United Kingdom is that novel agents are available only within license in the U.K., providing a powerful motive to both patients and providers to enroll. "The clinical oncology community within the NHS – there’s very little private oncology – were frustrated with the fact that they had limited ability to provide new agents or move forward and so, when it was given to them, they embraced it," Dr. Kaplan said.

Clinicians in the NHS system get an annual review, Dr. Kaplan said, "and nowadays they get asked how much they are participating in clinical trials. They lose face if they haven’t – people pay attention to the fact that if you’re an oncologist and don’t participate, it doesn’t look good."

Still, the U.K. trials system is not leading the way in phase II or biomarker-driven trials at the community level, Dr. Kaplan acknowledged. It has thus far emphasized phase III trials, though 4 years ago, it began to prioritize phase IIs, which have increased as a share of trials underway. Dr. Kaplan said many local NHS networks have tended to "avoid more complex studies, favoring easier studies."

Dr. Bertagnolli said in an interview following the conference that she was confident that cutting-edge science could be conducted well beyond the bounds of dedicated cancer centers in the United States.

"We need to make it possible for these types of studies to be done in our community oncology sites. I don’t think we can effectively accomplish even those goals in this era where we’re looking at smaller and smaller patient populations without engaging the community oncology sites."

Fortunately, Dr. Bertagnolli said, "we have a very experienced community oncology network in the United States, and I have no doubt whatsoever that they are capable, if properly resourced, of doing any of these studies."

[email protected]

Nearly 3 years after tasking themselves with overhauling the nation’s publicly funded cancer clinical trials system, which had been criticized as sluggish and unwieldy, researchers working for and with the National Cancer Institute are reporting a number of important successes.

The time between concept and activation of phase II trials sponsored by NCI has shrunk by more than a third, the researchers revealed at a 2-day workshop held this month in Washington. Time to activation for phase III trials has been halved since the overhaul process began.

Dr. James H. Doroshow of the NCI’s Division of Cancer Treatment and Diagnosis in Bethesda, Md., said that trial opening times would continue to shrink, with an ideal lag of between 6 and 7 months for early phase trials, compared to more than 2 years in the past.

But Dr. Doroshow and other presenters also acknowledged that the overhaul is a work in progress, with serious challenges remaining. Prominent among these, said workshop chair Monica Bertagnolli of the Dana-Farber Cancer Institute in Boston, is "maintaining the integration of the community centers into the research network" as NCI’s scientific emphasis shifts quickly from large phase III trials to smaller, biomarker-driven phase II trials. The trials cannot succeed without broad participation in cutting-edge trials at the community level.

The workshop was sponsored by the American Society for Clinical Oncology and presented by the Institute of Medicine, which had commissioned a 2010 report demanding critical changes to the NCI’s clinical trials cooperative group program. The report described the program as "approaching a state of crisis," and recommended that it streamline its bureaucracy, speed activation and improve completion rates of its trials, emphasize innovative biomarker-driven science, and increase reimbursement per patient for trial participation.

The program has since undergone a restructuring to reduce its 10 cooperative groups to 5, including 1 pediatric group. It has created common enrollment and data management systems to be used by all 3,100 affiliated community and research institutions. It standardized its agreements for industry collaborations, launched a review process for grading the quality of its trials, and is in the process of creating integrated biospecimen banks, among other accomplishments reported by NCI’s Dr. Doroshow.

The conviction that innovative, molecular phase II studies were the key to a more responsive and effective trials system was shared widely at the conference. "We need to rethink clinical trials, not just fund 7,000 patients in toothpaste A vs. toothpaste B," commented Dr. George Sledge of Stanford (Calif.) University. Presenters discussed a number of novel phase II trial designs, including "basket trials," or series of simultaneous single-arm trials matching biomarkers to target agents.

In a presentation on designing cutting-edge trials using genomic profiling for eligibility, Dr. Levi Garraway pointed to both the extraordinary possibilities and challenges of the new, nimble trial ideal.

"This is the first time that we can say for the major cancer signaling pathways, there are multiple drugs targeting multiple alterations in those pathways," said Dr. Garraway, a researcher at Dana Farber Cancer Institute in Boston, noting that in 40%-60% of tumors, there is a genetically-determined actionable target for which there is either an approved agent, an experimental agent, or an agent to avoid. Yet while genomics-driven "precision medicine," is exciting, it is"very hard, daunting even to the most advanced cancer centers," Dr. Garraway said.

Encouraging broad participation in these cutting-edge trials at the community level may prove a daunting task, however.

"The No. 1 job is to get these trials done and, without the community programs, they’re not going to get done fast enough," Dr. Steven Grubbs of Christiana Care Health System's Helen F. Graham Cancer Center in Newark, Del., told the conference. Nonacademic community oncology sites, both hospitals and private practices, are responsible for accruing between half and two-thirds of the patients currently taking part in the network’s trials, Dr. Grubbs pointed out, with most cancer patients receiving their first diagnosis outside a research center.

Dr. Robert Comis of Drexel University, Philadelphia, the cooperative groups’ chairman, commented that while the novel phase II trials "are essential to drive the process forward," many community sites hesitate to participate because these trials tend to be small, end quickly, and can be more complicated than are large phase IIIs.

As other participants noted throughout the conference, cancer trials increasingly require tissue submissions to enroll, a financial and logistical burden that falls on hospital pathology departments. Molecular research also means exponentially more data points and requires close collaboration with genetics labs – all at a time in which many of the NCI’s community-based research affiliates are plagued with tightening budgets and looming cuts.

Meanwhile, a broad new NCI initiative to consolidate the institute’s community research programs into one, whose agenda also includes parallel nonclinical research on cancer care delivery, had several of the workshop participants concerned about the potential for added financial and logistical strain on community affiliates.

"We don’t want to stress private practices," said Dr. Robin Zon of the Northern Indiana Cancer Research Consortium and Memorial Hospital in South Bend, Ind., of NCI’s added research focus on care delivery. "There has to be a streamlining, otherwise they will opt out."

Dr. Zon also cautioned that researchers on the community level face the "real issue of payers not covering clinical trial participation," at least until January 2014, when federal law will require that insurers not deny patients participation in clinical trials or limit coverage of routine patient costs stemming from a trial. "Let’s try to lobby to make sure that this becomes imperative," Dr. Zon said.

The trials network’s total funding for fiscal year 2014 was $152 million, Dr. Comis said, adding that he was hoping to increase that to $178 million. One of the stated goals of the overhaul was to increase reimbursement per patient enrolled from $2,000 to $6,000, but increases have not yet been universally adopted. The 2010 IOM report also recommended other incentives to increase accrual, such as reimbursing physicians for offering patients the option of enrolling in a trial, even if the patient ultimately chooses not to. This recommendation has not yet been adopted.

The United Kingdom’s experience overhauling its own trials network offered valuable perspective on what was happening in the United States, despite major structural differences between the countries’ health care systems. In 2001, the U.K.’s cancer trials network was reorganized out of a similar "sense of crisis and national purpose," said presenter Dr. Richard Kaplan of University College London Hospital and the U.K. National Cancer Research Network. Prior to 2001, Dr. Kaplan told the conference, research was not considered part of the National Health Service’s cancer care agenda. Now, it is understood that NHS exists partly to do clinical research, "a view that has become ever more firmly embedded in constitution of NHS."

Some of the key changes that allowed the NHS to manage clinical trials included the hiring of dedicated research staff, particularly research nurses, who cannot perform nonresearch-related duties within the hospitals. The NHS also covers costs for all patients enrolled in a trial. Currently, Dr. Kaplan said, 23% of cancer patients in the United Kingdom are enrolled in trials, and 7.5% in randomized trials. All in all 19,000 patients are currently taking part in trials, making the U.K. network comparable in size to the U.S. network, despite a vastly smaller national population. It is also comparable in terms of annual budget, Dr. Kaplan said, with the NCI trials network, with funding coming from government, charity, and industry sources.

One important difference between the United States and the United Kingdom is that novel agents are available only within license in the U.K., providing a powerful motive to both patients and providers to enroll. "The clinical oncology community within the NHS – there’s very little private oncology – were frustrated with the fact that they had limited ability to provide new agents or move forward and so, when it was given to them, they embraced it," Dr. Kaplan said.

Clinicians in the NHS system get an annual review, Dr. Kaplan said, "and nowadays they get asked how much they are participating in clinical trials. They lose face if they haven’t – people pay attention to the fact that if you’re an oncologist and don’t participate, it doesn’t look good."

Still, the U.K. trials system is not leading the way in phase II or biomarker-driven trials at the community level, Dr. Kaplan acknowledged. It has thus far emphasized phase III trials, though 4 years ago, it began to prioritize phase IIs, which have increased as a share of trials underway. Dr. Kaplan said many local NHS networks have tended to "avoid more complex studies, favoring easier studies."

Dr. Bertagnolli said in an interview following the conference that she was confident that cutting-edge science could be conducted well beyond the bounds of dedicated cancer centers in the United States.

"We need to make it possible for these types of studies to be done in our community oncology sites. I don’t think we can effectively accomplish even those goals in this era where we’re looking at smaller and smaller patient populations without engaging the community oncology sites."

Fortunately, Dr. Bertagnolli said, "we have a very experienced community oncology network in the United States, and I have no doubt whatsoever that they are capable, if properly resourced, of doing any of these studies."

[email protected]

New clinical guidelines on type 2 diabetes mellitus in children and adolescents from the American Academy of Pediatrics advise physicians to start metformin in newly diagnosed patients with moderate hyperglycemia, while also promoting diet and exercise changes.

The guidelines are addressed to the primary care physician, as children and adolescents with diabetes are most likely to be treated in primary care and not by an endocrinologist, according to the authors of the guidelines, led by pediatric endocrinologist Dr. Kenneth C. Copeland, of the University of Oklahoma (Pediatrics 2013;131:364-82,e648-e664).

The guidelines note that the sharp rise in incidence of type 2 diabetes among children and adolescents in recent decades has occurred alongside a severe shortage of pediatric endocrinologists in the United States. The scarcity of specialists, added to the fact that children with type 2 diabetes are disproportionately ethnic minorities living in poverty, means that access to pediatric endocrinologists will be "difficult or, in some cases, impossible." The guidelines, then, are intended to help primary care physicians who find themselves "unequipped to treat adult diseases encountered in children," according to the authors of the technical report that accompanies the guidelines, led by epidemiologist and neonatologist Dr. Shelley C. Springer of Big Lake, Minn. (Pediatrics 2013 Jan. 28 [doi: 10.1542/peds.2012-3496]).

An earlier guideline on type 2 diabetes in children and adolescents, issued by the International Society for Pediatric and Adolescent Diabetes (Pediatr. Diabetes 2009;10:17-32), had recommended initiation of metformin for youth with moderate hyperglycemia only after diet and exercise had failed.

The new American Academy of Pediatrics (AAP) guidelines recommend starting metformin as first-line therapy for children and adolescents aged 10-18 years with HbA_1c of 6.5% or higher, citing observational and randomized controlled trial evidence that metformin is more effective than lifestyle interventions alone. Metformin should be started at 500 mg daily and increased by 500 mg every 1-2 weeks, up to 2,000 mg daily.

The guidelines note that while metformin is the only antidiabetic agent besides insulin that is currently approved for children, it may be of more limited benefit than previously believed. "Since the completion of these guidelines, results of the TODAY trial (N. Engl. J. Med. 2012;366:2247-56) have become available and reveal that metformin alone is inadequate in effecting sustained glycemic control in the majority of youth with diabetes," the authors wrote, noting that other agents are likely to become "reasonable options for initial pharmacologic management" of children and adolescents with type 2 diabetes in the near future.

"The writing group for these guidelines continues to recommend metformin as first-line therapy in this age group but with close monitoring for glycemic deterioration and the early addition of insulin or another pharmacologic agent if needed," Dr. Copeland and his associates wrote.

The guidelines recommend that clinicians incorporate the Academy of Nutrition and Dietetics’ pediatric weight management guidelines in nutrition counseling at diagnosis and during ongoing management. Clinicians also should prescribe 1 hour a day of moderate to vigorous exercise, and the limiting of nonacademic "screen time," or time before computers, televisions, gaming devices, and the like, to less than 2 hours daily.

HbA_1c concentrations should be measured every 3 months, and treatment intensified if targets are not being met.

Physicians should initiate treatment with insulin for children and adolescents who are ketotic or present with diabetic ketoacidosis; children in whom the distinction between type 1 diabetes and type 2 diabetes is unclear; and those whose HbA_1c is greater than 9% or plasma glucose concentration is 250 mg/dL or higher.

Up to a quarter of adolescents with type 2 diabetes will present with ketoacidosis, the guidelines’ authors noted, and these patients should immediately be referred to an inpatient setting for treatment with insulin and fluid replacement under the care of a physician experienced in treating this complication.

Finger-stick monitoring should be used to measure blood glucose concentrations in patients who are taking insulin or other medications and have a risk of hypoglycemia; who are initiating or changing their diabetes treatment regimens; who have not met treatment goals; or who have intercurrent illnesses, according to the guidelines.

The AAP guidelines were produced by systematic literature review, with 58 studies included, and with the support of the American Diabetes Association, the Pediatric Endocrine Society, the American Academy of Family Physicians, and the Academy of Nutrition and Dietetics.

The guidelines’ lead author, Dr. Copeland, disclosed financial relationships with Novo Nordisk, Genentech, and Endo. Coauthor Dr. Janet Silverstein disclosed support from Pfizer, Novo Nordisk, Lilly, and other companies, and coauthor Dr. Kelly Roberta Moore disclosed a relationship with the Merck Company Foundation.

New clinical guidelines on type 2 diabetes mellitus in children and adolescents from the American Academy of Pediatrics advise physicians to start metformin in newly diagnosed patients with moderate hyperglycemia, while also promoting diet and exercise changes.

The guidelines are addressed to the primary care physician, as children and adolescents with diabetes are most likely to be treated in primary care and not by an endocrinologist, according to the authors of the guidelines, led by pediatric endocrinologist Dr. Kenneth C. Copeland, of the University of Oklahoma (Pediatrics 2013;131:364-82,e648-e664).

The guidelines note that the sharp rise in incidence of type 2 diabetes among children and adolescents in recent decades has occurred alongside a severe shortage of pediatric endocrinologists in the United States. The scarcity of specialists, added to the fact that children with type 2 diabetes are disproportionately ethnic minorities living in poverty, means that access to pediatric endocrinologists will be "difficult or, in some cases, impossible." The guidelines, then, are intended to help primary care physicians who find themselves "unequipped to treat adult diseases encountered in children," according to the authors of the technical report that accompanies the guidelines, led by epidemiologist and neonatologist Dr. Shelley C. Springer of Big Lake, Minn. (Pediatrics 2013 Jan. 28 [doi: 10.1542/peds.2012-3496]).

An earlier guideline on type 2 diabetes in children and adolescents, issued by the International Society for Pediatric and Adolescent Diabetes (Pediatr. Diabetes 2009;10:17-32), had recommended initiation of metformin for youth with moderate hyperglycemia only after diet and exercise had failed.

The new American Academy of Pediatrics (AAP) guidelines recommend starting metformin as first-line therapy for children and adolescents aged 10-18 years with HbA_1c of 6.5% or higher, citing observational and randomized controlled trial evidence that metformin is more effective than lifestyle interventions alone. Metformin should be started at 500 mg daily and increased by 500 mg every 1-2 weeks, up to 2,000 mg daily.

The guidelines note that while metformin is the only antidiabetic agent besides insulin that is currently approved for children, it may be of more limited benefit than previously believed. "Since the completion of these guidelines, results of the TODAY trial (N. Engl. J. Med. 2012;366:2247-56) have become available and reveal that metformin alone is inadequate in effecting sustained glycemic control in the majority of youth with diabetes," the authors wrote, noting that other agents are likely to become "reasonable options for initial pharmacologic management" of children and adolescents with type 2 diabetes in the near future.

"The writing group for these guidelines continues to recommend metformin as first-line therapy in this age group but with close monitoring for glycemic deterioration and the early addition of insulin or another pharmacologic agent if needed," Dr. Copeland and his associates wrote.

The guidelines recommend that clinicians incorporate the Academy of Nutrition and Dietetics’ pediatric weight management guidelines in nutrition counseling at diagnosis and during ongoing management. Clinicians also should prescribe 1 hour a day of moderate to vigorous exercise, and the limiting of nonacademic "screen time," or time before computers, televisions, gaming devices, and the like, to less than 2 hours daily.

HbA_1c concentrations should be measured every 3 months, and treatment intensified if targets are not being met.

Physicians should initiate treatment with insulin for children and adolescents who are ketotic or present with diabetic ketoacidosis; children in whom the distinction between type 1 diabetes and type 2 diabetes is unclear; and those whose HbA_1c is greater than 9% or plasma glucose concentration is 250 mg/dL or higher.

Up to a quarter of adolescents with type 2 diabetes will present with ketoacidosis, the guidelines’ authors noted, and these patients should immediately be referred to an inpatient setting for treatment with insulin and fluid replacement under the care of a physician experienced in treating this complication.

Finger-stick monitoring should be used to measure blood glucose concentrations in patients who are taking insulin or other medications and have a risk of hypoglycemia; who are initiating or changing their diabetes treatment regimens; who have not met treatment goals; or who have intercurrent illnesses, according to the guidelines.

The AAP guidelines were produced by systematic literature review, with 58 studies included, and with the support of the American Diabetes Association, the Pediatric Endocrine Society, the American Academy of Family Physicians, and the Academy of Nutrition and Dietetics.

The guidelines’ lead author, Dr. Copeland, disclosed financial relationships with Novo Nordisk, Genentech, and Endo. Coauthor Dr. Janet Silverstein disclosed support from Pfizer, Novo Nordisk, Lilly, and other companies, and coauthor Dr. Kelly Roberta Moore disclosed a relationship with the Merck Company Foundation.

New clinical guidelines on type 2 diabetes mellitus in children and adolescents from the American Academy of Pediatrics advise physicians to start metformin in newly diagnosed patients with moderate hyperglycemia, while also promoting diet and exercise changes.

The guidelines are addressed to the primary care physician, as children and adolescents with diabetes are most likely to be treated in primary care and not by an endocrinologist, according to the authors of the guidelines, led by pediatric endocrinologist Dr. Kenneth C. Copeland, of the University of Oklahoma (Pediatrics 2013;131:364-82,e648-e664).

The guidelines note that the sharp rise in incidence of type 2 diabetes among children and adolescents in recent decades has occurred alongside a severe shortage of pediatric endocrinologists in the United States. The scarcity of specialists, added to the fact that children with type 2 diabetes are disproportionately ethnic minorities living in poverty, means that access to pediatric endocrinologists will be "difficult or, in some cases, impossible." The guidelines, then, are intended to help primary care physicians who find themselves "unequipped to treat adult diseases encountered in children," according to the authors of the technical report that accompanies the guidelines, led by epidemiologist and neonatologist Dr. Shelley C. Springer of Big Lake, Minn. (Pediatrics 2013 Jan. 28 [doi: 10.1542/peds.2012-3496]).

An earlier guideline on type 2 diabetes in children and adolescents, issued by the International Society for Pediatric and Adolescent Diabetes (Pediatr. Diabetes 2009;10:17-32), had recommended initiation of metformin for youth with moderate hyperglycemia only after diet and exercise had failed.

The new American Academy of Pediatrics (AAP) guidelines recommend starting metformin as first-line therapy for children and adolescents aged 10-18 years with HbA_1c of 6.5% or higher, citing observational and randomized controlled trial evidence that metformin is more effective than lifestyle interventions alone. Metformin should be started at 500 mg daily and increased by 500 mg every 1-2 weeks, up to 2,000 mg daily.

The guidelines note that while metformin is the only antidiabetic agent besides insulin that is currently approved for children, it may be of more limited benefit than previously believed. "Since the completion of these guidelines, results of the TODAY trial (N. Engl. J. Med. 2012;366:2247-56) have become available and reveal that metformin alone is inadequate in effecting sustained glycemic control in the majority of youth with diabetes," the authors wrote, noting that other agents are likely to become "reasonable options for initial pharmacologic management" of children and adolescents with type 2 diabetes in the near future.

"The writing group for these guidelines continues to recommend metformin as first-line therapy in this age group but with close monitoring for glycemic deterioration and the early addition of insulin or another pharmacologic agent if needed," Dr. Copeland and his associates wrote.

The guidelines recommend that clinicians incorporate the Academy of Nutrition and Dietetics’ pediatric weight management guidelines in nutrition counseling at diagnosis and during ongoing management. Clinicians also should prescribe 1 hour a day of moderate to vigorous exercise, and the limiting of nonacademic "screen time," or time before computers, televisions, gaming devices, and the like, to less than 2 hours daily.

HbA_1c concentrations should be measured every 3 months, and treatment intensified if targets are not being met.

Physicians should initiate treatment with insulin for children and adolescents who are ketotic or present with diabetic ketoacidosis; children in whom the distinction between type 1 diabetes and type 2 diabetes is unclear; and those whose HbA_1c is greater than 9% or plasma glucose concentration is 250 mg/dL or higher.

Up to a quarter of adolescents with type 2 diabetes will present with ketoacidosis, the guidelines’ authors noted, and these patients should immediately be referred to an inpatient setting for treatment with insulin and fluid replacement under the care of a physician experienced in treating this complication.

Finger-stick monitoring should be used to measure blood glucose concentrations in patients who are taking insulin or other medications and have a risk of hypoglycemia; who are initiating or changing their diabetes treatment regimens; who have not met treatment goals; or who have intercurrent illnesses, according to the guidelines.

The AAP guidelines were produced by systematic literature review, with 58 studies included, and with the support of the American Diabetes Association, the Pediatric Endocrine Society, the American Academy of Family Physicians, and the Academy of Nutrition and Dietetics.

The guidelines’ lead author, Dr. Copeland, disclosed financial relationships with Novo Nordisk, Genentech, and Endo. Coauthor Dr. Janet Silverstein disclosed support from Pfizer, Novo Nordisk, Lilly, and other companies, and coauthor Dr. Kelly Roberta Moore disclosed a relationship with the Merck Company Foundation.

Lymph node counts of 12 or higher, widely considered a key marker of surgical quality in colon cancer resection, had no significant effect on 5-year survival rates in settings where surgeons are audited and credentialed and where surgical techniques are standardized.

Lymph node (LN) count is one of several measures used to determine the extent of surgical resection and an indicator of clear surgical margins, which have been assumed to result in better survival outcomes for colon cancer patients. A new data analysis, however, of the COST (Clinical Outcomes of Surgical Therapy) trial suggests reevaluating the use of surgical surrogates such as 12 LNs and margins.

The COST trial, a large, multicenter randomized trial of colon cancer procedures, compared outcomes for laparoscopic and open techniques in treating colon adenocarcinoma. The trial collected data on a number of surgical variables, including tumor location and LN count. A total of 787 patients were included: 267 with stage I disease, 284 with stage II, and 236 with stage III. Their median age was 70 years, and 50% were male.

In the current study, Dr. Kellie L. Mathis of the Mayo Clinic in Rochester, Minn., and her colleagues found that 5-year overall and disease-free survival were not influenced by LN count of above or below 12 (Ann. Surg. 2012;257:102-7 [doi:10.1097/SLA.0b013e318260a8e6]). When they adjusted for age and cancer stage, LN count was seen as not predictive of overall or disease-free survival (P = .60).

Other surgical surrogates, including total bowel length, margins, or mesenteric length, likewise did not have a significant effect on survival (P greater than .05 for all), nor did tumor location (right, left, or sigmoid), surgical technique (laparoscopic or open), and sex. Only patient age and cancer stage were found to be predictive of survival.

"On the basis of abundant literature and the acceptance of the 12 LN count as a surgical quality surrogate by National Quality Forum, most would expect the 12 LN count or other surgical variables to be predictive of survival," Dr. Mathis and her associates wrote. However, they hypothesized that procedural standardization, monitoring, and credentialing may provide a better strategy for quality control.

Overall 5-year survival results from the COST trial, they noted, were 77.2% – better than national rates for comparable patient groups in the same time period. All enrolling surgeons underwent pretrial credentialing and had performed a minimum of 20 laparoscopic colon resections, for which they had submitted operative and pathology reports. All laparoscopic resections were video recorded, and videos were randomly audited by an external review committee.

If the observations in the current study can be validated by others, Dr. Mathis and her colleagues said, "we submit that now is the time to invest in the development of technical quality control programs that directly measure and monitor surgical procedures."

Dr. Mathis and her colleagues stated that they had no conflicts of interest related to their findings.

Lymph node counts of 12 or higher, widely considered a key marker of surgical quality in colon cancer resection, had no significant effect on 5-year survival rates in settings where surgeons are audited and credentialed and where surgical techniques are standardized.

Lymph node (LN) count is one of several measures used to determine the extent of surgical resection and an indicator of clear surgical margins, which have been assumed to result in better survival outcomes for colon cancer patients. A new data analysis, however, of the COST (Clinical Outcomes of Surgical Therapy) trial suggests reevaluating the use of surgical surrogates such as 12 LNs and margins.

The COST trial, a large, multicenter randomized trial of colon cancer procedures, compared outcomes for laparoscopic and open techniques in treating colon adenocarcinoma. The trial collected data on a number of surgical variables, including tumor location and LN count. A total of 787 patients were included: 267 with stage I disease, 284 with stage II, and 236 with stage III. Their median age was 70 years, and 50% were male.

In the current study, Dr. Kellie L. Mathis of the Mayo Clinic in Rochester, Minn., and her colleagues found that 5-year overall and disease-free survival were not influenced by LN count of above or below 12 (Ann. Surg. 2012;257:102-7 [doi:10.1097/SLA.0b013e318260a8e6]). When they adjusted for age and cancer stage, LN count was seen as not predictive of overall or disease-free survival (P = .60).

Other surgical surrogates, including total bowel length, margins, or mesenteric length, likewise did not have a significant effect on survival (P greater than .05 for all), nor did tumor location (right, left, or sigmoid), surgical technique (laparoscopic or open), and sex. Only patient age and cancer stage were found to be predictive of survival.

"On the basis of abundant literature and the acceptance of the 12 LN count as a surgical quality surrogate by National Quality Forum, most would expect the 12 LN count or other surgical variables to be predictive of survival," Dr. Mathis and her associates wrote. However, they hypothesized that procedural standardization, monitoring, and credentialing may provide a better strategy for quality control.

Overall 5-year survival results from the COST trial, they noted, were 77.2% – better than national rates for comparable patient groups in the same time period. All enrolling surgeons underwent pretrial credentialing and had performed a minimum of 20 laparoscopic colon resections, for which they had submitted operative and pathology reports. All laparoscopic resections were video recorded, and videos were randomly audited by an external review committee.

If the observations in the current study can be validated by others, Dr. Mathis and her colleagues said, "we submit that now is the time to invest in the development of technical quality control programs that directly measure and monitor surgical procedures."

Dr. Mathis and her colleagues stated that they had no conflicts of interest related to their findings.

Lymph node counts of 12 or higher, widely considered a key marker of surgical quality in colon cancer resection, had no significant effect on 5-year survival rates in settings where surgeons are audited and credentialed and where surgical techniques are standardized.

Lymph node (LN) count is one of several measures used to determine the extent of surgical resection and an indicator of clear surgical margins, which have been assumed to result in better survival outcomes for colon cancer patients. A new data analysis, however, of the COST (Clinical Outcomes of Surgical Therapy) trial suggests reevaluating the use of surgical surrogates such as 12 LNs and margins.

The COST trial, a large, multicenter randomized trial of colon cancer procedures, compared outcomes for laparoscopic and open techniques in treating colon adenocarcinoma. The trial collected data on a number of surgical variables, including tumor location and LN count. A total of 787 patients were included: 267 with stage I disease, 284 with stage II, and 236 with stage III. Their median age was 70 years, and 50% were male.

In the current study, Dr. Kellie L. Mathis of the Mayo Clinic in Rochester, Minn., and her colleagues found that 5-year overall and disease-free survival were not influenced by LN count of above or below 12 (Ann. Surg. 2012;257:102-7 [doi:10.1097/SLA.0b013e318260a8e6]). When they adjusted for age and cancer stage, LN count was seen as not predictive of overall or disease-free survival (P = .60).

Other surgical surrogates, including total bowel length, margins, or mesenteric length, likewise did not have a significant effect on survival (P greater than .05 for all), nor did tumor location (right, left, or sigmoid), surgical technique (laparoscopic or open), and sex. Only patient age and cancer stage were found to be predictive of survival.

"On the basis of abundant literature and the acceptance of the 12 LN count as a surgical quality surrogate by National Quality Forum, most would expect the 12 LN count or other surgical variables to be predictive of survival," Dr. Mathis and her associates wrote. However, they hypothesized that procedural standardization, monitoring, and credentialing may provide a better strategy for quality control.

Overall 5-year survival results from the COST trial, they noted, were 77.2% – better than national rates for comparable patient groups in the same time period. All enrolling surgeons underwent pretrial credentialing and had performed a minimum of 20 laparoscopic colon resections, for which they had submitted operative and pathology reports. All laparoscopic resections were video recorded, and videos were randomly audited by an external review committee.

If the observations in the current study can be validated by others, Dr. Mathis and her colleagues said, "we submit that now is the time to invest in the development of technical quality control programs that directly measure and monitor surgical procedures."

Dr. Mathis and her colleagues stated that they had no conflicts of interest related to their findings.