Jennie Smith

The U.S. Food and Drug administration has approved a new indication for fixed-dose exenatide injections.

The medication’s manufacturers, Amylin and Eli Lilly, announced Oct. 19 that the exenatide injections, marketed as Byetta, had been approved as an add-on therapy to insulin glargine, with or without metformin and/or a thiazolidinedione, for adults with type 2 diabetes who are not achieving adequate glycemic control on long-acting insulin alone.

Exenatide was initially approved by the FDA in 2005 for use in combination with metformin with or without a sulfonylurea, and later for use with thiazolidinediones (TZDs). The medicine is modeled on a protein found in the saliva of Gila monsters, and is similar to glucose-dependent insulinotropic peptide or GLP-1, but lasts longer in the body.

In a phase III, manufacturer-sponsored, randomized, controlled trial of exenatide injections (Ann. Intern. Med. 2011;154:103-12), the findings of which were submitted to the FDA in support of the new indication, 261 patients receiving insulin glargine, with or without metformin and/or a TZD were randomized to receive exenatide 10 mcg twice daily or placebo in addition to aggressive insulin titration for 30 weeks.

Hemoglobin A_1c was seen to decrease by 1.74 percentage points after 30 weeks in patients in the exenatide arm, and by 1.04 points in those treated with insulin alone. Patients receiving exenatide required less insulin (increases in insulin dosage of 13 U/day for the treatment arm vs. 20 U/day in the control arm). The incidence of hypoglycemia was similar between arms.

Patients’ weights in the exenatide arm of the study also decreased by 1.8 kg, compared with an increase of 1 kg in the control arm, suggesting that exenatide improved glycemic control without causing weight gain. Nausea was the most frequently reported adverse event, affecting 41% in the treatment arm and 8% in the control arm.

Letters criticizing the study appeared after its publication. One questioned whether it was adequately powered to detect some of the reported effects, and another took issue with its short duration and use of HbA_1c as an outcome measure, when other, longer studies had not shown correlations between improvements in HbA_1c and diabetes mortality or vascular complications.

The U.S. Food and Drug administration has approved a new indication for fixed-dose exenatide injections.

The medication’s manufacturers, Amylin and Eli Lilly, announced Oct. 19 that the exenatide injections, marketed as Byetta, had been approved as an add-on therapy to insulin glargine, with or without metformin and/or a thiazolidinedione, for adults with type 2 diabetes who are not achieving adequate glycemic control on long-acting insulin alone.

Exenatide was initially approved by the FDA in 2005 for use in combination with metformin with or without a sulfonylurea, and later for use with thiazolidinediones (TZDs). The medicine is modeled on a protein found in the saliva of Gila monsters, and is similar to glucose-dependent insulinotropic peptide or GLP-1, but lasts longer in the body.

In a phase III, manufacturer-sponsored, randomized, controlled trial of exenatide injections (Ann. Intern. Med. 2011;154:103-12), the findings of which were submitted to the FDA in support of the new indication, 261 patients receiving insulin glargine, with or without metformin and/or a TZD were randomized to receive exenatide 10 mcg twice daily or placebo in addition to aggressive insulin titration for 30 weeks.

Hemoglobin A_1c was seen to decrease by 1.74 percentage points after 30 weeks in patients in the exenatide arm, and by 1.04 points in those treated with insulin alone. Patients receiving exenatide required less insulin (increases in insulin dosage of 13 U/day for the treatment arm vs. 20 U/day in the control arm). The incidence of hypoglycemia was similar between arms.

Patients’ weights in the exenatide arm of the study also decreased by 1.8 kg, compared with an increase of 1 kg in the control arm, suggesting that exenatide improved glycemic control without causing weight gain. Nausea was the most frequently reported adverse event, affecting 41% in the treatment arm and 8% in the control arm.

Letters criticizing the study appeared after its publication. One questioned whether it was adequately powered to detect some of the reported effects, and another took issue with its short duration and use of HbA_1c as an outcome measure, when other, longer studies had not shown correlations between improvements in HbA_1c and diabetes mortality or vascular complications.

The U.S. Food and Drug administration has approved a new indication for fixed-dose exenatide injections.

The medication’s manufacturers, Amylin and Eli Lilly, announced Oct. 19 that the exenatide injections, marketed as Byetta, had been approved as an add-on therapy to insulin glargine, with or without metformin and/or a thiazolidinedione, for adults with type 2 diabetes who are not achieving adequate glycemic control on long-acting insulin alone.

Exenatide was initially approved by the FDA in 2005 for use in combination with metformin with or without a sulfonylurea, and later for use with thiazolidinediones (TZDs). The medicine is modeled on a protein found in the saliva of Gila monsters, and is similar to glucose-dependent insulinotropic peptide or GLP-1, but lasts longer in the body.

In a phase III, manufacturer-sponsored, randomized, controlled trial of exenatide injections (Ann. Intern. Med. 2011;154:103-12), the findings of which were submitted to the FDA in support of the new indication, 261 patients receiving insulin glargine, with or without metformin and/or a TZD were randomized to receive exenatide 10 mcg twice daily or placebo in addition to aggressive insulin titration for 30 weeks.

Hemoglobin A_1c was seen to decrease by 1.74 percentage points after 30 weeks in patients in the exenatide arm, and by 1.04 points in those treated with insulin alone. Patients receiving exenatide required less insulin (increases in insulin dosage of 13 U/day for the treatment arm vs. 20 U/day in the control arm). The incidence of hypoglycemia was similar between arms.

Patients’ weights in the exenatide arm of the study also decreased by 1.8 kg, compared with an increase of 1 kg in the control arm, suggesting that exenatide improved glycemic control without causing weight gain. Nausea was the most frequently reported adverse event, affecting 41% in the treatment arm and 8% in the control arm.

Letters criticizing the study appeared after its publication. One questioned whether it was adequately powered to detect some of the reported effects, and another took issue with its short duration and use of HbA_1c as an outcome measure, when other, longer studies had not shown correlations between improvements in HbA_1c and diabetes mortality or vascular complications.

A new evidence-based guideline issued by the American Academy of Neurology for the treatment of essential tremor reinforces the use of propranolol and primidone as the go-to agents for the disease.

However, these first-line agents – used as monotherapy or combination therapy since the 1980s – do not work in between 30% and 50% of people with essential tremor (ET).

Moreover, a 2010 study of 223 ET patients in a clinical database revealed that more than half of patients taking primidone and/or propranolol had discontinued them, suggesting that the need for alternatives is great (Parkinsonism Relat. Disord. 2010;16:604-7). Primidone and propranolol are known to cause side effects at higher titrations.

Essential tremor is a common, progressive neurological disease, formerly called "benign essential tremor," that causes a rhythmic trembling of the hands, head, voice, legs, or trunk, and is sometimes mistaken for Parkinson’s disease.

In its new ET guideline, published online Oct. 19 in the journal Neurology as an update of its 2005 guideline for ET, the AAN continues to recommend topiramate, alprazolam, atenolol, gabapentin, and sotalol as second-line treatments, based on clinical evidence that they are probably effective. The AAN’s new recommendations are based on reviews of 589 articles (252 of these complete reviews) of randomized controlled trials, observational studies, cohort studies, and case series published between 2004 and 2010 (Neurology 2011 Oct. 19 [Epub ahead of print]).

The AAN’s team of reviewers, led by Dr. Theresa A. Zesiewicz of the University of South Florida in Tampa, found that they could not recommend levetiracetam and 3,4-diaminopyridine as second-line agents, based on quality (Level B) clinical evidence that they do not reduce limb tremor. The evidence on flunarizine suggests that it is probably ineffective in reducing limb tremor. And the reviewers could not recommend pregabalin, zonisamide, and clozapine, based on insufficient evidence to support or refute their use in ET.

"What's important to understand is that essential tremor may be a heterogeneous condition."

"There were some agents we had some hopes for that didn’t pan out, and levetiracetam was one of them," Dr. Zesiewicz said in an interview, adding that patients not responding to primidone or propranolol, or in whom these are contraindicated, might benefit from any of the currently recommended second-line agents with level B evidence supporting them. Of these, she said, topiramate is supported by the largest cohort studies, but "any of the level B, or level C agents" can be tried. Surgical interventions in ET patients, though seen to have greater treatment effect than medications, are seldom tried before a second-line agent doesn’t work and a tremor becomes debilitating.

"The reason we don’t go to [surgery] right away is because when the side effects do occur – which is relatively rare – they can be serious," Dr. Zesiewicz said.

The guideline’s advice on surgical interventions for ET remain unchanged from 2005, with deep brain stimulation (DBS) still recommended. DBS, by which a device is implanted in the brain to transmit electrical impulses, "has really become the surgery of choice," Dr. Zesiewicz said.

There is still too little evidence for the AAN to recommend gamma knife thalamotomy, which uses targeted radiotherapy, and concern remains about rare but serious side effects with the procedure. Nonetheless, "the story about gamma knife has yet to be completely written," Dr. Zesiewicz said.

Another surgical intervention currently being explored, which uses MR-guided focused ultrasound, was not mentioned in the current guidance, but Dr. Zesiewicz called it "extremely interesting," and hopes that the procedure, pioneered by Dr. W. Jeffrey Elias of the University of Virginia, Charlottesville, will hold up in long-term safety studies and randomized controlled trials. "Gamma ray looked good too," she noted – until some rare but severe delayed adverse effects were seen.

Dr. Zesiewicz and her colleagues noted that more and larger randomized controlled trials, with standardized outcome measures, were needed for ET treatments.

"We lost a lot of ground in research because of the [former] name ‘benign essential tremor,’ " Dr. Zesiewicz said. "Once that ‘benign’ was dropped it became a more serious priority. Hopefully we’ll be able to gain ground now that we know that this is a serious condition, it is a disease, and it’s certainly not benign."

However, the pathology of ET, now thought to be a heterogeneous set of degenerative changes in the brain, has become much better understood in recent years, thanks to researchers’ postmortem studies of the brains of ET patients at Columbia University in New York.

The Columbia brain bank’s research is being led by Dr. Elan Louis, one of the new ET guideline’s coauthors. Dr. Louis and colleagues have made "tremendous headway," Dr. Zesiewicz said, in elucidating the causes of ET.

Dr. Zesiewicz said she hopes new agents will be designed to target ET specifically. The currently recommended agents range from antiepileptics to medications used to treat schizophrenia – and only one, propranolol, is approved by the U.S. Food and Drug Administration to treat ET. (Even primidone is not FDA-approved, despite its widespread, long-term use.)

"What’s important to understand is that ET may be a heterogeneous condition," Dr. Zesiewicz said. "When we pick that apart and truly understand the mechanisms by which ET occurs, we may be able to develop research and medications specific to the problem."

Dr. Zesiewicz disclosed having received speakers’ fees other forms of support from Teva, Boehringer Ingelheim, Allergan, and Novartis, along with research support from Pfizer, and is an inventor on a provisional patent on the use of nicotinic modulators in treating ataxia and imbalance held by the University of South Florida. Several of Dr. Zesiewicz’s coauthors on the ET guideline acknowledged support from these and other companies, including GlaxoSmithKline, Phytopharm, Janssen, Allergan, Novartis, Ipsen, Merz, Lundbeck, and Bayer.

A new evidence-based guideline issued by the American Academy of Neurology for the treatment of essential tremor reinforces the use of propranolol and primidone as the go-to agents for the disease.

However, these first-line agents – used as monotherapy or combination therapy since the 1980s – do not work in between 30% and 50% of people with essential tremor (ET).

Moreover, a 2010 study of 223 ET patients in a clinical database revealed that more than half of patients taking primidone and/or propranolol had discontinued them, suggesting that the need for alternatives is great (Parkinsonism Relat. Disord. 2010;16:604-7). Primidone and propranolol are known to cause side effects at higher titrations.

Essential tremor is a common, progressive neurological disease, formerly called "benign essential tremor," that causes a rhythmic trembling of the hands, head, voice, legs, or trunk, and is sometimes mistaken for Parkinson’s disease.

In its new ET guideline, published online Oct. 19 in the journal Neurology as an update of its 2005 guideline for ET, the AAN continues to recommend topiramate, alprazolam, atenolol, gabapentin, and sotalol as second-line treatments, based on clinical evidence that they are probably effective. The AAN’s new recommendations are based on reviews of 589 articles (252 of these complete reviews) of randomized controlled trials, observational studies, cohort studies, and case series published between 2004 and 2010 (Neurology 2011 Oct. 19 [Epub ahead of print]).

The AAN’s team of reviewers, led by Dr. Theresa A. Zesiewicz of the University of South Florida in Tampa, found that they could not recommend levetiracetam and 3,4-diaminopyridine as second-line agents, based on quality (Level B) clinical evidence that they do not reduce limb tremor. The evidence on flunarizine suggests that it is probably ineffective in reducing limb tremor. And the reviewers could not recommend pregabalin, zonisamide, and clozapine, based on insufficient evidence to support or refute their use in ET.

"What's important to understand is that essential tremor may be a heterogeneous condition."

"There were some agents we had some hopes for that didn’t pan out, and levetiracetam was one of them," Dr. Zesiewicz said in an interview, adding that patients not responding to primidone or propranolol, or in whom these are contraindicated, might benefit from any of the currently recommended second-line agents with level B evidence supporting them. Of these, she said, topiramate is supported by the largest cohort studies, but "any of the level B, or level C agents" can be tried. Surgical interventions in ET patients, though seen to have greater treatment effect than medications, are seldom tried before a second-line agent doesn’t work and a tremor becomes debilitating.

"The reason we don’t go to [surgery] right away is because when the side effects do occur – which is relatively rare – they can be serious," Dr. Zesiewicz said.

The guideline’s advice on surgical interventions for ET remain unchanged from 2005, with deep brain stimulation (DBS) still recommended. DBS, by which a device is implanted in the brain to transmit electrical impulses, "has really become the surgery of choice," Dr. Zesiewicz said.

There is still too little evidence for the AAN to recommend gamma knife thalamotomy, which uses targeted radiotherapy, and concern remains about rare but serious side effects with the procedure. Nonetheless, "the story about gamma knife has yet to be completely written," Dr. Zesiewicz said.

Another surgical intervention currently being explored, which uses MR-guided focused ultrasound, was not mentioned in the current guidance, but Dr. Zesiewicz called it "extremely interesting," and hopes that the procedure, pioneered by Dr. W. Jeffrey Elias of the University of Virginia, Charlottesville, will hold up in long-term safety studies and randomized controlled trials. "Gamma ray looked good too," she noted – until some rare but severe delayed adverse effects were seen.

Dr. Zesiewicz and her colleagues noted that more and larger randomized controlled trials, with standardized outcome measures, were needed for ET treatments.

"We lost a lot of ground in research because of the [former] name ‘benign essential tremor,’ " Dr. Zesiewicz said. "Once that ‘benign’ was dropped it became a more serious priority. Hopefully we’ll be able to gain ground now that we know that this is a serious condition, it is a disease, and it’s certainly not benign."

However, the pathology of ET, now thought to be a heterogeneous set of degenerative changes in the brain, has become much better understood in recent years, thanks to researchers’ postmortem studies of the brains of ET patients at Columbia University in New York.

The Columbia brain bank’s research is being led by Dr. Elan Louis, one of the new ET guideline’s coauthors. Dr. Louis and colleagues have made "tremendous headway," Dr. Zesiewicz said, in elucidating the causes of ET.

Dr. Zesiewicz said she hopes new agents will be designed to target ET specifically. The currently recommended agents range from antiepileptics to medications used to treat schizophrenia – and only one, propranolol, is approved by the U.S. Food and Drug Administration to treat ET. (Even primidone is not FDA-approved, despite its widespread, long-term use.)

"What’s important to understand is that ET may be a heterogeneous condition," Dr. Zesiewicz said. "When we pick that apart and truly understand the mechanisms by which ET occurs, we may be able to develop research and medications specific to the problem."

Dr. Zesiewicz disclosed having received speakers’ fees other forms of support from Teva, Boehringer Ingelheim, Allergan, and Novartis, along with research support from Pfizer, and is an inventor on a provisional patent on the use of nicotinic modulators in treating ataxia and imbalance held by the University of South Florida. Several of Dr. Zesiewicz’s coauthors on the ET guideline acknowledged support from these and other companies, including GlaxoSmithKline, Phytopharm, Janssen, Allergan, Novartis, Ipsen, Merz, Lundbeck, and Bayer.

A new evidence-based guideline issued by the American Academy of Neurology for the treatment of essential tremor reinforces the use of propranolol and primidone as the go-to agents for the disease.

However, these first-line agents – used as monotherapy or combination therapy since the 1980s – do not work in between 30% and 50% of people with essential tremor (ET).

Moreover, a 2010 study of 223 ET patients in a clinical database revealed that more than half of patients taking primidone and/or propranolol had discontinued them, suggesting that the need for alternatives is great (Parkinsonism Relat. Disord. 2010;16:604-7). Primidone and propranolol are known to cause side effects at higher titrations.

Essential tremor is a common, progressive neurological disease, formerly called "benign essential tremor," that causes a rhythmic trembling of the hands, head, voice, legs, or trunk, and is sometimes mistaken for Parkinson’s disease.

In its new ET guideline, published online Oct. 19 in the journal Neurology as an update of its 2005 guideline for ET, the AAN continues to recommend topiramate, alprazolam, atenolol, gabapentin, and sotalol as second-line treatments, based on clinical evidence that they are probably effective. The AAN’s new recommendations are based on reviews of 589 articles (252 of these complete reviews) of randomized controlled trials, observational studies, cohort studies, and case series published between 2004 and 2010 (Neurology 2011 Oct. 19 [Epub ahead of print]).

The AAN’s team of reviewers, led by Dr. Theresa A. Zesiewicz of the University of South Florida in Tampa, found that they could not recommend levetiracetam and 3,4-diaminopyridine as second-line agents, based on quality (Level B) clinical evidence that they do not reduce limb tremor. The evidence on flunarizine suggests that it is probably ineffective in reducing limb tremor. And the reviewers could not recommend pregabalin, zonisamide, and clozapine, based on insufficient evidence to support or refute their use in ET.

"What's important to understand is that essential tremor may be a heterogeneous condition."

"There were some agents we had some hopes for that didn’t pan out, and levetiracetam was one of them," Dr. Zesiewicz said in an interview, adding that patients not responding to primidone or propranolol, or in whom these are contraindicated, might benefit from any of the currently recommended second-line agents with level B evidence supporting them. Of these, she said, topiramate is supported by the largest cohort studies, but "any of the level B, or level C agents" can be tried. Surgical interventions in ET patients, though seen to have greater treatment effect than medications, are seldom tried before a second-line agent doesn’t work and a tremor becomes debilitating.

"The reason we don’t go to [surgery] right away is because when the side effects do occur – which is relatively rare – they can be serious," Dr. Zesiewicz said.

The guideline’s advice on surgical interventions for ET remain unchanged from 2005, with deep brain stimulation (DBS) still recommended. DBS, by which a device is implanted in the brain to transmit electrical impulses, "has really become the surgery of choice," Dr. Zesiewicz said.

There is still too little evidence for the AAN to recommend gamma knife thalamotomy, which uses targeted radiotherapy, and concern remains about rare but serious side effects with the procedure. Nonetheless, "the story about gamma knife has yet to be completely written," Dr. Zesiewicz said.

Another surgical intervention currently being explored, which uses MR-guided focused ultrasound, was not mentioned in the current guidance, but Dr. Zesiewicz called it "extremely interesting," and hopes that the procedure, pioneered by Dr. W. Jeffrey Elias of the University of Virginia, Charlottesville, will hold up in long-term safety studies and randomized controlled trials. "Gamma ray looked good too," she noted – until some rare but severe delayed adverse effects were seen.

Dr. Zesiewicz and her colleagues noted that more and larger randomized controlled trials, with standardized outcome measures, were needed for ET treatments.

"We lost a lot of ground in research because of the [former] name ‘benign essential tremor,’ " Dr. Zesiewicz said. "Once that ‘benign’ was dropped it became a more serious priority. Hopefully we’ll be able to gain ground now that we know that this is a serious condition, it is a disease, and it’s certainly not benign."

However, the pathology of ET, now thought to be a heterogeneous set of degenerative changes in the brain, has become much better understood in recent years, thanks to researchers’ postmortem studies of the brains of ET patients at Columbia University in New York.

The Columbia brain bank’s research is being led by Dr. Elan Louis, one of the new ET guideline’s coauthors. Dr. Louis and colleagues have made "tremendous headway," Dr. Zesiewicz said, in elucidating the causes of ET.

Dr. Zesiewicz said she hopes new agents will be designed to target ET specifically. The currently recommended agents range from antiepileptics to medications used to treat schizophrenia – and only one, propranolol, is approved by the U.S. Food and Drug Administration to treat ET. (Even primidone is not FDA-approved, despite its widespread, long-term use.)

"What’s important to understand is that ET may be a heterogeneous condition," Dr. Zesiewicz said. "When we pick that apart and truly understand the mechanisms by which ET occurs, we may be able to develop research and medications specific to the problem."

Dr. Zesiewicz disclosed having received speakers’ fees other forms of support from Teva, Boehringer Ingelheim, Allergan, and Novartis, along with research support from Pfizer, and is an inventor on a provisional patent on the use of nicotinic modulators in treating ataxia and imbalance held by the University of South Florida. Several of Dr. Zesiewicz’s coauthors on the ET guideline acknowledged support from these and other companies, including GlaxoSmithKline, Phytopharm, Janssen, Allergan, Novartis, Ipsen, Merz, Lundbeck, and Bayer.

ACE inhibitors were not found more likely than other antihypertensive drugs to be associated with an increase in congenital heart defects when used in the first trimester only.

Rather, hypertension itself was suspected as the likeliest cause of increased risk.

The findings, from a large retrospective cohort study published online Oct. 18 in BMJ (BMJ 2011 Oct. 18 [doi: 10.1136/bmj.d5931]), challenge those of a smaller, 5-year-old study of similar design (N. Engl. J. Med. 2006;354:2443-51) that found first-trimester use of angiotensin converting enzyme (ACE) inhibitors associated with an increase in congenital heart and neural tube defects. (Other antihypertensives were not seen in that study as raising risk.)

ACE inhibitors have long been associated with birth defects when used in the second and third trimester, and are therefore contraindicated in pregnancy; however, it was not until the publication of the 2006 cohort study of about 30,000 infants that adverse outcomes were also linked to first-trimester use.

The question of teratogenicity in the first trimester is important, because many pregnancies are unplanned, and women may continue to use contraindicated drugs inadvertently after conceiving.

For their research, Dr. De-Kun Li of Kaiser Permanente in Oakland, Calif., and colleagues enrolled 465,754 mother-infant pairs representing all live births in Kaiser Permanente’s Northern California region between 1995 and 2008.

The researchers looked at incidence of heart and neural tube defects at birth, and the cohort included linked data on prescription history, maternal preexisting diabetes, pregnancy weight, age, ethnicity, and education, among other variables. Only 0.9 of every 1,000 women in the cohort used ACE inhibitors, and use of other antihypertensive medications was 2.4 per 1,000.

After adjustment for maternal age, ethnicity, parity, and obesity, use of ACE inhibitors was seen associated with congenital heart defects in 15 of 381 mother-infant pairs (3.9%), compared with 6,232 of 400,021 (1.6%) in infants born to normal controls, or women without hypertension and not taking take any antihypertensives during pregnancy (OR, 1.54; 95% CI 0.90-2.62).

Heart defects were seen in 28/1090 (2.6%) of infants whose mothers took other hypertensives in the first trimester only (OR, 1.52; 95% CI, 1.04-2.21).

Among hypertension controls – women diagnosed with hypertension but not taking antihypertensives – 708 of 29,735, (2.4%), of their infants had congenital heart defects.

Investigators found that, compared with hypertension controls, neither use of ACE inhibitors or other antihypertensives in the first trimester was associated with increased congenital heart defects risk (OR, 1.14 with a 95% CI of 0.65-1.98; OR, 1.12 with a 95% CI of 0.76-1.64).

Neural tube defects were not seen to differ significantly among the groups.

The findings, Dr. Li and colleagues wrote, "raise the question of whether the observed risk associated with antihypertensives in general was due to the effect of the drugs or the underlying hypertension."

In an editorial comment associated with Dr Li and colleagues’ study (BMJ 2011;343:d6667), Dr. Allen A. Mitchell of the Slone Epidemiology Center at Boston University, wrote that "[f]ew studies have been large and rigorous enough to provide useful information on the fetal safety of most antihypertensives." However, he praised the new findings as derived from a "larger and more diverse database" than were previous studies.

While Dr. Li and colleagues’ findings clashed with those of the 2006 study, which found an effect for ACE inhibitors in the first trimester (risk ratio 2.71; 95% CI, 1.72 to 4.27), Dr. Mitchell noted, two more recent studies found no increased risk when used in the first trimester only (Eur. J. Clin. Pharmacol. 2009;65:615-25 and Hypertension 2009;54:63-70).

"On the basis of all these findings, it is reasonable to conclude that exposure to ACE inhibitors during the first trimester poses no greater risk of birth defects than exposure to other antihypertensives," Dr. Mitchell wrote. "[I]t is possible that ACE inhibitors (and other antihypertensives) may be associated, if modestly, with one or another specific defect, but the greater concern is that the underlying hypertension itself places the fetus at risk."

The investigators conceded several weaknesses in their study, among which was that they had little information on the characteristics of women with treated and untreated hypertension. Therefore, they wrote, "we were not able to distinguish between the potential underlying differences in the risk of having a child with birth defects and treatment effect on the risk of birth defects."

Nevertheless, Dr. Li and colleagues continued, "untreated hypertension is likely to be less severe than treated hypertension, and the risk of having a child with birth defects was quite similar between women with treated hypertension (in the first trimester) and those with untreated hypertension."

Dr. Mitchell echoed this concern, writing that while it was reasonable to assume that untreated hypertension is less severe than treated hypertension, observational studies "have lacked data on crucial variables related to hypertension in pregnancy." He also questioned whether a "prehypertensive" condition could affect the fetus before an increase in maternal blood pressure is detected.

Dr. Li and colleagues’ study was funded by the U.S. Department of Health and Human Services and the Food and Drug Administration. Neither Dr. Li nor his colleagues declared conflicts of interest. Dr. Mitchell disclosed no conflicts of interest related to his editorial.

ACE inhibitors were not found more likely than other antihypertensive drugs to be associated with an increase in congenital heart defects when used in the first trimester only.

Rather, hypertension itself was suspected as the likeliest cause of increased risk.

The findings, from a large retrospective cohort study published online Oct. 18 in BMJ (BMJ 2011 Oct. 18 [doi: 10.1136/bmj.d5931]), challenge those of a smaller, 5-year-old study of similar design (N. Engl. J. Med. 2006;354:2443-51) that found first-trimester use of angiotensin converting enzyme (ACE) inhibitors associated with an increase in congenital heart and neural tube defects. (Other antihypertensives were not seen in that study as raising risk.)

ACE inhibitors have long been associated with birth defects when used in the second and third trimester, and are therefore contraindicated in pregnancy; however, it was not until the publication of the 2006 cohort study of about 30,000 infants that adverse outcomes were also linked to first-trimester use.

The question of teratogenicity in the first trimester is important, because many pregnancies are unplanned, and women may continue to use contraindicated drugs inadvertently after conceiving.

For their research, Dr. De-Kun Li of Kaiser Permanente in Oakland, Calif., and colleagues enrolled 465,754 mother-infant pairs representing all live births in Kaiser Permanente’s Northern California region between 1995 and 2008.

The researchers looked at incidence of heart and neural tube defects at birth, and the cohort included linked data on prescription history, maternal preexisting diabetes, pregnancy weight, age, ethnicity, and education, among other variables. Only 0.9 of every 1,000 women in the cohort used ACE inhibitors, and use of other antihypertensive medications was 2.4 per 1,000.

After adjustment for maternal age, ethnicity, parity, and obesity, use of ACE inhibitors was seen associated with congenital heart defects in 15 of 381 mother-infant pairs (3.9%), compared with 6,232 of 400,021 (1.6%) in infants born to normal controls, or women without hypertension and not taking take any antihypertensives during pregnancy (OR, 1.54; 95% CI 0.90-2.62).

Heart defects were seen in 28/1090 (2.6%) of infants whose mothers took other hypertensives in the first trimester only (OR, 1.52; 95% CI, 1.04-2.21).

Among hypertension controls – women diagnosed with hypertension but not taking antihypertensives – 708 of 29,735, (2.4%), of their infants had congenital heart defects.

Investigators found that, compared with hypertension controls, neither use of ACE inhibitors or other antihypertensives in the first trimester was associated with increased congenital heart defects risk (OR, 1.14 with a 95% CI of 0.65-1.98; OR, 1.12 with a 95% CI of 0.76-1.64).

Neural tube defects were not seen to differ significantly among the groups.

The findings, Dr. Li and colleagues wrote, "raise the question of whether the observed risk associated with antihypertensives in general was due to the effect of the drugs or the underlying hypertension."

In an editorial comment associated with Dr Li and colleagues’ study (BMJ 2011;343:d6667), Dr. Allen A. Mitchell of the Slone Epidemiology Center at Boston University, wrote that "[f]ew studies have been large and rigorous enough to provide useful information on the fetal safety of most antihypertensives." However, he praised the new findings as derived from a "larger and more diverse database" than were previous studies.

While Dr. Li and colleagues’ findings clashed with those of the 2006 study, which found an effect for ACE inhibitors in the first trimester (risk ratio 2.71; 95% CI, 1.72 to 4.27), Dr. Mitchell noted, two more recent studies found no increased risk when used in the first trimester only (Eur. J. Clin. Pharmacol. 2009;65:615-25 and Hypertension 2009;54:63-70).

"On the basis of all these findings, it is reasonable to conclude that exposure to ACE inhibitors during the first trimester poses no greater risk of birth defects than exposure to other antihypertensives," Dr. Mitchell wrote. "[I]t is possible that ACE inhibitors (and other antihypertensives) may be associated, if modestly, with one or another specific defect, but the greater concern is that the underlying hypertension itself places the fetus at risk."

The investigators conceded several weaknesses in their study, among which was that they had little information on the characteristics of women with treated and untreated hypertension. Therefore, they wrote, "we were not able to distinguish between the potential underlying differences in the risk of having a child with birth defects and treatment effect on the risk of birth defects."

Nevertheless, Dr. Li and colleagues continued, "untreated hypertension is likely to be less severe than treated hypertension, and the risk of having a child with birth defects was quite similar between women with treated hypertension (in the first trimester) and those with untreated hypertension."

Dr. Mitchell echoed this concern, writing that while it was reasonable to assume that untreated hypertension is less severe than treated hypertension, observational studies "have lacked data on crucial variables related to hypertension in pregnancy." He also questioned whether a "prehypertensive" condition could affect the fetus before an increase in maternal blood pressure is detected.

Dr. Li and colleagues’ study was funded by the U.S. Department of Health and Human Services and the Food and Drug Administration. Neither Dr. Li nor his colleagues declared conflicts of interest. Dr. Mitchell disclosed no conflicts of interest related to his editorial.

ACE inhibitors were not found more likely than other antihypertensive drugs to be associated with an increase in congenital heart defects when used in the first trimester only.

Rather, hypertension itself was suspected as the likeliest cause of increased risk.

The findings, from a large retrospective cohort study published online Oct. 18 in BMJ (BMJ 2011 Oct. 18 [doi: 10.1136/bmj.d5931]), challenge those of a smaller, 5-year-old study of similar design (N. Engl. J. Med. 2006;354:2443-51) that found first-trimester use of angiotensin converting enzyme (ACE) inhibitors associated with an increase in congenital heart and neural tube defects. (Other antihypertensives were not seen in that study as raising risk.)

ACE inhibitors have long been associated with birth defects when used in the second and third trimester, and are therefore contraindicated in pregnancy; however, it was not until the publication of the 2006 cohort study of about 30,000 infants that adverse outcomes were also linked to first-trimester use.

The question of teratogenicity in the first trimester is important, because many pregnancies are unplanned, and women may continue to use contraindicated drugs inadvertently after conceiving.

For their research, Dr. De-Kun Li of Kaiser Permanente in Oakland, Calif., and colleagues enrolled 465,754 mother-infant pairs representing all live births in Kaiser Permanente’s Northern California region between 1995 and 2008.

The researchers looked at incidence of heart and neural tube defects at birth, and the cohort included linked data on prescription history, maternal preexisting diabetes, pregnancy weight, age, ethnicity, and education, among other variables. Only 0.9 of every 1,000 women in the cohort used ACE inhibitors, and use of other antihypertensive medications was 2.4 per 1,000.

After adjustment for maternal age, ethnicity, parity, and obesity, use of ACE inhibitors was seen associated with congenital heart defects in 15 of 381 mother-infant pairs (3.9%), compared with 6,232 of 400,021 (1.6%) in infants born to normal controls, or women without hypertension and not taking take any antihypertensives during pregnancy (OR, 1.54; 95% CI 0.90-2.62).

Heart defects were seen in 28/1090 (2.6%) of infants whose mothers took other hypertensives in the first trimester only (OR, 1.52; 95% CI, 1.04-2.21).

Among hypertension controls – women diagnosed with hypertension but not taking antihypertensives – 708 of 29,735, (2.4%), of their infants had congenital heart defects.

Investigators found that, compared with hypertension controls, neither use of ACE inhibitors or other antihypertensives in the first trimester was associated with increased congenital heart defects risk (OR, 1.14 with a 95% CI of 0.65-1.98; OR, 1.12 with a 95% CI of 0.76-1.64).

Neural tube defects were not seen to differ significantly among the groups.

The findings, Dr. Li and colleagues wrote, "raise the question of whether the observed risk associated with antihypertensives in general was due to the effect of the drugs or the underlying hypertension."

In an editorial comment associated with Dr Li and colleagues’ study (BMJ 2011;343:d6667), Dr. Allen A. Mitchell of the Slone Epidemiology Center at Boston University, wrote that "[f]ew studies have been large and rigorous enough to provide useful information on the fetal safety of most antihypertensives." However, he praised the new findings as derived from a "larger and more diverse database" than were previous studies.

While Dr. Li and colleagues’ findings clashed with those of the 2006 study, which found an effect for ACE inhibitors in the first trimester (risk ratio 2.71; 95% CI, 1.72 to 4.27), Dr. Mitchell noted, two more recent studies found no increased risk when used in the first trimester only (Eur. J. Clin. Pharmacol. 2009;65:615-25 and Hypertension 2009;54:63-70).

"On the basis of all these findings, it is reasonable to conclude that exposure to ACE inhibitors during the first trimester poses no greater risk of birth defects than exposure to other antihypertensives," Dr. Mitchell wrote. "[I]t is possible that ACE inhibitors (and other antihypertensives) may be associated, if modestly, with one or another specific defect, but the greater concern is that the underlying hypertension itself places the fetus at risk."

The investigators conceded several weaknesses in their study, among which was that they had little information on the characteristics of women with treated and untreated hypertension. Therefore, they wrote, "we were not able to distinguish between the potential underlying differences in the risk of having a child with birth defects and treatment effect on the risk of birth defects."

Nevertheless, Dr. Li and colleagues continued, "untreated hypertension is likely to be less severe than treated hypertension, and the risk of having a child with birth defects was quite similar between women with treated hypertension (in the first trimester) and those with untreated hypertension."

Dr. Mitchell echoed this concern, writing that while it was reasonable to assume that untreated hypertension is less severe than treated hypertension, observational studies "have lacked data on crucial variables related to hypertension in pregnancy." He also questioned whether a "prehypertensive" condition could affect the fetus before an increase in maternal blood pressure is detected.

Dr. Li and colleagues’ study was funded by the U.S. Department of Health and Human Services and the Food and Drug Administration. Neither Dr. Li nor his colleagues declared conflicts of interest. Dr. Mitchell disclosed no conflicts of interest related to his editorial.

Up to one in five children and adolescents worldwide has a mental health disorder, according to a broad-ranging new study, yet mental health interventions, and the research to support them, are neglected in low- and middle-income countries.

While 90% of the world’s 2.2 billion children and adolescents live in low- and middle-income countries, researchers found, only 10% of mental health trials for this population are conducted in these countries.

A dearth of research expertise in low- and middle-income countries is one contributing factor, said Atif Rahman, Ph.D., of the University of Liverpool and Alder Hey Children’s NHS Foundation Trust, in Liverpool, U.K., the corresponding author of the study.

"In most developing countries, the universities are not really geared up for research," Dr. Rahman said in an interview. "If there’s not enough research infrastructure and no career structure for researchers, it’s not really going to be possible to do the research on the types of psychological and psychosocial interventions that work in these countries," he said. And less than a third of low- and middle-income countries have a national policy that deals with mental health among children and adolescents.

The findings were published Oct 17 in the Lancet ([2011 [doi:10.1016/S0140-6736[11]60827-1]) as part of a global mental health series that explored disparities in mental health prevention and treatment worldwide.

Another article in the series (Lancet 2011 [doi:10.1016/S0140-6736[11]61093-3]) found that trained mental health clinicians can be surprisingly scarce in developing countries, because of emigration: Sri Lanka, for example, had only 25 psychiatrists living there in 2007, while 142 who trained there had emigrated. A third paper, led by another group of international researchers (Lancet 2011 [doi:10.1016/S0140- 6736[11]60891-X]), found that children were not alone in getting inadequate mental health attention – that while 1 in 3 people with a mental health problem in wealthy nations receives treatment, in developing countries, it can be as few as 1 in 50.

For their research, Dr. Rahman and his colleagues analyzed epidemiologic studies to determine the prevalence of child and adolescent mental health problems in low- and middle-income countries. They also looked at randomized controlled trials evaluating preventative and treatment strategies.

They identified a number of effective interventions – particularly school- and community-based programs, in such diverse countries as China, Mauritius, and Iran – that were shown to successfully address behavioral problems, drug use initiation, and anxiety.

Maternal and child nutritional supplementation, immunization programs, reduction of exposure to toxins, maternal health interventions, malaria prevention, and early stimulation programs were all found to prevent cognitive deficits in low- and middle-income countries.

While there are a number of trials for preventative interventions in low- and middle-income countries, "There are only a handful of treatment trials," Dr. Rahman said. Of the more than 670 treatment trials the investigators identified for the study, 58 came from middle-income countries and only 1 was from a low-income country.

The researchers decided to include in their analysis some treatment trials done in low-income populations in higher-income countries, such as those enrolling African-American children in the United States, noting that many mental health risk factors for children and adolescents were found to be similar across higher- and lower-income countries.

But Dr. Rahman noted that interventions developed in the West might not be feasible in lower-income settings where, for example, mental health specialists may be few and far between.

"Mental health problems in children in high- and low-income countries may share similar risk factors, especially in poor and disadvantaged communities. How you treat them will be very different depending on the health, social, and community-based systems available. There is the issue of who is there to deliver them – in a low-income setting you might have to adapt your interventions or develop new ones so that nonspecialists can deliver them," he said.

"This is why the 90-10 research gap is so important," Dr. Rahman continued. "You can’t just implement a strategy developed in the West. You have to find the right one, which is culturally appropriate and feasible, and requires research, trials, and cost-effectiveness analyses."

In addition to calling for more randomized controlled trials, Dr. Rahman and his colleagues made several recommendations, based on their findings, for child and adolescent mental health programming in low- and middle-income countries.

Integration with existing, community-based systems is feasible, they wrote.

Early interventions and rehabilitative or curative interventions "need to develop side by side, which can be made efficient by task sharing," they wrote, and advised partnering with physical health programs and agencies outside the health sector – in education, social care, and criminal justice. And finally, they wrote, "awareness programs and mobilization of potential stakeholders should be considered as part of any child and adolescent mental health service development."

The researchers noted as a limitation of their study a heterogeneity in the prevalence studies that prevented either direct comparisons between countries or meta-analytic approaches. Two of Dr. Rahman’s coauthors reported disclosures: Dr. Christian Kieling took part in meetings sponsored by Novartis, Shire, and Deva. Dr. Luis Augusto Rohde acted as speaker or consultant for Eli Lilly, Janssen-Cilag, Novartis, and Shire, and received program funding and research support from those companies.

There was no external funding, and each of the researchers contributed their time to the study.

Up to one in five children and adolescents worldwide has a mental health disorder, according to a broad-ranging new study, yet mental health interventions, and the research to support them, are neglected in low- and middle-income countries.

While 90% of the world’s 2.2 billion children and adolescents live in low- and middle-income countries, researchers found, only 10% of mental health trials for this population are conducted in these countries.

A dearth of research expertise in low- and middle-income countries is one contributing factor, said Atif Rahman, Ph.D., of the University of Liverpool and Alder Hey Children’s NHS Foundation Trust, in Liverpool, U.K., the corresponding author of the study.

"In most developing countries, the universities are not really geared up for research," Dr. Rahman said in an interview. "If there’s not enough research infrastructure and no career structure for researchers, it’s not really going to be possible to do the research on the types of psychological and psychosocial interventions that work in these countries," he said. And less than a third of low- and middle-income countries have a national policy that deals with mental health among children and adolescents.

The findings were published Oct 17 in the Lancet ([2011 [doi:10.1016/S0140-6736[11]60827-1]) as part of a global mental health series that explored disparities in mental health prevention and treatment worldwide.

Another article in the series (Lancet 2011 [doi:10.1016/S0140-6736[11]61093-3]) found that trained mental health clinicians can be surprisingly scarce in developing countries, because of emigration: Sri Lanka, for example, had only 25 psychiatrists living there in 2007, while 142 who trained there had emigrated. A third paper, led by another group of international researchers (Lancet 2011 [doi:10.1016/S0140- 6736[11]60891-X]), found that children were not alone in getting inadequate mental health attention – that while 1 in 3 people with a mental health problem in wealthy nations receives treatment, in developing countries, it can be as few as 1 in 50.

For their research, Dr. Rahman and his colleagues analyzed epidemiologic studies to determine the prevalence of child and adolescent mental health problems in low- and middle-income countries. They also looked at randomized controlled trials evaluating preventative and treatment strategies.

They identified a number of effective interventions – particularly school- and community-based programs, in such diverse countries as China, Mauritius, and Iran – that were shown to successfully address behavioral problems, drug use initiation, and anxiety.

Maternal and child nutritional supplementation, immunization programs, reduction of exposure to toxins, maternal health interventions, malaria prevention, and early stimulation programs were all found to prevent cognitive deficits in low- and middle-income countries.

While there are a number of trials for preventative interventions in low- and middle-income countries, "There are only a handful of treatment trials," Dr. Rahman said. Of the more than 670 treatment trials the investigators identified for the study, 58 came from middle-income countries and only 1 was from a low-income country.

The researchers decided to include in their analysis some treatment trials done in low-income populations in higher-income countries, such as those enrolling African-American children in the United States, noting that many mental health risk factors for children and adolescents were found to be similar across higher- and lower-income countries.

But Dr. Rahman noted that interventions developed in the West might not be feasible in lower-income settings where, for example, mental health specialists may be few and far between.

"Mental health problems in children in high- and low-income countries may share similar risk factors, especially in poor and disadvantaged communities. How you treat them will be very different depending on the health, social, and community-based systems available. There is the issue of who is there to deliver them – in a low-income setting you might have to adapt your interventions or develop new ones so that nonspecialists can deliver them," he said.

"This is why the 90-10 research gap is so important," Dr. Rahman continued. "You can’t just implement a strategy developed in the West. You have to find the right one, which is culturally appropriate and feasible, and requires research, trials, and cost-effectiveness analyses."

In addition to calling for more randomized controlled trials, Dr. Rahman and his colleagues made several recommendations, based on their findings, for child and adolescent mental health programming in low- and middle-income countries.

Integration with existing, community-based systems is feasible, they wrote.

Early interventions and rehabilitative or curative interventions "need to develop side by side, which can be made efficient by task sharing," they wrote, and advised partnering with physical health programs and agencies outside the health sector – in education, social care, and criminal justice. And finally, they wrote, "awareness programs and mobilization of potential stakeholders should be considered as part of any child and adolescent mental health service development."

The researchers noted as a limitation of their study a heterogeneity in the prevalence studies that prevented either direct comparisons between countries or meta-analytic approaches. Two of Dr. Rahman’s coauthors reported disclosures: Dr. Christian Kieling took part in meetings sponsored by Novartis, Shire, and Deva. Dr. Luis Augusto Rohde acted as speaker or consultant for Eli Lilly, Janssen-Cilag, Novartis, and Shire, and received program funding and research support from those companies.

There was no external funding, and each of the researchers contributed their time to the study.

Up to one in five children and adolescents worldwide has a mental health disorder, according to a broad-ranging new study, yet mental health interventions, and the research to support them, are neglected in low- and middle-income countries.

While 90% of the world’s 2.2 billion children and adolescents live in low- and middle-income countries, researchers found, only 10% of mental health trials for this population are conducted in these countries.

A dearth of research expertise in low- and middle-income countries is one contributing factor, said Atif Rahman, Ph.D., of the University of Liverpool and Alder Hey Children’s NHS Foundation Trust, in Liverpool, U.K., the corresponding author of the study.

"In most developing countries, the universities are not really geared up for research," Dr. Rahman said in an interview. "If there’s not enough research infrastructure and no career structure for researchers, it’s not really going to be possible to do the research on the types of psychological and psychosocial interventions that work in these countries," he said. And less than a third of low- and middle-income countries have a national policy that deals with mental health among children and adolescents.

The findings were published Oct 17 in the Lancet ([2011 [doi:10.1016/S0140-6736[11]60827-1]) as part of a global mental health series that explored disparities in mental health prevention and treatment worldwide.

Another article in the series (Lancet 2011 [doi:10.1016/S0140-6736[11]61093-3]) found that trained mental health clinicians can be surprisingly scarce in developing countries, because of emigration: Sri Lanka, for example, had only 25 psychiatrists living there in 2007, while 142 who trained there had emigrated. A third paper, led by another group of international researchers (Lancet 2011 [doi:10.1016/S0140- 6736[11]60891-X]), found that children were not alone in getting inadequate mental health attention – that while 1 in 3 people with a mental health problem in wealthy nations receives treatment, in developing countries, it can be as few as 1 in 50.

For their research, Dr. Rahman and his colleagues analyzed epidemiologic studies to determine the prevalence of child and adolescent mental health problems in low- and middle-income countries. They also looked at randomized controlled trials evaluating preventative and treatment strategies.

They identified a number of effective interventions – particularly school- and community-based programs, in such diverse countries as China, Mauritius, and Iran – that were shown to successfully address behavioral problems, drug use initiation, and anxiety.

Maternal and child nutritional supplementation, immunization programs, reduction of exposure to toxins, maternal health interventions, malaria prevention, and early stimulation programs were all found to prevent cognitive deficits in low- and middle-income countries.

While there are a number of trials for preventative interventions in low- and middle-income countries, "There are only a handful of treatment trials," Dr. Rahman said. Of the more than 670 treatment trials the investigators identified for the study, 58 came from middle-income countries and only 1 was from a low-income country.

The researchers decided to include in their analysis some treatment trials done in low-income populations in higher-income countries, such as those enrolling African-American children in the United States, noting that many mental health risk factors for children and adolescents were found to be similar across higher- and lower-income countries.

But Dr. Rahman noted that interventions developed in the West might not be feasible in lower-income settings where, for example, mental health specialists may be few and far between.

"Mental health problems in children in high- and low-income countries may share similar risk factors, especially in poor and disadvantaged communities. How you treat them will be very different depending on the health, social, and community-based systems available. There is the issue of who is there to deliver them – in a low-income setting you might have to adapt your interventions or develop new ones so that nonspecialists can deliver them," he said.

"This is why the 90-10 research gap is so important," Dr. Rahman continued. "You can’t just implement a strategy developed in the West. You have to find the right one, which is culturally appropriate and feasible, and requires research, trials, and cost-effectiveness analyses."

In addition to calling for more randomized controlled trials, Dr. Rahman and his colleagues made several recommendations, based on their findings, for child and adolescent mental health programming in low- and middle-income countries.

Integration with existing, community-based systems is feasible, they wrote.

Early interventions and rehabilitative or curative interventions "need to develop side by side, which can be made efficient by task sharing," they wrote, and advised partnering with physical health programs and agencies outside the health sector – in education, social care, and criminal justice. And finally, they wrote, "awareness programs and mobilization of potential stakeholders should be considered as part of any child and adolescent mental health service development."

The researchers noted as a limitation of their study a heterogeneity in the prevalence studies that prevented either direct comparisons between countries or meta-analytic approaches. Two of Dr. Rahman’s coauthors reported disclosures: Dr. Christian Kieling took part in meetings sponsored by Novartis, Shire, and Deva. Dr. Luis Augusto Rohde acted as speaker or consultant for Eli Lilly, Janssen-Cilag, Novartis, and Shire, and received program funding and research support from those companies.

There was no external funding, and each of the researchers contributed their time to the study.

A drug considered a breakthrough treatment for advanced melanoma has been turned down by England’s clinical and cost-effectiveness agency.

In first draft guidance issued Oct. 14, the National Institute for Health and Clinical Excellence, which makes recommendations to the National Health Service in England and Wales, said that it was not likely to recommend ipilimumab (Bristol-Myers Squibb’s Yervoy).

The agency cited cost concerns and what it called insufficient follow-up results from a manufacturer-sponsored, phase III, randomized, placebo-controlled trial of ipilimumab (n = 676). The drug, a monoclonal antibody, was shown to significantly improve overall survival in previously treated patients with unresectable stage II or IV melanomas (J. Clin. Oncol. 28:18s, 2010 [suppl; abstr 4]).

Subjects who received ipilimumab alone or with a peptide vaccine saw a median survival of about 10 months, compared with 6.4 months for those receiving only the vaccine. At 1 year follow up, between 44% and 46% of subjects in the ipilimumab arms had survived, compared with 25% in the vaccine-only arm, and at 2 years, between 22% and 24% in the ipilimumab arms had survived, compared with 14% in the vaccine-only arm.

"Ipilimumab is not a cost-effective use of NHS resources."

On the strength of these results, in patient groups for whom few effective treatments exist, the Food and Drug Administration fast-tracked its review of ipilimumab, approving it in March; the European Medicines Agency recommended it in May, and it has been available Europe-wide since July.

But NICE chief executive Andrew Dillon criticized the same results in a news release, saying that ipilimumab had not been compared to the drugs currently used to treat stage III or IV melanoma. (In U.K. practice, this is carboplatin-based chemotherapy, dacarbazine, or supportive care.)

Although the results, Mr. Dillon continued, "did show the drug could potentially be very effective for a small percentage of patients," the follow up from the trial "was too short to determine how long this effect would last."

Clinical specialists have advised NICE that about 30% of people treated with ipilimumab would have improved survival, with an estimated 10% potentially experiencing long-term benefits.

Currently no biomarkers have been established to identify patients who will benefit, Mr. Dillon said, and "ipilimumab currently costs around £80k per patient whether the treatment is effective for them or not." On the basis of evidence submitted so far, he said, "ipilimumab is not a cost-effective use of NHS resources."

NICE’s decision on ipilimumab is likely to be met with fierce criticism and appeals in the United Kingdom, where about 10,000 new cases of malignant melanoma are registered each year, a fifth of them in young adults between the ages of 15 and 39. Some 400-500 Britons with advanced melanoma have disease that has progressed on second-line treatment, NICE said. The 5-year survival rates are between 40% and 50% for stage III disease and 5%-15% for stage IV disease, where median survival is 6-9 months.

Ipilimumab is administered intravenously. It works by blocking the activity of CTLA-4, boosting and prolonging the body’s T-cell response against cancer cells. At £20k per dose, and four doses per course of treatment, NICE estimates the incremental cost effectiveness ratio for ipilimumab at between £54,000 and £70,000 per quality-adjusted life-year gained, based on current evidence.

NICE’s draft guidance on ipilimumab is open for comment until Nov. 4.

A drug considered a breakthrough treatment for advanced melanoma has been turned down by England’s clinical and cost-effectiveness agency.

In first draft guidance issued Oct. 14, the National Institute for Health and Clinical Excellence, which makes recommendations to the National Health Service in England and Wales, said that it was not likely to recommend ipilimumab (Bristol-Myers Squibb’s Yervoy).

The agency cited cost concerns and what it called insufficient follow-up results from a manufacturer-sponsored, phase III, randomized, placebo-controlled trial of ipilimumab (n = 676). The drug, a monoclonal antibody, was shown to significantly improve overall survival in previously treated patients with unresectable stage II or IV melanomas (J. Clin. Oncol. 28:18s, 2010 [suppl; abstr 4]).

Subjects who received ipilimumab alone or with a peptide vaccine saw a median survival of about 10 months, compared with 6.4 months for those receiving only the vaccine. At 1 year follow up, between 44% and 46% of subjects in the ipilimumab arms had survived, compared with 25% in the vaccine-only arm, and at 2 years, between 22% and 24% in the ipilimumab arms had survived, compared with 14% in the vaccine-only arm.

"Ipilimumab is not a cost-effective use of NHS resources."

On the strength of these results, in patient groups for whom few effective treatments exist, the Food and Drug Administration fast-tracked its review of ipilimumab, approving it in March; the European Medicines Agency recommended it in May, and it has been available Europe-wide since July.

But NICE chief executive Andrew Dillon criticized the same results in a news release, saying that ipilimumab had not been compared to the drugs currently used to treat stage III or IV melanoma. (In U.K. practice, this is carboplatin-based chemotherapy, dacarbazine, or supportive care.)

Although the results, Mr. Dillon continued, "did show the drug could potentially be very effective for a small percentage of patients," the follow up from the trial "was too short to determine how long this effect would last."

Clinical specialists have advised NICE that about 30% of people treated with ipilimumab would have improved survival, with an estimated 10% potentially experiencing long-term benefits.

Currently no biomarkers have been established to identify patients who will benefit, Mr. Dillon said, and "ipilimumab currently costs around £80k per patient whether the treatment is effective for them or not." On the basis of evidence submitted so far, he said, "ipilimumab is not a cost-effective use of NHS resources."

NICE’s decision on ipilimumab is likely to be met with fierce criticism and appeals in the United Kingdom, where about 10,000 new cases of malignant melanoma are registered each year, a fifth of them in young adults between the ages of 15 and 39. Some 400-500 Britons with advanced melanoma have disease that has progressed on second-line treatment, NICE said. The 5-year survival rates are between 40% and 50% for stage III disease and 5%-15% for stage IV disease, where median survival is 6-9 months.

Ipilimumab is administered intravenously. It works by blocking the activity of CTLA-4, boosting and prolonging the body’s T-cell response against cancer cells. At £20k per dose, and four doses per course of treatment, NICE estimates the incremental cost effectiveness ratio for ipilimumab at between £54,000 and £70,000 per quality-adjusted life-year gained, based on current evidence.

NICE’s draft guidance on ipilimumab is open for comment until Nov. 4.

A drug considered a breakthrough treatment for advanced melanoma has been turned down by England’s clinical and cost-effectiveness agency.

In first draft guidance issued Oct. 14, the National Institute for Health and Clinical Excellence, which makes recommendations to the National Health Service in England and Wales, said that it was not likely to recommend ipilimumab (Bristol-Myers Squibb’s Yervoy).

The agency cited cost concerns and what it called insufficient follow-up results from a manufacturer-sponsored, phase III, randomized, placebo-controlled trial of ipilimumab (n = 676). The drug, a monoclonal antibody, was shown to significantly improve overall survival in previously treated patients with unresectable stage II or IV melanomas (J. Clin. Oncol. 28:18s, 2010 [suppl; abstr 4]).

Subjects who received ipilimumab alone or with a peptide vaccine saw a median survival of about 10 months, compared with 6.4 months for those receiving only the vaccine. At 1 year follow up, between 44% and 46% of subjects in the ipilimumab arms had survived, compared with 25% in the vaccine-only arm, and at 2 years, between 22% and 24% in the ipilimumab arms had survived, compared with 14% in the vaccine-only arm.

"Ipilimumab is not a cost-effective use of NHS resources."

On the strength of these results, in patient groups for whom few effective treatments exist, the Food and Drug Administration fast-tracked its review of ipilimumab, approving it in March; the European Medicines Agency recommended it in May, and it has been available Europe-wide since July.

But NICE chief executive Andrew Dillon criticized the same results in a news release, saying that ipilimumab had not been compared to the drugs currently used to treat stage III or IV melanoma. (In U.K. practice, this is carboplatin-based chemotherapy, dacarbazine, or supportive care.)

Although the results, Mr. Dillon continued, "did show the drug could potentially be very effective for a small percentage of patients," the follow up from the trial "was too short to determine how long this effect would last."

Clinical specialists have advised NICE that about 30% of people treated with ipilimumab would have improved survival, with an estimated 10% potentially experiencing long-term benefits.

Currently no biomarkers have been established to identify patients who will benefit, Mr. Dillon said, and "ipilimumab currently costs around £80k per patient whether the treatment is effective for them or not." On the basis of evidence submitted so far, he said, "ipilimumab is not a cost-effective use of NHS resources."

NICE’s decision on ipilimumab is likely to be met with fierce criticism and appeals in the United Kingdom, where about 10,000 new cases of malignant melanoma are registered each year, a fifth of them in young adults between the ages of 15 and 39. Some 400-500 Britons with advanced melanoma have disease that has progressed on second-line treatment, NICE said. The 5-year survival rates are between 40% and 50% for stage III disease and 5%-15% for stage IV disease, where median survival is 6-9 months.

Ipilimumab is administered intravenously. It works by blocking the activity of CTLA-4, boosting and prolonging the body’s T-cell response against cancer cells. At £20k per dose, and four doses per course of treatment, NICE estimates the incremental cost effectiveness ratio for ipilimumab at between £54,000 and £70,000 per quality-adjusted life-year gained, based on current evidence.

NICE’s draft guidance on ipilimumab is open for comment until Nov. 4.

Asthmatics hospitalized during the H1N1 influenza pandemic had less-severe outcomes than did nonasthmatics, U.K. researchers have found.

People with asthma saw a lower risk of dying or requiring intensive care than did nonasthmatics, including people without any comorbidities. They were just as sick as nonasthmatics at admission. And the difference in outcomes could not be wholly ascribed to asthmatics’ use of inhaled steroids: Nonasthmatics taking inhaled steroids for other conditions did not see any protective effect.

A multivariate analysis showed asthma itself to be an independent factor for less-severe outcomes in patients hospitalized with H1N1.

This finding, from a prospective cohort of 1,520 people admitted to 75 different U.K. hospitals during the pandemic, was "surprising," said Dr. Malcolm Semple, the University of Liverpool, England, who presented his findings to the European Respiratory Society annual congress in Amsterdam.

However, it did align with recent results from a global analysis of 70,000 H1N1 patients, in which asthma was also seen to be associated with less severe outcomes (PLoS Med 2011;8:e1001053).

"Respiratory viruses cause exacerbations of asthma, and so it would be tempting to assume that these people were admitted with exacerbations of asthma – that they were less sick than the rest," Dr. Semple said in an interview. "But if anything, they were more sick, with more dyspnea and the same amount of radiological changes of pneumonia" as the other patients admitted to hospital.

"Do steroids protect everyone? No. But do steroids protect asthmatics? Emphatically, yes."

For their research, Dr. Semple and his colleagues used data from a prospective cohort in a study funded by the U.K. Department of Health during the H1N1 pandemic of 2009 and 2010. The cohort was used to provide real-time information on the pandemic and its clinical features to the Department of Health, and data collected were standardized to include information on age, comorbidities, inhaled steroid use, time from symptom onset to admission, and medications administered in hospital.

"It was something innovative that we had never tried before," Dr. Semple said of the cohort, adding that its large size "allowed us to catch this signal – it would be very hard to replicate this study in a non–pandemic situation."

The researchers found that the asthmatics, who comprised a quarter of the cohort (n = 385), were half as likely as nonasthmatics to die or require intensive care (11.2% vs. 19.8%; unadjusted odds ratio, 0.51) despite similar rates of pneumonia at admission.

Three variables – inhaled steroid use, admission within the first 4 days of symptoms, and systemic steroid use – were all seen as contributing to less severe outcomes for asthmatics. However, even after adjusting for these, simply having asthma was still associated with a 45% reduced likelihood of death or intensive care (adjusted OR, 0.55).

Asthmatics taking inhaled steroids were significantly less likely to die or require intensive care (7.4%) than were those not taking inhaled steroids (15.4%).

But inhaled steroids protected only the asthmatics in the study. About a fifth of the patients taking inhaled steroids were not taking them for asthma – and these patients saw no benefit, meaning that the findings do not support the use of inhaled corticosteroids in nonasthmatics.

"Do steroids protect everyone? No. But do steroids protect asthmatics? Emphatically, yes," Dr. Semple said. "The implication for practice is that, if you have a diagnosis of asthma, you should adhere to the published guidance if you’re a physician; and if you’re a patient, you should do as you’re told and take your steroids regularly."

Dr. Semple and his colleagues’ study was funded by the U.K. Department of Health. The researchers disclosed no conflicts of interest.

Asthmatics hospitalized during the H1N1 influenza pandemic had less-severe outcomes than did nonasthmatics, U.K. researchers have found.

People with asthma saw a lower risk of dying or requiring intensive care than did nonasthmatics, including people without any comorbidities. They were just as sick as nonasthmatics at admission. And the difference in outcomes could not be wholly ascribed to asthmatics’ use of inhaled steroids: Nonasthmatics taking inhaled steroids for other conditions did not see any protective effect.

A multivariate analysis showed asthma itself to be an independent factor for less-severe outcomes in patients hospitalized with H1N1.

This finding, from a prospective cohort of 1,520 people admitted to 75 different U.K. hospitals during the pandemic, was "surprising," said Dr. Malcolm Semple, the University of Liverpool, England, who presented his findings to the European Respiratory Society annual congress in Amsterdam.

However, it did align with recent results from a global analysis of 70,000 H1N1 patients, in which asthma was also seen to be associated with less severe outcomes (PLoS Med 2011;8:e1001053).

"Respiratory viruses cause exacerbations of asthma, and so it would be tempting to assume that these people were admitted with exacerbations of asthma – that they were less sick than the rest," Dr. Semple said in an interview. "But if anything, they were more sick, with more dyspnea and the same amount of radiological changes of pneumonia" as the other patients admitted to hospital.

"Do steroids protect everyone? No. But do steroids protect asthmatics? Emphatically, yes."

For their research, Dr. Semple and his colleagues used data from a prospective cohort in a study funded by the U.K. Department of Health during the H1N1 pandemic of 2009 and 2010. The cohort was used to provide real-time information on the pandemic and its clinical features to the Department of Health, and data collected were standardized to include information on age, comorbidities, inhaled steroid use, time from symptom onset to admission, and medications administered in hospital.

"It was something innovative that we had never tried before," Dr. Semple said of the cohort, adding that its large size "allowed us to catch this signal – it would be very hard to replicate this study in a non–pandemic situation."

The researchers found that the asthmatics, who comprised a quarter of the cohort (n = 385), were half as likely as nonasthmatics to die or require intensive care (11.2% vs. 19.8%; unadjusted odds ratio, 0.51) despite similar rates of pneumonia at admission.

Three variables – inhaled steroid use, admission within the first 4 days of symptoms, and systemic steroid use – were all seen as contributing to less severe outcomes for asthmatics. However, even after adjusting for these, simply having asthma was still associated with a 45% reduced likelihood of death or intensive care (adjusted OR, 0.55).

Asthmatics taking inhaled steroids were significantly less likely to die or require intensive care (7.4%) than were those not taking inhaled steroids (15.4%).

But inhaled steroids protected only the asthmatics in the study. About a fifth of the patients taking inhaled steroids were not taking them for asthma – and these patients saw no benefit, meaning that the findings do not support the use of inhaled corticosteroids in nonasthmatics.

"Do steroids protect everyone? No. But do steroids protect asthmatics? Emphatically, yes," Dr. Semple said. "The implication for practice is that, if you have a diagnosis of asthma, you should adhere to the published guidance if you’re a physician; and if you’re a patient, you should do as you’re told and take your steroids regularly."

Dr. Semple and his colleagues’ study was funded by the U.K. Department of Health. The researchers disclosed no conflicts of interest.

Asthmatics hospitalized during the H1N1 influenza pandemic had less-severe outcomes than did nonasthmatics, U.K. researchers have found.

People with asthma saw a lower risk of dying or requiring intensive care than did nonasthmatics, including people without any comorbidities. They were just as sick as nonasthmatics at admission. And the difference in outcomes could not be wholly ascribed to asthmatics’ use of inhaled steroids: Nonasthmatics taking inhaled steroids for other conditions did not see any protective effect.

A multivariate analysis showed asthma itself to be an independent factor for less-severe outcomes in patients hospitalized with H1N1.

This finding, from a prospective cohort of 1,520 people admitted to 75 different U.K. hospitals during the pandemic, was "surprising," said Dr. Malcolm Semple, the University of Liverpool, England, who presented his findings to the European Respiratory Society annual congress in Amsterdam.

However, it did align with recent results from a global analysis of 70,000 H1N1 patients, in which asthma was also seen to be associated with less severe outcomes (PLoS Med 2011;8:e1001053).

"Respiratory viruses cause exacerbations of asthma, and so it would be tempting to assume that these people were admitted with exacerbations of asthma – that they were less sick than the rest," Dr. Semple said in an interview. "But if anything, they were more sick, with more dyspnea and the same amount of radiological changes of pneumonia" as the other patients admitted to hospital.

"Do steroids protect everyone? No. But do steroids protect asthmatics? Emphatically, yes."

For their research, Dr. Semple and his colleagues used data from a prospective cohort in a study funded by the U.K. Department of Health during the H1N1 pandemic of 2009 and 2010. The cohort was used to provide real-time information on the pandemic and its clinical features to the Department of Health, and data collected were standardized to include information on age, comorbidities, inhaled steroid use, time from symptom onset to admission, and medications administered in hospital.

"It was something innovative that we had never tried before," Dr. Semple said of the cohort, adding that its large size "allowed us to catch this signal – it would be very hard to replicate this study in a non–pandemic situation."

The researchers found that the asthmatics, who comprised a quarter of the cohort (n = 385), were half as likely as nonasthmatics to die or require intensive care (11.2% vs. 19.8%; unadjusted odds ratio, 0.51) despite similar rates of pneumonia at admission.

Three variables – inhaled steroid use, admission within the first 4 days of symptoms, and systemic steroid use – were all seen as contributing to less severe outcomes for asthmatics. However, even after adjusting for these, simply having asthma was still associated with a 45% reduced likelihood of death or intensive care (adjusted OR, 0.55).

Asthmatics taking inhaled steroids were significantly less likely to die or require intensive care (7.4%) than were those not taking inhaled steroids (15.4%).

But inhaled steroids protected only the asthmatics in the study. About a fifth of the patients taking inhaled steroids were not taking them for asthma – and these patients saw no benefit, meaning that the findings do not support the use of inhaled corticosteroids in nonasthmatics.

"Do steroids protect everyone? No. But do steroids protect asthmatics? Emphatically, yes," Dr. Semple said. "The implication for practice is that, if you have a diagnosis of asthma, you should adhere to the published guidance if you’re a physician; and if you’re a patient, you should do as you’re told and take your steroids regularly."

Dr. Semple and his colleagues’ study was funded by the U.K. Department of Health. The researchers disclosed no conflicts of interest.

With European measles cases at more than 28,000 so far this year, the World Health Organization and the European Center for Disease Prevention and Control acknowledge that Europe’s goal of eliminating measles by 2015 – a deadline already extended from 2010 – is looking increasingly remote.

Instead, WHO now says, "a truly [European] region-wide epidemic is underway," thanks to suboptimal vaccine coverage in large swaths of western Europe. More than half of this year’s measles cases, and the lion’s share of recorded measles fatalities, are in France.

Photo credit: CDC/Dr. Heinz F. Eichenwald

Now, WHO and ECDC are targeting clinicians in their efforts to stem the measles tide, finding them both part of the problem and the likeliest hope of a solution.

"Providers hold the information parents want," said Robb Butler, a WHO technical officer developing communications strategies for increasing uptake of measles, mumps, and rubella vaccine (MMR) in Europe. "They’re also agents of change. But having information and being agents of change require different skills." The latter, he said, "is the piece that may be missing at the moment."

Writing in the journal Eurosurveillance late last month, Dr. Pier Luigi Lopalco, head of the ECDC’s vaccine-preventable diseases program, and ECDC director Marc Sprenger made a case that pediatricians and family practice physicians made up "the backbone" of MMR programs in the EU (Euro. Surveill. 2011;16:pii 19979). They also cited a study that found clinicians to be more trusted sources of vaccination information than governments (Vaccine 2010;28:4235-48). And yet clinicians, they argued, weren’t advocating effectively for vaccination.

In their editorial, Dr. Lopalco and Dr. Sprenger cited a 10-year old study from France’s public health agency suggesting that a significant minority of French family doctors were not, in fact, strongly supportive of MMR vaccinations; this message, they surmised, may have rubbed off in recent years. However, they also cited a more recent U.K. study in which clinicians who delivered pro-vaccination messages too stridently were questioned by patients about their motives (BMC Public Health 2007;7:42), suggesting that the problem was more complex.

Mr. Butler said that clinicians aren’t always natural communicators and that fast improvement on this front will be essential to meeting vaccination coverage goals.

"For the most part, it’s not about providers being convinced," he said. "It’s about how to better package the message." Often, clinicians and other health care workers find themselves too busy, he said, to engage in the type of dialogue that is needed to increase uptake among the 5%-20% of people reluctant to vaccinate.

Clinicians "can put things in technical terms expertly, and can sit in workshops and tell you every last thing about the safety of the MMR vaccines," Mr. Butler said, but something may not be translating in the clinic.

Mr. Butler said that that WHO’s efforts to engage physicians are part of a revamping of its approach to MMR outreach that focuses less on broadly informing the general population and more on pinpointing areas where the message hasn’t penetrated. "We’ll never reach the goal of measles elimination with traditional information campaigns alone," he said.

One of WHO’s new communications strategies for MMR involves using the Internet and social media to identify physicians skeptical of MMR or who have trouble encouraging uptake, and to engage them, Mr. Butler said. "We’re bringing provider focus into the spotlight," he said. "But it’s crucial that we now act upon it, to be a voice for them, and to talk to them about their barriers and their concerns."

So far WHO’s new-media strategies have been aimed at English- and Russian-speaking communities. Mr. Butler also said that his WHO team, along with representatives from ECDC, is planning a mission to France this year, he said, to talk about novel communications strategies there for MMR, including clinician concerns.

"Editorials are good and well," Mr. Butler said. "But now we need their side of the story."

With European measles cases at more than 28,000 so far this year, the World Health Organization and the European Center for Disease Prevention and Control acknowledge that Europe’s goal of eliminating measles by 2015 – a deadline already extended from 2010 – is looking increasingly remote.

Instead, WHO now says, "a truly [European] region-wide epidemic is underway," thanks to suboptimal vaccine coverage in large swaths of western Europe. More than half of this year’s measles cases, and the lion’s share of recorded measles fatalities, are in France.

Photo credit: CDC/Dr. Heinz F. Eichenwald

Now, WHO and ECDC are targeting clinicians in their efforts to stem the measles tide, finding them both part of the problem and the likeliest hope of a solution.

"Providers hold the information parents want," said Robb Butler, a WHO technical officer developing communications strategies for increasing uptake of measles, mumps, and rubella vaccine (MMR) in Europe. "They’re also agents of change. But having information and being agents of change require different skills." The latter, he said, "is the piece that may be missing at the moment."

Writing in the journal Eurosurveillance late last month, Dr. Pier Luigi Lopalco, head of the ECDC’s vaccine-preventable diseases program, and ECDC director Marc Sprenger made a case that pediatricians and family practice physicians made up "the backbone" of MMR programs in the EU (Euro. Surveill. 2011;16:pii 19979). They also cited a study that found clinicians to be more trusted sources of vaccination information than governments (Vaccine 2010;28:4235-48). And yet clinicians, they argued, weren’t advocating effectively for vaccination.

In their editorial, Dr. Lopalco and Dr. Sprenger cited a 10-year old study from France’s public health agency suggesting that a significant minority of French family doctors were not, in fact, strongly supportive of MMR vaccinations; this message, they surmised, may have rubbed off in recent years. However, they also cited a more recent U.K. study in which clinicians who delivered pro-vaccination messages too stridently were questioned by patients about their motives (BMC Public Health 2007;7:42), suggesting that the problem was more complex.

Mr. Butler said that clinicians aren’t always natural communicators and that fast improvement on this front will be essential to meeting vaccination coverage goals.

"For the most part, it’s not about providers being convinced," he said. "It’s about how to better package the message." Often, clinicians and other health care workers find themselves too busy, he said, to engage in the type of dialogue that is needed to increase uptake among the 5%-20% of people reluctant to vaccinate.

Clinicians "can put things in technical terms expertly, and can sit in workshops and tell you every last thing about the safety of the MMR vaccines," Mr. Butler said, but something may not be translating in the clinic.

Mr. Butler said that that WHO’s efforts to engage physicians are part of a revamping of its approach to MMR outreach that focuses less on broadly informing the general population and more on pinpointing areas where the message hasn’t penetrated. "We’ll never reach the goal of measles elimination with traditional information campaigns alone," he said.

One of WHO’s new communications strategies for MMR involves using the Internet and social media to identify physicians skeptical of MMR or who have trouble encouraging uptake, and to engage them, Mr. Butler said. "We’re bringing provider focus into the spotlight," he said. "But it’s crucial that we now act upon it, to be a voice for them, and to talk to them about their barriers and their concerns."

So far WHO’s new-media strategies have been aimed at English- and Russian-speaking communities. Mr. Butler also said that his WHO team, along with representatives from ECDC, is planning a mission to France this year, he said, to talk about novel communications strategies there for MMR, including clinician concerns.

"Editorials are good and well," Mr. Butler said. "But now we need their side of the story."

With European measles cases at more than 28,000 so far this year, the World Health Organization and the European Center for Disease Prevention and Control acknowledge that Europe’s goal of eliminating measles by 2015 – a deadline already extended from 2010 – is looking increasingly remote.

Instead, WHO now says, "a truly [European] region-wide epidemic is underway," thanks to suboptimal vaccine coverage in large swaths of western Europe. More than half of this year’s measles cases, and the lion’s share of recorded measles fatalities, are in France.

Photo credit: CDC/Dr. Heinz F. Eichenwald

Now, WHO and ECDC are targeting clinicians in their efforts to stem the measles tide, finding them both part of the problem and the likeliest hope of a solution.

"Providers hold the information parents want," said Robb Butler, a WHO technical officer developing communications strategies for increasing uptake of measles, mumps, and rubella vaccine (MMR) in Europe. "They’re also agents of change. But having information and being agents of change require different skills." The latter, he said, "is the piece that may be missing at the moment."

Writing in the journal Eurosurveillance late last month, Dr. Pier Luigi Lopalco, head of the ECDC’s vaccine-preventable diseases program, and ECDC director Marc Sprenger made a case that pediatricians and family practice physicians made up "the backbone" of MMR programs in the EU (Euro. Surveill. 2011;16:pii 19979). They also cited a study that found clinicians to be more trusted sources of vaccination information than governments (Vaccine 2010;28:4235-48). And yet clinicians, they argued, weren’t advocating effectively for vaccination.

In their editorial, Dr. Lopalco and Dr. Sprenger cited a 10-year old study from France’s public health agency suggesting that a significant minority of French family doctors were not, in fact, strongly supportive of MMR vaccinations; this message, they surmised, may have rubbed off in recent years. However, they also cited a more recent U.K. study in which clinicians who delivered pro-vaccination messages too stridently were questioned by patients about their motives (BMC Public Health 2007;7:42), suggesting that the problem was more complex.

Mr. Butler said that clinicians aren’t always natural communicators and that fast improvement on this front will be essential to meeting vaccination coverage goals.

"For the most part, it’s not about providers being convinced," he said. "It’s about how to better package the message." Often, clinicians and other health care workers find themselves too busy, he said, to engage in the type of dialogue that is needed to increase uptake among the 5%-20% of people reluctant to vaccinate.

Clinicians "can put things in technical terms expertly, and can sit in workshops and tell you every last thing about the safety of the MMR vaccines," Mr. Butler said, but something may not be translating in the clinic.

Mr. Butler said that that WHO’s efforts to engage physicians are part of a revamping of its approach to MMR outreach that focuses less on broadly informing the general population and more on pinpointing areas where the message hasn’t penetrated. "We’ll never reach the goal of measles elimination with traditional information campaigns alone," he said.

One of WHO’s new communications strategies for MMR involves using the Internet and social media to identify physicians skeptical of MMR or who have trouble encouraging uptake, and to engage them, Mr. Butler said. "We’re bringing provider focus into the spotlight," he said. "But it’s crucial that we now act upon it, to be a voice for them, and to talk to them about their barriers and their concerns."

So far WHO’s new-media strategies have been aimed at English- and Russian-speaking communities. Mr. Butler also said that his WHO team, along with representatives from ECDC, is planning a mission to France this year, he said, to talk about novel communications strategies there for MMR, including clinician concerns.

"Editorials are good and well," Mr. Butler said. "But now we need their side of the story."

More than a tenth of parents did not follow nationally recommended schedules for vaccinating their young children, according to results from a survey-based study published online Oct. 3 in Pediatrics.

Moreover, about a quarter (22%) of the parents of the 748 children in the study who followed published schedules expressed doubts about the merits of doing so, a finding that suggests that they might change to alternative schedules in the future. In the sample of respondents with young children, not having a regular health care provider for the child was associated with a likelihood of using an alternative schedule (adjusted OR, 18.66).

For their research, Dr. Amanda F. Dempsey and her colleagues at the University of Michigan in Ann Arbor analyzed survey responses from randomly selected parents of children between 6 months and 6 years of age (Pediatrics 2011 [doi:10.1542/peds.2011-0400]).

The surveys collected information on vaccine uptake and scheduling, and also parents’ attitudes about vaccination. Alternative vaccination was defined as having even one alteration from the schedule recommended by the Centers for Disease Control and Prevention.

Photo credit: Micah Young/iStock.com

Of the 13% of parents who reported following a vaccination schedule different from that published by the CDC, 53% said they had refused only certain vaccines, and 55% said they had delayed some vaccines until the child was older than the recommended age. A majority – 61% – said that their main rationale for deviating from published schedules was because doing so seemed safer. Very few parents – 2% overall and 17% of alternative vaccinators – refused all vaccines for their children.

Despite such perceptions, delaying or skipping vaccinations has been shown to increase individual and community risks for vaccine-preventable diseases. It is nonetheless increasingly common: The study found more formerly schedule-abiding parents moving to alternative schedules (30%) than the other way around (11%).

Only 8% of alternative vaccinators, meanwhile, reported using alternative schedules described by physician proponents of alternative vaccination. Rather, 41% said that they had created the schedules themselves, and 15% said a friend had influenced them.

DTaP and polio vaccines (6% each) were the least likely to be skipped; H1N1 and seasonal influenza vaccines the most (86% and 76%, respectively). Some parents said they deviated from published schedules by extending the intervals between doses of scheduled multidose vaccines, most commonly measles-mumps-rubella (MMR) and DTaP.

In their analysis of their results, Dr. Dempsey and her colleagues questioned whether the association between not having a regular care provider and alternative vaccination was because parents had trouble locating providers who would cooperate with their plans, or because "parents who tend not to engage in regular health care for their children ... also tend to follow an alternative vaccination schedule." Another possibility, they wrote, was that parents missed or delayed doses because of difficulty accessing care.

The study found many providers not explicitly discouraging of alternative vaccination practices, with 40% alternative vaccinators reporting that their clinicians "seemed supportive" of their plans, and 22% saying that their clinicians had recommended alternative schedules to them.

While 30% of alternative vaccinators described their doctors as hesitant to endorse an alternative schedule, only a small number – 8% – said they sought different doctors after their regular providers appeared hostile to the idea.

One encouraging finding, Dr. Dempsey and her colleagues wrote, was that "a large proportion of alternative vaccinators agreed that under-vaccination of children increases the risk of infection and spread of disease." This suggests that "parents who are ‘on the fence’ about vaccination have views that might be modifiable through targeted educational approaches."

Dr. Dempsey and her colleagues described as weaknesses of their study the fact that its participants were registered by a research firm, and "might have differed from the general population with respect to education or baseline health status." Sample sizes for specific types of schedule alterations were also small.

The study, part of the C.S. Mott Children’s Hospital National Poll on Children’s Health, was funded by the Clinical Sciences Scholars Program at the University of Michigan.

Dr. Dempsey receives compensation for service on an advisory board for Merck related to male human papillomavirus vaccination; the company had no input into the design, implementation, analysis, or presentation of the results of this study, and Dr. Dempsey receives no research support from Merck. The other authors indicated they have no financial relationships relevant to this article.

More than a tenth of parents did not follow nationally recommended schedules for vaccinating their young children, according to results from a survey-based study published online Oct. 3 in Pediatrics.

Moreover, about a quarter (22%) of the parents of the 748 children in the study who followed published schedules expressed doubts about the merits of doing so, a finding that suggests that they might change to alternative schedules in the future. In the sample of respondents with young children, not having a regular health care provider for the child was associated with a likelihood of using an alternative schedule (adjusted OR, 18.66).

For their research, Dr. Amanda F. Dempsey and her colleagues at the University of Michigan in Ann Arbor analyzed survey responses from randomly selected parents of children between 6 months and 6 years of age (Pediatrics 2011 [doi:10.1542/peds.2011-0400]).

The surveys collected information on vaccine uptake and scheduling, and also parents’ attitudes about vaccination. Alternative vaccination was defined as having even one alteration from the schedule recommended by the Centers for Disease Control and Prevention.

Photo credit: Micah Young/iStock.com

Of the 13% of parents who reported following a vaccination schedule different from that published by the CDC, 53% said they had refused only certain vaccines, and 55% said they had delayed some vaccines until the child was older than the recommended age. A majority – 61% – said that their main rationale for deviating from published schedules was because doing so seemed safer. Very few parents – 2% overall and 17% of alternative vaccinators – refused all vaccines for their children.

Despite such perceptions, delaying or skipping vaccinations has been shown to increase individual and community risks for vaccine-preventable diseases. It is nonetheless increasingly common: The study found more formerly schedule-abiding parents moving to alternative schedules (30%) than the other way around (11%).

Only 8% of alternative vaccinators, meanwhile, reported using alternative schedules described by physician proponents of alternative vaccination. Rather, 41% said that they had created the schedules themselves, and 15% said a friend had influenced them.

DTaP and polio vaccines (6% each) were the least likely to be skipped; H1N1 and seasonal influenza vaccines the most (86% and 76%, respectively). Some parents said they deviated from published schedules by extending the intervals between doses of scheduled multidose vaccines, most commonly measles-mumps-rubella (MMR) and DTaP.

In their analysis of their results, Dr. Dempsey and her colleagues questioned whether the association between not having a regular care provider and alternative vaccination was because parents had trouble locating providers who would cooperate with their plans, or because "parents who tend not to engage in regular health care for their children ... also tend to follow an alternative vaccination schedule." Another possibility, they wrote, was that parents missed or delayed doses because of difficulty accessing care.

The study found many providers not explicitly discouraging of alternative vaccination practices, with 40% alternative vaccinators reporting that their clinicians "seemed supportive" of their plans, and 22% saying that their clinicians had recommended alternative schedules to them.

While 30% of alternative vaccinators described their doctors as hesitant to endorse an alternative schedule, only a small number – 8% – said they sought different doctors after their regular providers appeared hostile to the idea.

One encouraging finding, Dr. Dempsey and her colleagues wrote, was that "a large proportion of alternative vaccinators agreed that under-vaccination of children increases the risk of infection and spread of disease." This suggests that "parents who are ‘on the fence’ about vaccination have views that might be modifiable through targeted educational approaches."

Dr. Dempsey and her colleagues described as weaknesses of their study the fact that its participants were registered by a research firm, and "might have differed from the general population with respect to education or baseline health status." Sample sizes for specific types of schedule alterations were also small.

The study, part of the C.S. Mott Children’s Hospital National Poll on Children’s Health, was funded by the Clinical Sciences Scholars Program at the University of Michigan.

Dr. Dempsey receives compensation for service on an advisory board for Merck related to male human papillomavirus vaccination; the company had no input into the design, implementation, analysis, or presentation of the results of this study, and Dr. Dempsey receives no research support from Merck. The other authors indicated they have no financial relationships relevant to this article.

More than a tenth of parents did not follow nationally recommended schedules for vaccinating their young children, according to results from a survey-based study published online Oct. 3 in Pediatrics.

Moreover, about a quarter (22%) of the parents of the 748 children in the study who followed published schedules expressed doubts about the merits of doing so, a finding that suggests that they might change to alternative schedules in the future. In the sample of respondents with young children, not having a regular health care provider for the child was associated with a likelihood of using an alternative schedule (adjusted OR, 18.66).

For their research, Dr. Amanda F. Dempsey and her colleagues at the University of Michigan in Ann Arbor analyzed survey responses from randomly selected parents of children between 6 months and 6 years of age (Pediatrics 2011 [doi:10.1542/peds.2011-0400]).

The surveys collected information on vaccine uptake and scheduling, and also parents’ attitudes about vaccination. Alternative vaccination was defined as having even one alteration from the schedule recommended by the Centers for Disease Control and Prevention.

Photo credit: Micah Young/iStock.com

Of the 13% of parents who reported following a vaccination schedule different from that published by the CDC, 53% said they had refused only certain vaccines, and 55% said they had delayed some vaccines until the child was older than the recommended age. A majority – 61% – said that their main rationale for deviating from published schedules was because doing so seemed safer. Very few parents – 2% overall and 17% of alternative vaccinators – refused all vaccines for their children.

Despite such perceptions, delaying or skipping vaccinations has been shown to increase individual and community risks for vaccine-preventable diseases. It is nonetheless increasingly common: The study found more formerly schedule-abiding parents moving to alternative schedules (30%) than the other way around (11%).

Only 8% of alternative vaccinators, meanwhile, reported using alternative schedules described by physician proponents of alternative vaccination. Rather, 41% said that they had created the schedules themselves, and 15% said a friend had influenced them.

DTaP and polio vaccines (6% each) were the least likely to be skipped; H1N1 and seasonal influenza vaccines the most (86% and 76%, respectively). Some parents said they deviated from published schedules by extending the intervals between doses of scheduled multidose vaccines, most commonly measles-mumps-rubella (MMR) and DTaP.

In their analysis of their results, Dr. Dempsey and her colleagues questioned whether the association between not having a regular care provider and alternative vaccination was because parents had trouble locating providers who would cooperate with their plans, or because "parents who tend not to engage in regular health care for their children ... also tend to follow an alternative vaccination schedule." Another possibility, they wrote, was that parents missed or delayed doses because of difficulty accessing care.

The study found many providers not explicitly discouraging of alternative vaccination practices, with 40% alternative vaccinators reporting that their clinicians "seemed supportive" of their plans, and 22% saying that their clinicians had recommended alternative schedules to them.

While 30% of alternative vaccinators described their doctors as hesitant to endorse an alternative schedule, only a small number – 8% – said they sought different doctors after their regular providers appeared hostile to the idea.

One encouraging finding, Dr. Dempsey and her colleagues wrote, was that "a large proportion of alternative vaccinators agreed that under-vaccination of children increases the risk of infection and spread of disease." This suggests that "parents who are ‘on the fence’ about vaccination have views that might be modifiable through targeted educational approaches."

Dr. Dempsey and her colleagues described as weaknesses of their study the fact that its participants were registered by a research firm, and "might have differed from the general population with respect to education or baseline health status." Sample sizes for specific types of schedule alterations were also small.

The study, part of the C.S. Mott Children’s Hospital National Poll on Children’s Health, was funded by the Clinical Sciences Scholars Program at the University of Michigan.

Dr. Dempsey receives compensation for service on an advisory board for Merck related to male human papillomavirus vaccination; the company had no input into the design, implementation, analysis, or presentation of the results of this study, and Dr. Dempsey receives no research support from Merck. The other authors indicated they have no financial relationships relevant to this article.

Major Finding: Of 41 children given active treatment, 83.7% achieved at least an ACR Pedi 30 response, compared to 9.8% of 41 given placebo.

Data Source: A 15-day follow-up of 84 children with JIA who received either a single dose of canakinumab or placebo.

Disclosures: The study was funded by Novartis. Dr. Ruperto reported having no financial conflicts of interest. Two of his coinvestigators are Novartis shareholders and one is a Novartis employee.

BRUGES, BELGIUM – Canakinumab, an investigational interleukin-1b antibody also known as ACZ885, has been shown to lessen symptoms of systemic juvenile idiopathic arthritis more than placebo.

The medication, which has yet to be licensed in any country, is administered once a month by subcutaneous injection, instead of intravenous infusion.

The end point of the study was a reduction in disease activity by 30% according to American College of Rheumatology Pediatric criteria (ACR Pedi 30), which were modified for the study to include absence of fever, according to Dr. Nicolino Ruperto of the Pediatric Rheumatology International Trials Organization (PRINTO) and Istituto G Gaslini in Genoa, Italy.

Results from a phase III, manufacturer-sponsored, randomized controlled trial (n = 84) of canakinumab showed that a single injection of 4 mg/kg lessened symptoms by 30% or more in 83.7% of patients in the treatment arm (n = 43), compared with 9.8% in the placebo arm (n = 41), at 15 days (Pediatr. Rheum. 2011;9[Suppl 1]:O21).

Patients enrolled in the study were between 2 and 19 years old, with active disease but no macrophage activation syndrome.

For the study group as a whole, the mean disease duration was 3.4 years; mean CRP was 200.6 mg/L; mean number of active joints was 14.1; and mean prednisone equivalent therapy was 0.3 mg/kg per day.

Dr. Ruperto told the conference that the study participants had spiking intermittent fever at enrollment lasting at least 3 days, and they were allowed to continue on methotrexate or corticosteroids during the trial, but no biological agents besides the study medication.

A majority of patients in the treatment arm (67.4%) achieved ACR Pedi 50 improvement, compared with 4.9% for placebo, and about a third (32.6%) in the study arm saw improvement of ACR Pedi 100, compared with none for placebo. Both ACR Pedi 30 and ACR Pedi 50 responses with canakinumab remained significantly higher than with placebo at day 29.

Adverse events occurred in 55.8% of canakinumab and 39% of placebo patients. Dr. Ruperto said that the most frequently reported adverse events in the study group were upper respiratory problems and gastrointestinal complaints.

No patients discontinued the trial because of side effects; however, 6 patients in the treatment arm and 37 in the placebo arm discontinued because for lack of therapeutic effect.

Two deaths occurred in the study group after the completion of the trial, during the long-term follow-up period, Dr. Ruperto told the congress. Both deaths were due to macrophage activation syndrome; one complicated with sepsis and the other with pulmonary hypertension.

Major Finding: Of 41 children given active treatment, 83.7% achieved at least an ACR Pedi 30 response, compared to 9.8% of 41 given placebo.

Data Source: A 15-day follow-up of 84 children with JIA who received either a single dose of canakinumab or placebo.

Disclosures: The study was funded by Novartis. Dr. Ruperto reported having no financial conflicts of interest. Two of his coinvestigators are Novartis shareholders and one is a Novartis employee.

BRUGES, BELGIUM – Canakinumab, an investigational interleukin-1b antibody also known as ACZ885, has been shown to lessen symptoms of systemic juvenile idiopathic arthritis more than placebo.

The medication, which has yet to be licensed in any country, is administered once a month by subcutaneous injection, instead of intravenous infusion.

The end point of the study was a reduction in disease activity by 30% according to American College of Rheumatology Pediatric criteria (ACR Pedi 30), which were modified for the study to include absence of fever, according to Dr. Nicolino Ruperto of the Pediatric Rheumatology International Trials Organization (PRINTO) and Istituto G Gaslini in Genoa, Italy.

Results from a phase III, manufacturer-sponsored, randomized controlled trial (n = 84) of canakinumab showed that a single injection of 4 mg/kg lessened symptoms by 30% or more in 83.7% of patients in the treatment arm (n = 43), compared with 9.8% in the placebo arm (n = 41), at 15 days (Pediatr. Rheum. 2011;9[Suppl 1]:O21).

Patients enrolled in the study were between 2 and 19 years old, with active disease but no macrophage activation syndrome.

For the study group as a whole, the mean disease duration was 3.4 years; mean CRP was 200.6 mg/L; mean number of active joints was 14.1; and mean prednisone equivalent therapy was 0.3 mg/kg per day.

Dr. Ruperto told the conference that the study participants had spiking intermittent fever at enrollment lasting at least 3 days, and they were allowed to continue on methotrexate or corticosteroids during the trial, but no biological agents besides the study medication.

A majority of patients in the treatment arm (67.4%) achieved ACR Pedi 50 improvement, compared with 4.9% for placebo, and about a third (32.6%) in the study arm saw improvement of ACR Pedi 100, compared with none for placebo. Both ACR Pedi 30 and ACR Pedi 50 responses with canakinumab remained significantly higher than with placebo at day 29.

Adverse events occurred in 55.8% of canakinumab and 39% of placebo patients. Dr. Ruperto said that the most frequently reported adverse events in the study group were upper respiratory problems and gastrointestinal complaints.

No patients discontinued the trial because of side effects; however, 6 patients in the treatment arm and 37 in the placebo arm discontinued because for lack of therapeutic effect.

Two deaths occurred in the study group after the completion of the trial, during the long-term follow-up period, Dr. Ruperto told the congress. Both deaths were due to macrophage activation syndrome; one complicated with sepsis and the other with pulmonary hypertension.

Major Finding: Of 41 children given active treatment, 83.7% achieved at least an ACR Pedi 30 response, compared to 9.8% of 41 given placebo.

Data Source: A 15-day follow-up of 84 children with JIA who received either a single dose of canakinumab or placebo.

Disclosures: The study was funded by Novartis. Dr. Ruperto reported having no financial conflicts of interest. Two of his coinvestigators are Novartis shareholders and one is a Novartis employee.

BRUGES, BELGIUM – Canakinumab, an investigational interleukin-1b antibody also known as ACZ885, has been shown to lessen symptoms of systemic juvenile idiopathic arthritis more than placebo.

The medication, which has yet to be licensed in any country, is administered once a month by subcutaneous injection, instead of intravenous infusion.

The end point of the study was a reduction in disease activity by 30% according to American College of Rheumatology Pediatric criteria (ACR Pedi 30), which were modified for the study to include absence of fever, according to Dr. Nicolino Ruperto of the Pediatric Rheumatology International Trials Organization (PRINTO) and Istituto G Gaslini in Genoa, Italy.

Results from a phase III, manufacturer-sponsored, randomized controlled trial (n = 84) of canakinumab showed that a single injection of 4 mg/kg lessened symptoms by 30% or more in 83.7% of patients in the treatment arm (n = 43), compared with 9.8% in the placebo arm (n = 41), at 15 days (Pediatr. Rheum. 2011;9[Suppl 1]:O21).

Patients enrolled in the study were between 2 and 19 years old, with active disease but no macrophage activation syndrome.

For the study group as a whole, the mean disease duration was 3.4 years; mean CRP was 200.6 mg/L; mean number of active joints was 14.1; and mean prednisone equivalent therapy was 0.3 mg/kg per day.

Dr. Ruperto told the conference that the study participants had spiking intermittent fever at enrollment lasting at least 3 days, and they were allowed to continue on methotrexate or corticosteroids during the trial, but no biological agents besides the study medication.

A majority of patients in the treatment arm (67.4%) achieved ACR Pedi 50 improvement, compared with 4.9% for placebo, and about a third (32.6%) in the study arm saw improvement of ACR Pedi 100, compared with none for placebo. Both ACR Pedi 30 and ACR Pedi 50 responses with canakinumab remained significantly higher than with placebo at day 29.

Adverse events occurred in 55.8% of canakinumab and 39% of placebo patients. Dr. Ruperto said that the most frequently reported adverse events in the study group were upper respiratory problems and gastrointestinal complaints.

No patients discontinued the trial because of side effects; however, 6 patients in the treatment arm and 37 in the placebo arm discontinued because for lack of therapeutic effect.

Two deaths occurred in the study group after the completion of the trial, during the long-term follow-up period, Dr. Ruperto told the congress. Both deaths were due to macrophage activation syndrome; one complicated with sepsis and the other with pulmonary hypertension.

BRUGES, BELGIUM – A normal physical examination may be all that it takes to confirm inactive disease in a child with juvenile-onset systemic lupus erythematosus, according to new criteria.

Dr. Rina Mina of Cincinnati Children's Medical Center said that she and her associates developed the criteria to determine clinical remission and clinically inactive disease in juvenile-onset systemic lupus erythematosus (JSLE), a complex disease. They used Delphi surveys of 210 pediatric rheumatologists. The senior author on the paper (Pediatr. Rheum. 2011;9[suppl. 1]:O17) was Dr. Hermine I. Brunner, also of Cincinnati Children's.

The surveys achieved consensus on four descriptors: clinically inactive disease – which is defined without regard to medications used – and clinical remission on medication (including steroids and immunosuppressants), clinical remission on preventive medication, and clinical remission off medication. Consensus was lowest – only 86% – on what defined clinical remission off medication, while consensus for the other categories was between 94% and 96%.

According to the criteria, a JSLE patient with either inactive disease or clinical remission “should have no signs of disease activity on physical examination,” Dr. Mina explained, adding that physical examination may ultimately prove to be enough to define inactivity. A patient with inactive disease or remission can have at most two nonlimiting symptoms such as headaches or fatigue.

Some select laboratory abnormalities can persist under either definition, she said, including a persistently positive antinuclear antibody test result, proteinuria from lupus-related kidney damage, or low levels of C4, for example. Members of the conference challenged Dr. Mina on the proteinuria, suggesting that it was dangerous to accept a patient with proteinuria as in remission; however, Dr. Mina argued that proteinuria was defined as a stable proteinuria as the result of damage, not a changing condition.

Use of preventive medication other than a steroid or immunosuppressant was defined as any medication to thwart disease progression or the development of disease-related damage. This category includes angiotensin-converting enzyme inhibitors, vitamin D, omega-3 acids, statins, and/or bisphosphonates. There was no consensus among the surveyed pediatric rheumatologists on whether nonsteroidal anti-inflammatory agents used daily could be considered preventive, Dr. Mina said at the meeting. Also lacking was any consensus on whether antimalarial drugs were to be considered preventive.

One of the key areas of consensus achieved by the surveys was that “inactive disease and clinical remission are distinct and should be differentiated from cure as well as from minimal disease activity,” Dr. Mina said. What was “crucial” in differentiating between inactive disease and clinical remission was the time frame. Clinical remission on medication or with preventive medication is defined as requiring 6 continuous months. The criteria, she noted, are similar to current American College of Rheumatology/European League Against Rheumatism criteria for defining clinically inactive disease and remission in juvenile idiopathic arthritis.

Remission off medication was defined as disease inactivity for at least 12 continuous months. Patients could be considered “off medication” if they were not being treated with steroids, immunosuppressants, or preventive medications; however, a patient could be treated with insulin to treat steroid-induced diabetes, for example, and still be included.

Dr. Mina reported that her group had validated the consensus definitions with a cohort of JSLE patients and had found the accuracy to be “outstanding” compared with scores from widely used disease indexes for JSLE. The new criteria surpassed both the SLE Disease Activity Index and the British Isles Lupus Assessment Group score in establishing inactive disease and remission. “All core parameters support the content validity of the consensus process,” she said.

Dr. Mina said she had no relevant financial disclosures.

BRUGES, BELGIUM – A normal physical examination may be all that it takes to confirm inactive disease in a child with juvenile-onset systemic lupus erythematosus, according to new criteria.

Dr. Rina Mina of Cincinnati Children's Medical Center said that she and her associates developed the criteria to determine clinical remission and clinically inactive disease in juvenile-onset systemic lupus erythematosus (JSLE), a complex disease. They used Delphi surveys of 210 pediatric rheumatologists. The senior author on the paper (Pediatr. Rheum. 2011;9[suppl. 1]:O17) was Dr. Hermine I. Brunner, also of Cincinnati Children's.

The surveys achieved consensus on four descriptors: clinically inactive disease – which is defined without regard to medications used – and clinical remission on medication (including steroids and immunosuppressants), clinical remission on preventive medication, and clinical remission off medication. Consensus was lowest – only 86% – on what defined clinical remission off medication, while consensus for the other categories was between 94% and 96%.

According to the criteria, a JSLE patient with either inactive disease or clinical remission “should have no signs of disease activity on physical examination,” Dr. Mina explained, adding that physical examination may ultimately prove to be enough to define inactivity. A patient with inactive disease or remission can have at most two nonlimiting symptoms such as headaches or fatigue.

Some select laboratory abnormalities can persist under either definition, she said, including a persistently positive antinuclear antibody test result, proteinuria from lupus-related kidney damage, or low levels of C4, for example. Members of the conference challenged Dr. Mina on the proteinuria, suggesting that it was dangerous to accept a patient with proteinuria as in remission; however, Dr. Mina argued that proteinuria was defined as a stable proteinuria as the result of damage, not a changing condition.

Use of preventive medication other than a steroid or immunosuppressant was defined as any medication to thwart disease progression or the development of disease-related damage. This category includes angiotensin-converting enzyme inhibitors, vitamin D, omega-3 acids, statins, and/or bisphosphonates. There was no consensus among the surveyed pediatric rheumatologists on whether nonsteroidal anti-inflammatory agents used daily could be considered preventive, Dr. Mina said at the meeting. Also lacking was any consensus on whether antimalarial drugs were to be considered preventive.

One of the key areas of consensus achieved by the surveys was that “inactive disease and clinical remission are distinct and should be differentiated from cure as well as from minimal disease activity,” Dr. Mina said. What was “crucial” in differentiating between inactive disease and clinical remission was the time frame. Clinical remission on medication or with preventive medication is defined as requiring 6 continuous months. The criteria, she noted, are similar to current American College of Rheumatology/European League Against Rheumatism criteria for defining clinically inactive disease and remission in juvenile idiopathic arthritis.

Remission off medication was defined as disease inactivity for at least 12 continuous months. Patients could be considered “off medication” if they were not being treated with steroids, immunosuppressants, or preventive medications; however, a patient could be treated with insulin to treat steroid-induced diabetes, for example, and still be included.

Dr. Mina reported that her group had validated the consensus definitions with a cohort of JSLE patients and had found the accuracy to be “outstanding” compared with scores from widely used disease indexes for JSLE. The new criteria surpassed both the SLE Disease Activity Index and the British Isles Lupus Assessment Group score in establishing inactive disease and remission. “All core parameters support the content validity of the consensus process,” she said.

Dr. Mina said she had no relevant financial disclosures.

BRUGES, BELGIUM – A normal physical examination may be all that it takes to confirm inactive disease in a child with juvenile-onset systemic lupus erythematosus, according to new criteria.

Dr. Rina Mina of Cincinnati Children's Medical Center said that she and her associates developed the criteria to determine clinical remission and clinically inactive disease in juvenile-onset systemic lupus erythematosus (JSLE), a complex disease. They used Delphi surveys of 210 pediatric rheumatologists. The senior author on the paper (Pediatr. Rheum. 2011;9[suppl. 1]:O17) was Dr. Hermine I. Brunner, also of Cincinnati Children's.

The surveys achieved consensus on four descriptors: clinically inactive disease – which is defined without regard to medications used – and clinical remission on medication (including steroids and immunosuppressants), clinical remission on preventive medication, and clinical remission off medication. Consensus was lowest – only 86% – on what defined clinical remission off medication, while consensus for the other categories was between 94% and 96%.

According to the criteria, a JSLE patient with either inactive disease or clinical remission “should have no signs of disease activity on physical examination,” Dr. Mina explained, adding that physical examination may ultimately prove to be enough to define inactivity. A patient with inactive disease or remission can have at most two nonlimiting symptoms such as headaches or fatigue.

Some select laboratory abnormalities can persist under either definition, she said, including a persistently positive antinuclear antibody test result, proteinuria from lupus-related kidney damage, or low levels of C4, for example. Members of the conference challenged Dr. Mina on the proteinuria, suggesting that it was dangerous to accept a patient with proteinuria as in remission; however, Dr. Mina argued that proteinuria was defined as a stable proteinuria as the result of damage, not a changing condition.

Use of preventive medication other than a steroid or immunosuppressant was defined as any medication to thwart disease progression or the development of disease-related damage. This category includes angiotensin-converting enzyme inhibitors, vitamin D, omega-3 acids, statins, and/or bisphosphonates. There was no consensus among the surveyed pediatric rheumatologists on whether nonsteroidal anti-inflammatory agents used daily could be considered preventive, Dr. Mina said at the meeting. Also lacking was any consensus on whether antimalarial drugs were to be considered preventive.

One of the key areas of consensus achieved by the surveys was that “inactive disease and clinical remission are distinct and should be differentiated from cure as well as from minimal disease activity,” Dr. Mina said. What was “crucial” in differentiating between inactive disease and clinical remission was the time frame. Clinical remission on medication or with preventive medication is defined as requiring 6 continuous months. The criteria, she noted, are similar to current American College of Rheumatology/European League Against Rheumatism criteria for defining clinically inactive disease and remission in juvenile idiopathic arthritis.

Remission off medication was defined as disease inactivity for at least 12 continuous months. Patients could be considered “off medication” if they were not being treated with steroids, immunosuppressants, or preventive medications; however, a patient could be treated with insulin to treat steroid-induced diabetes, for example, and still be included.

Dr. Mina reported that her group had validated the consensus definitions with a cohort of JSLE patients and had found the accuracy to be “outstanding” compared with scores from widely used disease indexes for JSLE. The new criteria surpassed both the SLE Disease Activity Index and the British Isles Lupus Assessment Group score in establishing inactive disease and remission. “All core parameters support the content validity of the consensus process,” she said.

Dr. Mina said she had no relevant financial disclosures.