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Study finds brivaracetam well tolerated but with unclear efficacy
Brivaracetam was found to be a safe and tolerable add-on treatment for uncontrolled epilepsy in adults, in a phase III, randomized, double-blind placebo-controlled trial.
This confirms findings from previous phase II trials of the investigational antiepileptic drug.
The current industry-sponsored study found similar rates of adverse events in the placebo and treatment groups. Efficacy endpoints were secondary in this trial; however, most of these did not reach statistical significance (Epilepsia 2013 Oct. 3 [doi:10.1111/epi.12391]).
Dr. Patrick Kwan, chair of neurology at the University of Melbourne, and his colleagues, recruited 480 adults with focal epilepsy (n = 431) subjects) or generalized epilepsy (n = 49) who were already taking one to three antiepileptic drugs, and randomized them (3:1) to brivaracetam or placebo. A total of 74 outpatient centers in 15 countries enrolled the patients between October 2007 and December 2008.
Doses of brivaracetam could begin at 20 mg/day, with titration up to 150 mg/day during an initial 8-week dose-finding period, after which fixed-dose treatment was continued for another 8 weeks. More than 70% of patients in the treatment group ended up on a dose of 100 mg or higher.
The 16-week study was completed by 90% of patients in the treatment group and 92% in the placebo group. Similar percentages of patients in the treatment (66%) and placebo groups (65%) reported adverse events, most frequently headache, somnolence, and dizziness, mostly in the dose-finding period. Patients with generalized seizures, a group for which treatment options are more limited, tolerated brivaracetam as well as did patients with focal seizures.
In patients with focal seizures, the baseline-adjusted percent reduction in seizure frequency per week in the brivaracetam group (n = 323) over the placebo group (n = 108) was 7.3% (P = .125) during the treatment period. The median percent reduction in baseline-adjusted seizure frequency per week was 26.9% for brivaracetam, compared with 18.9% for placebo (P = .070).
In the smaller group of patients with generalized seizures, seizure days per week decreased from 1.42 at baseline to 0.63 during the treatment period in the brivaracetam group and from 1.47 at baseline to 1.26 during the treatment period in placebo-treated patients.
One efficacy endpoint that did meet statistical significance was the 50% or higher responder rate in patients with focal seizures, which was 30.3% for the treatment group, compared with 16.7% for the placebo group (P = .006).
Dr. Kwan and his colleagues wrote in their analysis that both the 50% or higher responder rate and median percent reduction from baseline in the treatment group were comparable with findings from a study that evaluated brivaracetam at 50 mg/day and 150 mg/day (Epilepsia 2013;54:89-97), but lower than those reported in another study that investigated dosing up to 50 mg/day (Neurology 2010;75:519-25). The optimal dose "remains to be defined," they wrote.
Brivaracetam is an analogue of the antiepileptic drug levetiracetam, and was shown in preclinical studies to be a far more powerful inhibitor of seizures than levetiracetam. However, Dr. Kwan and his colleagues wrote, "the expected corresponding efficacy benefit was not observed in this study." Another phase III trial is currently in progress to determine the most efficacious dose of brivaracetam.
The investigators acknowledged the flexible dosing design as a limitation of their study, "which may hinder conclusions regarding efficacy." They also noted that the numbers of patients with generalized epilepsy included were small, meaning that any results from that group should be considered exploratory and approached with caution.
The study was funded by UCB Pharma, the manufacturer of brivaracetam. Dr. Kwan disclosed financial relationships with UCB and GlaxoSmithKline and having served on scientific advisory boards for Eisai. Dr. Kwan’s coauthors disclosed consulting, honoraria, or advisory relationships with UCB and many other companies marketing antiepileptic drugs. Two coauthors are employees of UCB.
Brivaracetam was found to be a safe and tolerable add-on treatment for uncontrolled epilepsy in adults, in a phase III, randomized, double-blind placebo-controlled trial.
This confirms findings from previous phase II trials of the investigational antiepileptic drug.
The current industry-sponsored study found similar rates of adverse events in the placebo and treatment groups. Efficacy endpoints were secondary in this trial; however, most of these did not reach statistical significance (Epilepsia 2013 Oct. 3 [doi:10.1111/epi.12391]).
Dr. Patrick Kwan, chair of neurology at the University of Melbourne, and his colleagues, recruited 480 adults with focal epilepsy (n = 431) subjects) or generalized epilepsy (n = 49) who were already taking one to three antiepileptic drugs, and randomized them (3:1) to brivaracetam or placebo. A total of 74 outpatient centers in 15 countries enrolled the patients between October 2007 and December 2008.
Doses of brivaracetam could begin at 20 mg/day, with titration up to 150 mg/day during an initial 8-week dose-finding period, after which fixed-dose treatment was continued for another 8 weeks. More than 70% of patients in the treatment group ended up on a dose of 100 mg or higher.
The 16-week study was completed by 90% of patients in the treatment group and 92% in the placebo group. Similar percentages of patients in the treatment (66%) and placebo groups (65%) reported adverse events, most frequently headache, somnolence, and dizziness, mostly in the dose-finding period. Patients with generalized seizures, a group for which treatment options are more limited, tolerated brivaracetam as well as did patients with focal seizures.
In patients with focal seizures, the baseline-adjusted percent reduction in seizure frequency per week in the brivaracetam group (n = 323) over the placebo group (n = 108) was 7.3% (P = .125) during the treatment period. The median percent reduction in baseline-adjusted seizure frequency per week was 26.9% for brivaracetam, compared with 18.9% for placebo (P = .070).
In the smaller group of patients with generalized seizures, seizure days per week decreased from 1.42 at baseline to 0.63 during the treatment period in the brivaracetam group and from 1.47 at baseline to 1.26 during the treatment period in placebo-treated patients.
One efficacy endpoint that did meet statistical significance was the 50% or higher responder rate in patients with focal seizures, which was 30.3% for the treatment group, compared with 16.7% for the placebo group (P = .006).
Dr. Kwan and his colleagues wrote in their analysis that both the 50% or higher responder rate and median percent reduction from baseline in the treatment group were comparable with findings from a study that evaluated brivaracetam at 50 mg/day and 150 mg/day (Epilepsia 2013;54:89-97), but lower than those reported in another study that investigated dosing up to 50 mg/day (Neurology 2010;75:519-25). The optimal dose "remains to be defined," they wrote.
Brivaracetam is an analogue of the antiepileptic drug levetiracetam, and was shown in preclinical studies to be a far more powerful inhibitor of seizures than levetiracetam. However, Dr. Kwan and his colleagues wrote, "the expected corresponding efficacy benefit was not observed in this study." Another phase III trial is currently in progress to determine the most efficacious dose of brivaracetam.
The investigators acknowledged the flexible dosing design as a limitation of their study, "which may hinder conclusions regarding efficacy." They also noted that the numbers of patients with generalized epilepsy included were small, meaning that any results from that group should be considered exploratory and approached with caution.
The study was funded by UCB Pharma, the manufacturer of brivaracetam. Dr. Kwan disclosed financial relationships with UCB and GlaxoSmithKline and having served on scientific advisory boards for Eisai. Dr. Kwan’s coauthors disclosed consulting, honoraria, or advisory relationships with UCB and many other companies marketing antiepileptic drugs. Two coauthors are employees of UCB.
Brivaracetam was found to be a safe and tolerable add-on treatment for uncontrolled epilepsy in adults, in a phase III, randomized, double-blind placebo-controlled trial.
This confirms findings from previous phase II trials of the investigational antiepileptic drug.
The current industry-sponsored study found similar rates of adverse events in the placebo and treatment groups. Efficacy endpoints were secondary in this trial; however, most of these did not reach statistical significance (Epilepsia 2013 Oct. 3 [doi:10.1111/epi.12391]).
Dr. Patrick Kwan, chair of neurology at the University of Melbourne, and his colleagues, recruited 480 adults with focal epilepsy (n = 431) subjects) or generalized epilepsy (n = 49) who were already taking one to three antiepileptic drugs, and randomized them (3:1) to brivaracetam or placebo. A total of 74 outpatient centers in 15 countries enrolled the patients between October 2007 and December 2008.
Doses of brivaracetam could begin at 20 mg/day, with titration up to 150 mg/day during an initial 8-week dose-finding period, after which fixed-dose treatment was continued for another 8 weeks. More than 70% of patients in the treatment group ended up on a dose of 100 mg or higher.
The 16-week study was completed by 90% of patients in the treatment group and 92% in the placebo group. Similar percentages of patients in the treatment (66%) and placebo groups (65%) reported adverse events, most frequently headache, somnolence, and dizziness, mostly in the dose-finding period. Patients with generalized seizures, a group for which treatment options are more limited, tolerated brivaracetam as well as did patients with focal seizures.
In patients with focal seizures, the baseline-adjusted percent reduction in seizure frequency per week in the brivaracetam group (n = 323) over the placebo group (n = 108) was 7.3% (P = .125) during the treatment period. The median percent reduction in baseline-adjusted seizure frequency per week was 26.9% for brivaracetam, compared with 18.9% for placebo (P = .070).
In the smaller group of patients with generalized seizures, seizure days per week decreased from 1.42 at baseline to 0.63 during the treatment period in the brivaracetam group and from 1.47 at baseline to 1.26 during the treatment period in placebo-treated patients.
One efficacy endpoint that did meet statistical significance was the 50% or higher responder rate in patients with focal seizures, which was 30.3% for the treatment group, compared with 16.7% for the placebo group (P = .006).
Dr. Kwan and his colleagues wrote in their analysis that both the 50% or higher responder rate and median percent reduction from baseline in the treatment group were comparable with findings from a study that evaluated brivaracetam at 50 mg/day and 150 mg/day (Epilepsia 2013;54:89-97), but lower than those reported in another study that investigated dosing up to 50 mg/day (Neurology 2010;75:519-25). The optimal dose "remains to be defined," they wrote.
Brivaracetam is an analogue of the antiepileptic drug levetiracetam, and was shown in preclinical studies to be a far more powerful inhibitor of seizures than levetiracetam. However, Dr. Kwan and his colleagues wrote, "the expected corresponding efficacy benefit was not observed in this study." Another phase III trial is currently in progress to determine the most efficacious dose of brivaracetam.
The investigators acknowledged the flexible dosing design as a limitation of their study, "which may hinder conclusions regarding efficacy." They also noted that the numbers of patients with generalized epilepsy included were small, meaning that any results from that group should be considered exploratory and approached with caution.
The study was funded by UCB Pharma, the manufacturer of brivaracetam. Dr. Kwan disclosed financial relationships with UCB and GlaxoSmithKline and having served on scientific advisory boards for Eisai. Dr. Kwan’s coauthors disclosed consulting, honoraria, or advisory relationships with UCB and many other companies marketing antiepileptic drugs. Two coauthors are employees of UCB.
FROM EPILEPSIA
Major finding: The median percent reduction in baseline-adjusted seizure frequency per week was 26.9% for brivaracetam, compared with 18.9% for placebo (P = .070).
Data source: A double-blind, randomized placebo-controlled trial of 480 patients with uncontrolled focal or generalized seizures.
Disclosures: The study was funded by UCB Pharma, the manufacturer of brivaracetam. Dr. Kwan disclosed financial relationships with UCB and GlaxoSmithKline and having served on scientific advisory boards for Eisai. Dr. Kwan’s coauthors disclosed consulting, honoraria, or advisory relationships with UCB and many other companies marketing antiepileptic drugs. Two coauthors are employees of UCB.
Varicella Vaccine: Two Doses are Better Than One
A two-dose varicella vaccination program, begun in 2006, has been shown to be more effective in promoting population immunity than the single-dose regimen introduced more than a decade earlier, in addition to further reducing disease severity and incidence.
Although the single-dose regimen, implemented in 1995, was associated with dramatic declines in varicella-related illness and deaths of 90% and 88%, respectively (Pediatrics 2011;128:214-20), a new study, published online Oct. 7 in Pediatrics showed that implementation of the two-dose scheme not only slashed cases further, but conferred protection even among unvaccinated infants and adults (Pediatrics 2013;132:1-7 [doi: 10.1542/peds.2013-0863]).
For their research, Dr. Stephanie R. Bialek of the National Center for Immunization and Respiratory Diseases, Atlanta, and her colleagues analyzed incidence rates and disease characteristics in two metropolitan centers totaling 650,000 in population between 1995 and 2010; one was a suburb of Los Angeles and the other was an inner-city area of Philadelphia. The study period covered the rollout of the single-dose vaccine and the two-dose scheme.
In 2010, the California surveillance area showed an incidence of 0.3 cases per 1,000 population, a decline of 76% since 2006 and a 97% decline from 1995. The Pennsylvania site, with 0.1 cases per 1,000, saw a 67% decline since 2006 and a 97% decline since 1995. From 2006 to 2010, 61.7% of case patients in both surveillance areas had been vaccinated with a single dose and 7.5% with two doses. Hospitalizations declined by half in both areas between 2006 and 2010.
Approximately 15%-20% of children do not adequately respond to a single dose of vaccine, Dr. Bialek and her colleagues noted, and the two surveillance areas continued to see outbreaks even after the single-dose scheme was in effect. About 65% of outbreak cases after 2007 in California had received one dose, and a larger proportion had milder disease (50 lesions or less) than in outbreaks earlier in the study period. During the two-dose period, the California surveillance area saw a fourfold decrease in outbreaks while the Pennsylvania area reported no outbreaks at all.
"The substantial declines in varicella incidence and outbreaks we report on from these two active surveillance areas during the first 5 years of the two-dose varicella vaccination program provide additional evidence of the program’s sustained impact," Dr. Bialek and her colleagues wrote in their analysis. "With full implementation of the two-dose varicella vaccination program, it may be possible to eliminate the most severe outcomes of varicella."
Dr. Bialek and her colleagues noted as limitations to their study the fact that not all cases reported in the study were laboratory confirmed, allowing for potential overreporting of cases and an underestimation of declines. They also acknowledged that some varicella cases may not have been reported, leading to overestimation of declines, and that their data sources for estimating two-dose coverage levels were limited.
The research was publicly funded, and none of the investigators reported conflicts of interest.
Dr. Bialek and her colleagues’ results definitively show that the current two-dose schedule is superior to the one-dose schedule, with decreased varicella disease among two-dose vaccine recipients, but perhaps even more encouraging, with decreased rates of varicella disease among adults and among groups who cannot receive the varicella vaccine (e.g., infants). This evidence of herd immunity is very promising. Prior to the varicella immunization program in the United States, 125 children each year died of chickenpox, and thousands of survivors were left with serious sequelae. We now can prevent that, and the work of Dr. Bialek and her colleagues clearly demonstrates this benefit.
Dr. David W. Kimberlin is codirector of the division of pediatric infectious diseases at the University of Alabama at Birmingham. He responded to a request to comment on Dr. Bialek and her colleagues’ article.
Dr. Bialek and her colleagues’ results definitively show that the current two-dose schedule is superior to the one-dose schedule, with decreased varicella disease among two-dose vaccine recipients, but perhaps even more encouraging, with decreased rates of varicella disease among adults and among groups who cannot receive the varicella vaccine (e.g., infants). This evidence of herd immunity is very promising. Prior to the varicella immunization program in the United States, 125 children each year died of chickenpox, and thousands of survivors were left with serious sequelae. We now can prevent that, and the work of Dr. Bialek and her colleagues clearly demonstrates this benefit.
Dr. David W. Kimberlin is codirector of the division of pediatric infectious diseases at the University of Alabama at Birmingham. He responded to a request to comment on Dr. Bialek and her colleagues’ article.
Dr. Bialek and her colleagues’ results definitively show that the current two-dose schedule is superior to the one-dose schedule, with decreased varicella disease among two-dose vaccine recipients, but perhaps even more encouraging, with decreased rates of varicella disease among adults and among groups who cannot receive the varicella vaccine (e.g., infants). This evidence of herd immunity is very promising. Prior to the varicella immunization program in the United States, 125 children each year died of chickenpox, and thousands of survivors were left with serious sequelae. We now can prevent that, and the work of Dr. Bialek and her colleagues clearly demonstrates this benefit.
Dr. David W. Kimberlin is codirector of the division of pediatric infectious diseases at the University of Alabama at Birmingham. He responded to a request to comment on Dr. Bialek and her colleagues’ article.
A two-dose varicella vaccination program, begun in 2006, has been shown to be more effective in promoting population immunity than the single-dose regimen introduced more than a decade earlier, in addition to further reducing disease severity and incidence.
Although the single-dose regimen, implemented in 1995, was associated with dramatic declines in varicella-related illness and deaths of 90% and 88%, respectively (Pediatrics 2011;128:214-20), a new study, published online Oct. 7 in Pediatrics showed that implementation of the two-dose scheme not only slashed cases further, but conferred protection even among unvaccinated infants and adults (Pediatrics 2013;132:1-7 [doi: 10.1542/peds.2013-0863]).
For their research, Dr. Stephanie R. Bialek of the National Center for Immunization and Respiratory Diseases, Atlanta, and her colleagues analyzed incidence rates and disease characteristics in two metropolitan centers totaling 650,000 in population between 1995 and 2010; one was a suburb of Los Angeles and the other was an inner-city area of Philadelphia. The study period covered the rollout of the single-dose vaccine and the two-dose scheme.
In 2010, the California surveillance area showed an incidence of 0.3 cases per 1,000 population, a decline of 76% since 2006 and a 97% decline from 1995. The Pennsylvania site, with 0.1 cases per 1,000, saw a 67% decline since 2006 and a 97% decline since 1995. From 2006 to 2010, 61.7% of case patients in both surveillance areas had been vaccinated with a single dose and 7.5% with two doses. Hospitalizations declined by half in both areas between 2006 and 2010.
Approximately 15%-20% of children do not adequately respond to a single dose of vaccine, Dr. Bialek and her colleagues noted, and the two surveillance areas continued to see outbreaks even after the single-dose scheme was in effect. About 65% of outbreak cases after 2007 in California had received one dose, and a larger proportion had milder disease (50 lesions or less) than in outbreaks earlier in the study period. During the two-dose period, the California surveillance area saw a fourfold decrease in outbreaks while the Pennsylvania area reported no outbreaks at all.
"The substantial declines in varicella incidence and outbreaks we report on from these two active surveillance areas during the first 5 years of the two-dose varicella vaccination program provide additional evidence of the program’s sustained impact," Dr. Bialek and her colleagues wrote in their analysis. "With full implementation of the two-dose varicella vaccination program, it may be possible to eliminate the most severe outcomes of varicella."
Dr. Bialek and her colleagues noted as limitations to their study the fact that not all cases reported in the study were laboratory confirmed, allowing for potential overreporting of cases and an underestimation of declines. They also acknowledged that some varicella cases may not have been reported, leading to overestimation of declines, and that their data sources for estimating two-dose coverage levels were limited.
The research was publicly funded, and none of the investigators reported conflicts of interest.
A two-dose varicella vaccination program, begun in 2006, has been shown to be more effective in promoting population immunity than the single-dose regimen introduced more than a decade earlier, in addition to further reducing disease severity and incidence.
Although the single-dose regimen, implemented in 1995, was associated with dramatic declines in varicella-related illness and deaths of 90% and 88%, respectively (Pediatrics 2011;128:214-20), a new study, published online Oct. 7 in Pediatrics showed that implementation of the two-dose scheme not only slashed cases further, but conferred protection even among unvaccinated infants and adults (Pediatrics 2013;132:1-7 [doi: 10.1542/peds.2013-0863]).
For their research, Dr. Stephanie R. Bialek of the National Center for Immunization and Respiratory Diseases, Atlanta, and her colleagues analyzed incidence rates and disease characteristics in two metropolitan centers totaling 650,000 in population between 1995 and 2010; one was a suburb of Los Angeles and the other was an inner-city area of Philadelphia. The study period covered the rollout of the single-dose vaccine and the two-dose scheme.
In 2010, the California surveillance area showed an incidence of 0.3 cases per 1,000 population, a decline of 76% since 2006 and a 97% decline from 1995. The Pennsylvania site, with 0.1 cases per 1,000, saw a 67% decline since 2006 and a 97% decline since 1995. From 2006 to 2010, 61.7% of case patients in both surveillance areas had been vaccinated with a single dose and 7.5% with two doses. Hospitalizations declined by half in both areas between 2006 and 2010.
Approximately 15%-20% of children do not adequately respond to a single dose of vaccine, Dr. Bialek and her colleagues noted, and the two surveillance areas continued to see outbreaks even after the single-dose scheme was in effect. About 65% of outbreak cases after 2007 in California had received one dose, and a larger proportion had milder disease (50 lesions or less) than in outbreaks earlier in the study period. During the two-dose period, the California surveillance area saw a fourfold decrease in outbreaks while the Pennsylvania area reported no outbreaks at all.
"The substantial declines in varicella incidence and outbreaks we report on from these two active surveillance areas during the first 5 years of the two-dose varicella vaccination program provide additional evidence of the program’s sustained impact," Dr. Bialek and her colleagues wrote in their analysis. "With full implementation of the two-dose varicella vaccination program, it may be possible to eliminate the most severe outcomes of varicella."
Dr. Bialek and her colleagues noted as limitations to their study the fact that not all cases reported in the study were laboratory confirmed, allowing for potential overreporting of cases and an underestimation of declines. They also acknowledged that some varicella cases may not have been reported, leading to overestimation of declines, and that their data sources for estimating two-dose coverage levels were limited.
The research was publicly funded, and none of the investigators reported conflicts of interest.
FROM PEDIATRICS
Varicella vaccine: Two doses are better than one
A two-dose varicella vaccination program, begun in 2006, has been shown to be more effective in promoting population immunity than the single-dose regimen introduced more than a decade earlier, in addition to further reducing disease severity and incidence.
Although the single-dose regimen, implemented in 1995, was associated with dramatic declines in varicella-related illness and deaths of 90% and 88%, respectively (Pediatrics 2011;128:214-20), a new study, published online Oct. 7 in Pediatrics showed that implementation of the two-dose scheme not only slashed cases further, but conferred protection even among unvaccinated infants and adults (Pediatrics 2013;132:1-7 [doi: 10.1542/peds.2013-0863]).
For their research, Dr. Stephanie R. Bialek of the National Center for Immunization and Respiratory Diseases, Atlanta, and her colleagues analyzed incidence rates and disease characteristics in two metropolitan centers totaling 650,000 in population between 1995 and 2010; one was a suburb of Los Angeles and the other was an inner-city area of Philadelphia. The study period covered the rollout of the single-dose vaccine and the two-dose scheme.
In 2010, the California surveillance area showed an incidence of 0.3 cases per 1,000 population, a decline of 76% since 2006 and a 97% decline from 1995. The Pennsylvania site, with 0.1 cases per 1,000, saw a 67% decline since 2006 and a 97% decline since 1995. From 2006 to 2010, 61.7% of case patients in both surveillance areas had been vaccinated with a single dose and 7.5% with two doses. Hospitalizations declined by half in both areas between 2006 and 2010.
Approximately 15%-20% of children do not adequately respond to a single dose of vaccine, Dr. Bialek and her colleagues noted, and the two surveillance areas continued to see outbreaks even after the single-dose scheme was in effect. About 65% of outbreak cases after 2007 in California had received one dose, and a larger proportion had milder disease (50 lesions or less) than in outbreaks earlier in the study period. During the two-dose period, the California surveillance area saw a fourfold decrease in outbreaks while the Pennsylvania area reported no outbreaks at all.
"The substantial declines in varicella incidence and outbreaks we report on from these two active surveillance areas during the first 5 years of the two-dose varicella vaccination program provide additional evidence of the program’s sustained impact," Dr. Bialek and her colleagues wrote in their analysis. "With full implementation of the two-dose varicella vaccination program, it may be possible to eliminate the most severe outcomes of varicella."
Dr. Bialek and her colleagues noted as limitations to their study the fact that not all cases reported in the study were laboratory confirmed, allowing for potential overreporting of cases and an underestimation of declines. They also acknowledged that some varicella cases may not have been reported, leading to overestimation of declines, and that their data sources for estimating two-dose coverage levels were limited.
The research was publicly funded, and none of the investigators reported conflicts of interest.
Dr. Bialek and her colleagues’ results definitively show that the current two-dose schedule is superior to the one-dose schedule, with decreased varicella disease among two-dose vaccine recipients, but perhaps even more encouraging, with decreased rates of varicella disease among adults and among groups who cannot receive the varicella vaccine (e.g., infants). This evidence of herd immunity is very promising. Prior to the varicella immunization program in the United States, 125 children each year died of chickenpox, and thousands of survivors were left with serious sequelae. We now can prevent that, and the work of Dr. Bialek and her colleagues clearly demonstrates this benefit.
Dr. David W. Kimberlin is codirector of the division of pediatric infectious diseases at the University of Alabama at Birmingham. He responded to a request to comment on Dr. Bialek and her colleagues’ article.
Dr. Bialek and her colleagues’ results definitively show that the current two-dose schedule is superior to the one-dose schedule, with decreased varicella disease among two-dose vaccine recipients, but perhaps even more encouraging, with decreased rates of varicella disease among adults and among groups who cannot receive the varicella vaccine (e.g., infants). This evidence of herd immunity is very promising. Prior to the varicella immunization program in the United States, 125 children each year died of chickenpox, and thousands of survivors were left with serious sequelae. We now can prevent that, and the work of Dr. Bialek and her colleagues clearly demonstrates this benefit.
Dr. David W. Kimberlin is codirector of the division of pediatric infectious diseases at the University of Alabama at Birmingham. He responded to a request to comment on Dr. Bialek and her colleagues’ article.
Dr. Bialek and her colleagues’ results definitively show that the current two-dose schedule is superior to the one-dose schedule, with decreased varicella disease among two-dose vaccine recipients, but perhaps even more encouraging, with decreased rates of varicella disease among adults and among groups who cannot receive the varicella vaccine (e.g., infants). This evidence of herd immunity is very promising. Prior to the varicella immunization program in the United States, 125 children each year died of chickenpox, and thousands of survivors were left with serious sequelae. We now can prevent that, and the work of Dr. Bialek and her colleagues clearly demonstrates this benefit.
Dr. David W. Kimberlin is codirector of the division of pediatric infectious diseases at the University of Alabama at Birmingham. He responded to a request to comment on Dr. Bialek and her colleagues’ article.
A two-dose varicella vaccination program, begun in 2006, has been shown to be more effective in promoting population immunity than the single-dose regimen introduced more than a decade earlier, in addition to further reducing disease severity and incidence.
Although the single-dose regimen, implemented in 1995, was associated with dramatic declines in varicella-related illness and deaths of 90% and 88%, respectively (Pediatrics 2011;128:214-20), a new study, published online Oct. 7 in Pediatrics showed that implementation of the two-dose scheme not only slashed cases further, but conferred protection even among unvaccinated infants and adults (Pediatrics 2013;132:1-7 [doi: 10.1542/peds.2013-0863]).
For their research, Dr. Stephanie R. Bialek of the National Center for Immunization and Respiratory Diseases, Atlanta, and her colleagues analyzed incidence rates and disease characteristics in two metropolitan centers totaling 650,000 in population between 1995 and 2010; one was a suburb of Los Angeles and the other was an inner-city area of Philadelphia. The study period covered the rollout of the single-dose vaccine and the two-dose scheme.
In 2010, the California surveillance area showed an incidence of 0.3 cases per 1,000 population, a decline of 76% since 2006 and a 97% decline from 1995. The Pennsylvania site, with 0.1 cases per 1,000, saw a 67% decline since 2006 and a 97% decline since 1995. From 2006 to 2010, 61.7% of case patients in both surveillance areas had been vaccinated with a single dose and 7.5% with two doses. Hospitalizations declined by half in both areas between 2006 and 2010.
Approximately 15%-20% of children do not adequately respond to a single dose of vaccine, Dr. Bialek and her colleagues noted, and the two surveillance areas continued to see outbreaks even after the single-dose scheme was in effect. About 65% of outbreak cases after 2007 in California had received one dose, and a larger proportion had milder disease (50 lesions or less) than in outbreaks earlier in the study period. During the two-dose period, the California surveillance area saw a fourfold decrease in outbreaks while the Pennsylvania area reported no outbreaks at all.
"The substantial declines in varicella incidence and outbreaks we report on from these two active surveillance areas during the first 5 years of the two-dose varicella vaccination program provide additional evidence of the program’s sustained impact," Dr. Bialek and her colleagues wrote in their analysis. "With full implementation of the two-dose varicella vaccination program, it may be possible to eliminate the most severe outcomes of varicella."
Dr. Bialek and her colleagues noted as limitations to their study the fact that not all cases reported in the study were laboratory confirmed, allowing for potential overreporting of cases and an underestimation of declines. They also acknowledged that some varicella cases may not have been reported, leading to overestimation of declines, and that their data sources for estimating two-dose coverage levels were limited.
The research was publicly funded, and none of the investigators reported conflicts of interest.
A two-dose varicella vaccination program, begun in 2006, has been shown to be more effective in promoting population immunity than the single-dose regimen introduced more than a decade earlier, in addition to further reducing disease severity and incidence.
Although the single-dose regimen, implemented in 1995, was associated with dramatic declines in varicella-related illness and deaths of 90% and 88%, respectively (Pediatrics 2011;128:214-20), a new study, published online Oct. 7 in Pediatrics showed that implementation of the two-dose scheme not only slashed cases further, but conferred protection even among unvaccinated infants and adults (Pediatrics 2013;132:1-7 [doi: 10.1542/peds.2013-0863]).
For their research, Dr. Stephanie R. Bialek of the National Center for Immunization and Respiratory Diseases, Atlanta, and her colleagues analyzed incidence rates and disease characteristics in two metropolitan centers totaling 650,000 in population between 1995 and 2010; one was a suburb of Los Angeles and the other was an inner-city area of Philadelphia. The study period covered the rollout of the single-dose vaccine and the two-dose scheme.
In 2010, the California surveillance area showed an incidence of 0.3 cases per 1,000 population, a decline of 76% since 2006 and a 97% decline from 1995. The Pennsylvania site, with 0.1 cases per 1,000, saw a 67% decline since 2006 and a 97% decline since 1995. From 2006 to 2010, 61.7% of case patients in both surveillance areas had been vaccinated with a single dose and 7.5% with two doses. Hospitalizations declined by half in both areas between 2006 and 2010.
Approximately 15%-20% of children do not adequately respond to a single dose of vaccine, Dr. Bialek and her colleagues noted, and the two surveillance areas continued to see outbreaks even after the single-dose scheme was in effect. About 65% of outbreak cases after 2007 in California had received one dose, and a larger proportion had milder disease (50 lesions or less) than in outbreaks earlier in the study period. During the two-dose period, the California surveillance area saw a fourfold decrease in outbreaks while the Pennsylvania area reported no outbreaks at all.
"The substantial declines in varicella incidence and outbreaks we report on from these two active surveillance areas during the first 5 years of the two-dose varicella vaccination program provide additional evidence of the program’s sustained impact," Dr. Bialek and her colleagues wrote in their analysis. "With full implementation of the two-dose varicella vaccination program, it may be possible to eliminate the most severe outcomes of varicella."
Dr. Bialek and her colleagues noted as limitations to their study the fact that not all cases reported in the study were laboratory confirmed, allowing for potential overreporting of cases and an underestimation of declines. They also acknowledged that some varicella cases may not have been reported, leading to overestimation of declines, and that their data sources for estimating two-dose coverage levels were limited.
The research was publicly funded, and none of the investigators reported conflicts of interest.
FROM PEDIATRICS
Major finding: Implementation of a two-dose varicella vaccine was associated with decreased disease incidence, hospitalizations, and outbreaks, compared with a prior single-dose regimen, and there was evidence of enhanced population immunity
Data source: Epidemiologic surveillance on two separate metropolitan regions totaling 650,000 in population over a 5-year study period.
Disclosures: The research was publicly funded, and none of the investigators reported conflicts of interest.
New apnea risk study: RSV is not the only culprit
A large prospective study of infants hospitalized for bronchiolitis has revealed a number of previously unknown risk factors associated with apnea, a potentially life-threatening complication.
While high preadmission respiratory rates were found associated with increased apnea risk, so were low respiratory rates, a surprising finding that investigators could not explain. Low room air oxygen saturation was seen as contributing to risk. And one usual-suspect risk factor in apnea – respiratory syncytial virus – turned out not to be more dangerous than other viruses in terms of apnea risk.
Clinicians should not be reassured by either a low respiratory rate or infection with an organism other than RSV in assessing apnea risk, said Dr. Alan R. Schroeder of the Santa Clara Medical Center in San Jose, Calif., and his colleagues.
At 16 study sites nationwide starting in 2007, the researchers collected enrollment and outcome data on 2,156 children under age 2 (median age 4 months, with age corrected for birth at less than 37 weeks). The patients were admitted with bronchiolitis over three consecutive winter seasons. Of these children, 108 (5%) developed apnea while hospitalized, according to the study, which was published online Oct. 7 in Pediatrics (2013;132:1-8 [doi: 10.1542/peds.2013-1501]). The study was part of the Multicenter Airway Research Collaboration, a program of the Emergency Medicine Network.
The study confirmed the known risk factors of young corrected age, low birth weight, and previous apnea during the same bronchiolitis episode. Dr. Schroeder and his colleagues found that the statistically significant predictors of apnea included age of less than 2 weeks (odds ratio, 9.67) and 2-8 weeks (OR, 4.72), compared with age 6 months or older; birth weight of less than 2.3 kg (OR, 2.15), compared with birth weight of 3.2 kg or more; and previous apnea during the same bronchiolitis episode (OR, 3.63).
There also was risk associated with preadmission respiratory rates of less than 30 (OR, 4.05) and 30-39 (OR, 2.35), compared with 40-49, as well as a preadmission respiratory rate of 70 or more (OR, 2.26). Risk of apnea was also associated with having a preadmission room air oxygen saturation of less than 90% (OR, 1.60).
Apnea risk was shown to be similar across the major viral infections seen in the cohort. While more infants presented with RSV than with other viruses, there was roughly equal apnea risk seen among children infected with human rhinovirus, adenovirus, human metapneumovirus, enterovirus, coronavirus, and parainfluenza virus.
"These data suggest that using RSV status to drive admission decisions and admission locations (e.g., ward, step-down unit, ICU) due to apnea concerns may be misguided," Dr. Schroeder and his colleagues wrote in their analysis.
The study contained a number of other novel findings. While a recent, smaller study of 42 patients had suggested a possible protective effect associated with acetaminophen administered the week before hospitalization (Resuscitation 2012;83:440-46), the study by Dr. Schroeder and his colleagues found no such effect.
It also shed light on the timing of apnea during the course of bronchiolitis. While previous studies had shown apnea occurring early in the course of RSV infection, "our results challenge this notion," the authors wrote. One-third of the infants with apnea in the study began having difficulty breathing 4 or more days before the preadmission visit. "Furthermore, the time from the beginning of the ‘difficulty breathing’ to the preadmission visit was not different between children with and without apnea. Therefore, using the duration of symptoms to predict future risk of apnea or need for hospitalization may be problematic."
The investigators acknowledged as limitations of their study the possibility that the reported incidence of apnea may have been biased by oversampling of sicker patients, as the investigators recruited 20% of patients from intensive care. Some infants may have been included based on chart data that did not meet strict criteria for apnea, allowing for overreporting, they said, and apnea may have been harder to detect in intubated patients, leading to underreporting in this population.
The study was funded by the National Institutes of Health. Dr. Schroeder and his colleagues reported no disclosures.
A large prospective study of infants hospitalized for bronchiolitis has revealed a number of previously unknown risk factors associated with apnea, a potentially life-threatening complication.
While high preadmission respiratory rates were found associated with increased apnea risk, so were low respiratory rates, a surprising finding that investigators could not explain. Low room air oxygen saturation was seen as contributing to risk. And one usual-suspect risk factor in apnea – respiratory syncytial virus – turned out not to be more dangerous than other viruses in terms of apnea risk.
Clinicians should not be reassured by either a low respiratory rate or infection with an organism other than RSV in assessing apnea risk, said Dr. Alan R. Schroeder of the Santa Clara Medical Center in San Jose, Calif., and his colleagues.
At 16 study sites nationwide starting in 2007, the researchers collected enrollment and outcome data on 2,156 children under age 2 (median age 4 months, with age corrected for birth at less than 37 weeks). The patients were admitted with bronchiolitis over three consecutive winter seasons. Of these children, 108 (5%) developed apnea while hospitalized, according to the study, which was published online Oct. 7 in Pediatrics (2013;132:1-8 [doi: 10.1542/peds.2013-1501]). The study was part of the Multicenter Airway Research Collaboration, a program of the Emergency Medicine Network.
The study confirmed the known risk factors of young corrected age, low birth weight, and previous apnea during the same bronchiolitis episode. Dr. Schroeder and his colleagues found that the statistically significant predictors of apnea included age of less than 2 weeks (odds ratio, 9.67) and 2-8 weeks (OR, 4.72), compared with age 6 months or older; birth weight of less than 2.3 kg (OR, 2.15), compared with birth weight of 3.2 kg or more; and previous apnea during the same bronchiolitis episode (OR, 3.63).
There also was risk associated with preadmission respiratory rates of less than 30 (OR, 4.05) and 30-39 (OR, 2.35), compared with 40-49, as well as a preadmission respiratory rate of 70 or more (OR, 2.26). Risk of apnea was also associated with having a preadmission room air oxygen saturation of less than 90% (OR, 1.60).
Apnea risk was shown to be similar across the major viral infections seen in the cohort. While more infants presented with RSV than with other viruses, there was roughly equal apnea risk seen among children infected with human rhinovirus, adenovirus, human metapneumovirus, enterovirus, coronavirus, and parainfluenza virus.
"These data suggest that using RSV status to drive admission decisions and admission locations (e.g., ward, step-down unit, ICU) due to apnea concerns may be misguided," Dr. Schroeder and his colleagues wrote in their analysis.
The study contained a number of other novel findings. While a recent, smaller study of 42 patients had suggested a possible protective effect associated with acetaminophen administered the week before hospitalization (Resuscitation 2012;83:440-46), the study by Dr. Schroeder and his colleagues found no such effect.
It also shed light on the timing of apnea during the course of bronchiolitis. While previous studies had shown apnea occurring early in the course of RSV infection, "our results challenge this notion," the authors wrote. One-third of the infants with apnea in the study began having difficulty breathing 4 or more days before the preadmission visit. "Furthermore, the time from the beginning of the ‘difficulty breathing’ to the preadmission visit was not different between children with and without apnea. Therefore, using the duration of symptoms to predict future risk of apnea or need for hospitalization may be problematic."
The investigators acknowledged as limitations of their study the possibility that the reported incidence of apnea may have been biased by oversampling of sicker patients, as the investigators recruited 20% of patients from intensive care. Some infants may have been included based on chart data that did not meet strict criteria for apnea, allowing for overreporting, they said, and apnea may have been harder to detect in intubated patients, leading to underreporting in this population.
The study was funded by the National Institutes of Health. Dr. Schroeder and his colleagues reported no disclosures.
A large prospective study of infants hospitalized for bronchiolitis has revealed a number of previously unknown risk factors associated with apnea, a potentially life-threatening complication.
While high preadmission respiratory rates were found associated with increased apnea risk, so were low respiratory rates, a surprising finding that investigators could not explain. Low room air oxygen saturation was seen as contributing to risk. And one usual-suspect risk factor in apnea – respiratory syncytial virus – turned out not to be more dangerous than other viruses in terms of apnea risk.
Clinicians should not be reassured by either a low respiratory rate or infection with an organism other than RSV in assessing apnea risk, said Dr. Alan R. Schroeder of the Santa Clara Medical Center in San Jose, Calif., and his colleagues.
At 16 study sites nationwide starting in 2007, the researchers collected enrollment and outcome data on 2,156 children under age 2 (median age 4 months, with age corrected for birth at less than 37 weeks). The patients were admitted with bronchiolitis over three consecutive winter seasons. Of these children, 108 (5%) developed apnea while hospitalized, according to the study, which was published online Oct. 7 in Pediatrics (2013;132:1-8 [doi: 10.1542/peds.2013-1501]). The study was part of the Multicenter Airway Research Collaboration, a program of the Emergency Medicine Network.
The study confirmed the known risk factors of young corrected age, low birth weight, and previous apnea during the same bronchiolitis episode. Dr. Schroeder and his colleagues found that the statistically significant predictors of apnea included age of less than 2 weeks (odds ratio, 9.67) and 2-8 weeks (OR, 4.72), compared with age 6 months or older; birth weight of less than 2.3 kg (OR, 2.15), compared with birth weight of 3.2 kg or more; and previous apnea during the same bronchiolitis episode (OR, 3.63).
There also was risk associated with preadmission respiratory rates of less than 30 (OR, 4.05) and 30-39 (OR, 2.35), compared with 40-49, as well as a preadmission respiratory rate of 70 or more (OR, 2.26). Risk of apnea was also associated with having a preadmission room air oxygen saturation of less than 90% (OR, 1.60).
Apnea risk was shown to be similar across the major viral infections seen in the cohort. While more infants presented with RSV than with other viruses, there was roughly equal apnea risk seen among children infected with human rhinovirus, adenovirus, human metapneumovirus, enterovirus, coronavirus, and parainfluenza virus.
"These data suggest that using RSV status to drive admission decisions and admission locations (e.g., ward, step-down unit, ICU) due to apnea concerns may be misguided," Dr. Schroeder and his colleagues wrote in their analysis.
The study contained a number of other novel findings. While a recent, smaller study of 42 patients had suggested a possible protective effect associated with acetaminophen administered the week before hospitalization (Resuscitation 2012;83:440-46), the study by Dr. Schroeder and his colleagues found no such effect.
It also shed light on the timing of apnea during the course of bronchiolitis. While previous studies had shown apnea occurring early in the course of RSV infection, "our results challenge this notion," the authors wrote. One-third of the infants with apnea in the study began having difficulty breathing 4 or more days before the preadmission visit. "Furthermore, the time from the beginning of the ‘difficulty breathing’ to the preadmission visit was not different between children with and without apnea. Therefore, using the duration of symptoms to predict future risk of apnea or need for hospitalization may be problematic."
The investigators acknowledged as limitations of their study the possibility that the reported incidence of apnea may have been biased by oversampling of sicker patients, as the investigators recruited 20% of patients from intensive care. Some infants may have been included based on chart data that did not meet strict criteria for apnea, allowing for overreporting, they said, and apnea may have been harder to detect in intubated patients, leading to underreporting in this population.
The study was funded by the National Institutes of Health. Dr. Schroeder and his colleagues reported no disclosures.
FROM PEDIATRICS
Major finding: Low or high respiratory rates or low oxygen saturation on presentation were associated with apnea in the hospital among infants admitted with bronchiolitis. The apnea risk was not seen as greater among patients infected with respiratory syncytial virus than in those infected with other viruses.
Data source: More than 2,000 infants enrolled during three winter seasons starting in 2007 at 16 study sites in the United States.
Disclosures: The study was funded by the National Institutes of Health. Dr. Schroeder and his colleagues reported no disclosures.
USPSTF: No Evidence for Routine Blood Pressure Screening in Children
The U.S. Preventive Services Task Force has determined, for the second time in 10 years, that there is not enough quality evidence to recommend – or not recommend – regular blood pressure screening as part of standard pediatric care.
The task force, chaired by Dr. Virginia A. Moyer, argues that the evidence to support routine screening for primary hypertension remains insufficient in a paper published online Oct. 7 in Pediatrics (2013;132:1-8 [doi:10.1542/peds.2013-2864]). The task force’s position on pediatric screening is little changed from 2003 when it issued recommendations on screening for both children and adults (Am. Fam. Physician 2003;68:2019-22).
For its newest recommendation, however, the task force authors looked solely at the issue of screening in asymptomatic children and adolescents without a risk factor for hypertension, such as high body mass index.
It evaluated studies on diagnostic accuracy, the relationship of childhood primary hypertension with adult hypertension and cardiovascular disease, the effectiveness of treatment, and the harms related to screening or treatment. But the task force determined that it had not found enough quality evidence to weigh in.
One of the rationales for regular blood pressure screening in asymptomatic children 3 years and older – a practice that has been recommended for more than 35 years (Pediatrics 1977;59(suppl.):797-820)and is currently advocated by the American Academy of Pediatrics, the American Heart Association, and the National Heart, Lung, and Blood Institute – is to identify children at increased risk for adult hypertension and cardiovascular disease.
However, predictive values of childhood hypertension for adult hypertension "are at best modest," wrote the authors. A recent, related study also conducted by the task force found no direct evidence that screening for hypertension in children and adolescents reduces adverse cardiovascular outcomes in adults (Pediatrics 2013;131:490-525).
Some practitioners have criticized the USPSTF’s focus on primary hypertension and adult outcomes, saying that pediatricians have other reasons to screen children routinely for hypertension, including identifying asymptomatic secondary hypertension. Indeed, for some pediatricians, reducing adult cardiovascular events is not seen as the primary goal of screening. Dr. Bonita Falkner, then incoming chair of the International Pediatric Hypertension Association, clearly outlined this position in a letter to the editor published in Pediatrics in March 2013 in response to a review conducted for the USPSTF.
The task force emphasized that "clinical decisions involve more considerations than evidence alone," and noted that screening between the ages of 3 and 17 years is recommended by the AAP and other organizations.
Dr. Sarah de Ferranti, the director of the preventive cardiology clinic at Boston Children’s Hospital and a member of the AAP committee on nutrition, said in an interview that she, like the task force authors, would like to see more evidence on the relationship between childhood and adult hypertension, and that she would not dismiss the important question of risk or harms related to screening.
But she also said she had no intention of abandoning routine screening as part of her practice, and would counsel other pediatricians not to do so, either. "There are definitely patients identified as having other medical problems by blood pressure – such as kidney problems and endocrine problems. There are cases where the blood pressure is the identifying cause," she said.
"We still identify children with primary and secondary hypertension, and that is important in terms of outcomes," Dr. de Ferranti continued. Observational and longitudinal studies, she pointed out, have found evidence linking pediatric hypertension with adult arterial stiffness, subclinical atherosclerosis, and carotid intima-media thickness, and even with cardiovascular damage that occurs before adulthood.
Moreover, Dr. de Ferranti said, there are logistical barriers to obtaining the type of evidence the USPSTF seeks in its recommendations, such as a randomized controlled trial to determine whether blood pressure reduction improves adult outcomes. "Few parents would be interested in having their child take a placebo or dummy pill for 30 years to find out the answers to these questions," she said.
The U.S. Preventive Services Task Force has determined, for the second time in 10 years, that there is not enough quality evidence to recommend – or not recommend – regular blood pressure screening as part of standard pediatric care.
The task force, chaired by Dr. Virginia A. Moyer, argues that the evidence to support routine screening for primary hypertension remains insufficient in a paper published online Oct. 7 in Pediatrics (2013;132:1-8 [doi:10.1542/peds.2013-2864]). The task force’s position on pediatric screening is little changed from 2003 when it issued recommendations on screening for both children and adults (Am. Fam. Physician 2003;68:2019-22).
For its newest recommendation, however, the task force authors looked solely at the issue of screening in asymptomatic children and adolescents without a risk factor for hypertension, such as high body mass index.
It evaluated studies on diagnostic accuracy, the relationship of childhood primary hypertension with adult hypertension and cardiovascular disease, the effectiveness of treatment, and the harms related to screening or treatment. But the task force determined that it had not found enough quality evidence to weigh in.
One of the rationales for regular blood pressure screening in asymptomatic children 3 years and older – a practice that has been recommended for more than 35 years (Pediatrics 1977;59(suppl.):797-820)and is currently advocated by the American Academy of Pediatrics, the American Heart Association, and the National Heart, Lung, and Blood Institute – is to identify children at increased risk for adult hypertension and cardiovascular disease.
However, predictive values of childhood hypertension for adult hypertension "are at best modest," wrote the authors. A recent, related study also conducted by the task force found no direct evidence that screening for hypertension in children and adolescents reduces adverse cardiovascular outcomes in adults (Pediatrics 2013;131:490-525).
Some practitioners have criticized the USPSTF’s focus on primary hypertension and adult outcomes, saying that pediatricians have other reasons to screen children routinely for hypertension, including identifying asymptomatic secondary hypertension. Indeed, for some pediatricians, reducing adult cardiovascular events is not seen as the primary goal of screening. Dr. Bonita Falkner, then incoming chair of the International Pediatric Hypertension Association, clearly outlined this position in a letter to the editor published in Pediatrics in March 2013 in response to a review conducted for the USPSTF.
The task force emphasized that "clinical decisions involve more considerations than evidence alone," and noted that screening between the ages of 3 and 17 years is recommended by the AAP and other organizations.
Dr. Sarah de Ferranti, the director of the preventive cardiology clinic at Boston Children’s Hospital and a member of the AAP committee on nutrition, said in an interview that she, like the task force authors, would like to see more evidence on the relationship between childhood and adult hypertension, and that she would not dismiss the important question of risk or harms related to screening.
But she also said she had no intention of abandoning routine screening as part of her practice, and would counsel other pediatricians not to do so, either. "There are definitely patients identified as having other medical problems by blood pressure – such as kidney problems and endocrine problems. There are cases where the blood pressure is the identifying cause," she said.
"We still identify children with primary and secondary hypertension, and that is important in terms of outcomes," Dr. de Ferranti continued. Observational and longitudinal studies, she pointed out, have found evidence linking pediatric hypertension with adult arterial stiffness, subclinical atherosclerosis, and carotid intima-media thickness, and even with cardiovascular damage that occurs before adulthood.
Moreover, Dr. de Ferranti said, there are logistical barriers to obtaining the type of evidence the USPSTF seeks in its recommendations, such as a randomized controlled trial to determine whether blood pressure reduction improves adult outcomes. "Few parents would be interested in having their child take a placebo or dummy pill for 30 years to find out the answers to these questions," she said.
The U.S. Preventive Services Task Force has determined, for the second time in 10 years, that there is not enough quality evidence to recommend – or not recommend – regular blood pressure screening as part of standard pediatric care.
The task force, chaired by Dr. Virginia A. Moyer, argues that the evidence to support routine screening for primary hypertension remains insufficient in a paper published online Oct. 7 in Pediatrics (2013;132:1-8 [doi:10.1542/peds.2013-2864]). The task force’s position on pediatric screening is little changed from 2003 when it issued recommendations on screening for both children and adults (Am. Fam. Physician 2003;68:2019-22).
For its newest recommendation, however, the task force authors looked solely at the issue of screening in asymptomatic children and adolescents without a risk factor for hypertension, such as high body mass index.
It evaluated studies on diagnostic accuracy, the relationship of childhood primary hypertension with adult hypertension and cardiovascular disease, the effectiveness of treatment, and the harms related to screening or treatment. But the task force determined that it had not found enough quality evidence to weigh in.
One of the rationales for regular blood pressure screening in asymptomatic children 3 years and older – a practice that has been recommended for more than 35 years (Pediatrics 1977;59(suppl.):797-820)and is currently advocated by the American Academy of Pediatrics, the American Heart Association, and the National Heart, Lung, and Blood Institute – is to identify children at increased risk for adult hypertension and cardiovascular disease.
However, predictive values of childhood hypertension for adult hypertension "are at best modest," wrote the authors. A recent, related study also conducted by the task force found no direct evidence that screening for hypertension in children and adolescents reduces adverse cardiovascular outcomes in adults (Pediatrics 2013;131:490-525).
Some practitioners have criticized the USPSTF’s focus on primary hypertension and adult outcomes, saying that pediatricians have other reasons to screen children routinely for hypertension, including identifying asymptomatic secondary hypertension. Indeed, for some pediatricians, reducing adult cardiovascular events is not seen as the primary goal of screening. Dr. Bonita Falkner, then incoming chair of the International Pediatric Hypertension Association, clearly outlined this position in a letter to the editor published in Pediatrics in March 2013 in response to a review conducted for the USPSTF.
The task force emphasized that "clinical decisions involve more considerations than evidence alone," and noted that screening between the ages of 3 and 17 years is recommended by the AAP and other organizations.
Dr. Sarah de Ferranti, the director of the preventive cardiology clinic at Boston Children’s Hospital and a member of the AAP committee on nutrition, said in an interview that she, like the task force authors, would like to see more evidence on the relationship between childhood and adult hypertension, and that she would not dismiss the important question of risk or harms related to screening.
But she also said she had no intention of abandoning routine screening as part of her practice, and would counsel other pediatricians not to do so, either. "There are definitely patients identified as having other medical problems by blood pressure – such as kidney problems and endocrine problems. There are cases where the blood pressure is the identifying cause," she said.
"We still identify children with primary and secondary hypertension, and that is important in terms of outcomes," Dr. de Ferranti continued. Observational and longitudinal studies, she pointed out, have found evidence linking pediatric hypertension with adult arterial stiffness, subclinical atherosclerosis, and carotid intima-media thickness, and even with cardiovascular damage that occurs before adulthood.
Moreover, Dr. de Ferranti said, there are logistical barriers to obtaining the type of evidence the USPSTF seeks in its recommendations, such as a randomized controlled trial to determine whether blood pressure reduction improves adult outcomes. "Few parents would be interested in having their child take a placebo or dummy pill for 30 years to find out the answers to these questions," she said.
USPSTF: No evidence for routine blood pressure screening in children
The U.S. Preventive Services Task Force has determined, for the second time in 10 years, that there is not enough quality evidence to recommend – or not recommend – regular blood pressure screening as part of standard pediatric care.
The task force, chaired by Dr. Virginia A. Moyer, argues that the evidence to support routine screening for primary hypertension remains insufficient in a paper published online Oct. 7 in Pediatrics (2013;132:1-8 [doi:10.1542/peds.2013-2864]). The task force’s position on pediatric screening is little changed from 2003 when it issued recommendations on screening for both children and adults (Am. Fam. Physician 2003;68:2019-22).
For its newest recommendation, however, the task force authors looked solely at the issue of screening in asymptomatic children and adolescents without a risk factor for hypertension, such as high body mass index.
It evaluated studies on diagnostic accuracy, the relationship of childhood primary hypertension with adult hypertension and cardiovascular disease, the effectiveness of treatment, and the harms related to screening or treatment. But the task force determined that it had not found enough quality evidence to weigh in.
One of the rationales for regular blood pressure screening in asymptomatic children 3 years and older – a practice that has been recommended for more than 35 years (Pediatrics 1977;59(suppl.):797-820)and is currently advocated by the American Academy of Pediatrics, the American Heart Association, and the National Heart, Lung, and Blood Institute – is to identify children at increased risk for adult hypertension and cardiovascular disease.
However, predictive values of childhood hypertension for adult hypertension "are at best modest," wrote the authors. A recent, related study also conducted by the task force found no direct evidence that screening for hypertension in children and adolescents reduces adverse cardiovascular outcomes in adults (Pediatrics 2013;131:490-525).
Some practitioners have criticized the USPSTF’s focus on primary hypertension and adult outcomes, saying that pediatricians have other reasons to screen children routinely for hypertension, including identifying asymptomatic secondary hypertension. Indeed, for some pediatricians, reducing adult cardiovascular events is not seen as the primary goal of screening. Dr. Bonita Falkner, then incoming chair of the International Pediatric Hypertension Association, clearly outlined this position in a letter to the editor published in Pediatrics in March 2013 in response to a review conducted for the USPSTF.
The task force emphasized that "clinical decisions involve more considerations than evidence alone," and noted that screening between the ages of 3 and 17 years is recommended by the AAP and other organizations.
Dr. Sarah de Ferranti, the director of the preventive cardiology clinic at Boston Children’s Hospital and a member of the AAP committee on nutrition, said in an interview that she, like the task force authors, would like to see more evidence on the relationship between childhood and adult hypertension, and that she would not dismiss the important question of risk or harms related to screening.
But she also said she had no intention of abandoning routine screening as part of her practice, and would counsel other pediatricians not to do so, either. "There are definitely patients identified as having other medical problems by blood pressure – such as kidney problems and endocrine problems. There are cases where the blood pressure is the identifying cause," she said.
"We still identify children with primary and secondary hypertension, and that is important in terms of outcomes," Dr. de Ferranti continued. Observational and longitudinal studies, she pointed out, have found evidence linking pediatric hypertension with adult arterial stiffness, subclinical atherosclerosis, and carotid intima-media thickness, and even with cardiovascular damage that occurs before adulthood.
Moreover, Dr. de Ferranti said, there are logistical barriers to obtaining the type of evidence the USPSTF seeks in its recommendations, such as a randomized controlled trial to determine whether blood pressure reduction improves adult outcomes. "Few parents would be interested in having their child take a placebo or dummy pill for 30 years to find out the answers to these questions," she said.
The U.S. Preventive Services Task Force has determined, for the second time in 10 years, that there is not enough quality evidence to recommend – or not recommend – regular blood pressure screening as part of standard pediatric care.
The task force, chaired by Dr. Virginia A. Moyer, argues that the evidence to support routine screening for primary hypertension remains insufficient in a paper published online Oct. 7 in Pediatrics (2013;132:1-8 [doi:10.1542/peds.2013-2864]). The task force’s position on pediatric screening is little changed from 2003 when it issued recommendations on screening for both children and adults (Am. Fam. Physician 2003;68:2019-22).
For its newest recommendation, however, the task force authors looked solely at the issue of screening in asymptomatic children and adolescents without a risk factor for hypertension, such as high body mass index.
It evaluated studies on diagnostic accuracy, the relationship of childhood primary hypertension with adult hypertension and cardiovascular disease, the effectiveness of treatment, and the harms related to screening or treatment. But the task force determined that it had not found enough quality evidence to weigh in.
One of the rationales for regular blood pressure screening in asymptomatic children 3 years and older – a practice that has been recommended for more than 35 years (Pediatrics 1977;59(suppl.):797-820)and is currently advocated by the American Academy of Pediatrics, the American Heart Association, and the National Heart, Lung, and Blood Institute – is to identify children at increased risk for adult hypertension and cardiovascular disease.
However, predictive values of childhood hypertension for adult hypertension "are at best modest," wrote the authors. A recent, related study also conducted by the task force found no direct evidence that screening for hypertension in children and adolescents reduces adverse cardiovascular outcomes in adults (Pediatrics 2013;131:490-525).
Some practitioners have criticized the USPSTF’s focus on primary hypertension and adult outcomes, saying that pediatricians have other reasons to screen children routinely for hypertension, including identifying asymptomatic secondary hypertension. Indeed, for some pediatricians, reducing adult cardiovascular events is not seen as the primary goal of screening. Dr. Bonita Falkner, then incoming chair of the International Pediatric Hypertension Association, clearly outlined this position in a letter to the editor published in Pediatrics in March 2013 in response to a review conducted for the USPSTF.
The task force emphasized that "clinical decisions involve more considerations than evidence alone," and noted that screening between the ages of 3 and 17 years is recommended by the AAP and other organizations.
Dr. Sarah de Ferranti, the director of the preventive cardiology clinic at Boston Children’s Hospital and a member of the AAP committee on nutrition, said in an interview that she, like the task force authors, would like to see more evidence on the relationship between childhood and adult hypertension, and that she would not dismiss the important question of risk or harms related to screening.
But she also said she had no intention of abandoning routine screening as part of her practice, and would counsel other pediatricians not to do so, either. "There are definitely patients identified as having other medical problems by blood pressure – such as kidney problems and endocrine problems. There are cases where the blood pressure is the identifying cause," she said.
"We still identify children with primary and secondary hypertension, and that is important in terms of outcomes," Dr. de Ferranti continued. Observational and longitudinal studies, she pointed out, have found evidence linking pediatric hypertension with adult arterial stiffness, subclinical atherosclerosis, and carotid intima-media thickness, and even with cardiovascular damage that occurs before adulthood.
Moreover, Dr. de Ferranti said, there are logistical barriers to obtaining the type of evidence the USPSTF seeks in its recommendations, such as a randomized controlled trial to determine whether blood pressure reduction improves adult outcomes. "Few parents would be interested in having their child take a placebo or dummy pill for 30 years to find out the answers to these questions," she said.
The U.S. Preventive Services Task Force has determined, for the second time in 10 years, that there is not enough quality evidence to recommend – or not recommend – regular blood pressure screening as part of standard pediatric care.
The task force, chaired by Dr. Virginia A. Moyer, argues that the evidence to support routine screening for primary hypertension remains insufficient in a paper published online Oct. 7 in Pediatrics (2013;132:1-8 [doi:10.1542/peds.2013-2864]). The task force’s position on pediatric screening is little changed from 2003 when it issued recommendations on screening for both children and adults (Am. Fam. Physician 2003;68:2019-22).
For its newest recommendation, however, the task force authors looked solely at the issue of screening in asymptomatic children and adolescents without a risk factor for hypertension, such as high body mass index.
It evaluated studies on diagnostic accuracy, the relationship of childhood primary hypertension with adult hypertension and cardiovascular disease, the effectiveness of treatment, and the harms related to screening or treatment. But the task force determined that it had not found enough quality evidence to weigh in.
One of the rationales for regular blood pressure screening in asymptomatic children 3 years and older – a practice that has been recommended for more than 35 years (Pediatrics 1977;59(suppl.):797-820)and is currently advocated by the American Academy of Pediatrics, the American Heart Association, and the National Heart, Lung, and Blood Institute – is to identify children at increased risk for adult hypertension and cardiovascular disease.
However, predictive values of childhood hypertension for adult hypertension "are at best modest," wrote the authors. A recent, related study also conducted by the task force found no direct evidence that screening for hypertension in children and adolescents reduces adverse cardiovascular outcomes in adults (Pediatrics 2013;131:490-525).
Some practitioners have criticized the USPSTF’s focus on primary hypertension and adult outcomes, saying that pediatricians have other reasons to screen children routinely for hypertension, including identifying asymptomatic secondary hypertension. Indeed, for some pediatricians, reducing adult cardiovascular events is not seen as the primary goal of screening. Dr. Bonita Falkner, then incoming chair of the International Pediatric Hypertension Association, clearly outlined this position in a letter to the editor published in Pediatrics in March 2013 in response to a review conducted for the USPSTF.
The task force emphasized that "clinical decisions involve more considerations than evidence alone," and noted that screening between the ages of 3 and 17 years is recommended by the AAP and other organizations.
Dr. Sarah de Ferranti, the director of the preventive cardiology clinic at Boston Children’s Hospital and a member of the AAP committee on nutrition, said in an interview that she, like the task force authors, would like to see more evidence on the relationship between childhood and adult hypertension, and that she would not dismiss the important question of risk or harms related to screening.
But she also said she had no intention of abandoning routine screening as part of her practice, and would counsel other pediatricians not to do so, either. "There are definitely patients identified as having other medical problems by blood pressure – such as kidney problems and endocrine problems. There are cases where the blood pressure is the identifying cause," she said.
"We still identify children with primary and secondary hypertension, and that is important in terms of outcomes," Dr. de Ferranti continued. Observational and longitudinal studies, she pointed out, have found evidence linking pediatric hypertension with adult arterial stiffness, subclinical atherosclerosis, and carotid intima-media thickness, and even with cardiovascular damage that occurs before adulthood.
Moreover, Dr. de Ferranti said, there are logistical barriers to obtaining the type of evidence the USPSTF seeks in its recommendations, such as a randomized controlled trial to determine whether blood pressure reduction improves adult outcomes. "Few parents would be interested in having their child take a placebo or dummy pill for 30 years to find out the answers to these questions," she said.
More evidence TNF inhibitors slash diabetes risk
Recent research has suggested that tumor necrosis factor inhibitors can significantly reduce diabetes risk in people with rheumatoid arthritis.
Dr. Siri Lillegraven of Diakonhjemmet Hospital in Oslo presented results from the CORRONA (Consortium of Rheumatology Researchers of North America) study, which Dr. Lillegraven, its lead author, called "the first large study to find the same association" at the annual European Congress of Rheumatology. The study used CORRONA registry data from 22,943 patients and about 22,000 RA treatment regimens with a mean duration between 1.5 and 2.4 years.
Dr. Lillegraven and her colleagues found an adjusted hazard ratio for type 2 diabetes of 0.35 for TNF inhibitors (95% confidence interval, 0.13-0.91), compared with a reference group of non-methotrexate, non-hydroxychloroquine, nonbiologic disease-modifying antirheumatic drugs such as cyclosporine, sulfasalazine, and leflunomide. The DMARDs hydroxychloroquine and methotrexate were separately compared with this reference group.
"It was a statistically significant finding, and the model was adjusted for differences between patients who received TNF inhibitors and the patients who received the comparator drugs," Dr. Lillegraven said in an interview.
One of Dr. Lillegraven’s coauthors on the study, Dr. Daniel Solomon of Brigham and Women’s Hospital in Boston earlier reported a lower risk of type 2 diabetes for individuals taking TNF inhibitors or hydroxychloroquine, compared with nonbiologic DMARDs (JAMA 2011;305:2525-31).
In that study, which enrolled about 14,000 patients and evaluated about 22,000 treatment episodes, the multivariate adjusted hazard ratio for diabetes was 0.62 (95% CI, 0.42-0.91) for TNF inhibitors, compared with other nonbiologic DMARDs. The effect was even greater for hydroxychloroquine, compared with other nonbiologics (hazard ratio, 0.54; 95% CI, 0.36-0.80).
Dr. Lillegraven and her colleagues saw a similar effect size for hydroxychloroquine, compared with the nonbiologic DMARDs, but this did not reach statistical significance.
As both studies were observational in design, Dr. Lillegraven noted, the results do not carry the weight of randomized, controlled trial findings. "We would have loved to have a clinical trial that confirmed the findings," she said, adding that designing such a trial would be difficult. "The outcome is relatively rare, and you will not likely get enough diabetes outcomes to be able to conclude whether an exposure had an effect." In Dr. Lillegraven and her colleagues’ study, for example, only 84 incident cases of diabetes occurred.
Last year, investigators reported that TNF inhibitors were associated with a halving of diabetes risk, compared with RA patients who had never used them (HR, 0.49; 95% CI 0.24-0.99), in a cohort of 1,587 RA patients without diabetes at enrollment who were followed for 3-4 years (Arthritis Care Res. 2012;64:215-21), and several studies have suggested a relationship between the biologic pathways that TNF inhibitors affect and diabetes.
Dr. Lillegraven also analyzed the impact of body-mass index (BMI) and steroid dosage on diabetes incidence in these patients. Those with a BMI of more than 30 kg/m2 had a statistically significant sixfold increased rate of incident diabetes, compared with patients with a BMI of less than 25 kg/m2. Patients with a BMI of 25-30 kg/m2 had a significant, nearly twofold increased rate. Patients who received a steroid dose of at least 7.5 mg/day had a statistically significant, twofold increased diabetes incidence, compared with patients who did not receive any steroid treatment.
Dr. Lillegraven said that her study’s findings, added to the earlier findings, support "a potential for tailoring treatment in high-risk individuals." But it is still too early to draw any definite conclusions regarding how this should be carried out in the clinic, she cautioned.
Dr. Lillegraven declared no conflicts of interest relevant to her study. Dr. Solomon declared unpaid consultancies for Pfizer and Novartis. Three other coauthors reported financial relationships with pharmaceutical firms and CORRONA, a database registry for rheumatologic diseases; one is an employee of CORRONA.
Recent research has suggested that tumor necrosis factor inhibitors can significantly reduce diabetes risk in people with rheumatoid arthritis.
Dr. Siri Lillegraven of Diakonhjemmet Hospital in Oslo presented results from the CORRONA (Consortium of Rheumatology Researchers of North America) study, which Dr. Lillegraven, its lead author, called "the first large study to find the same association" at the annual European Congress of Rheumatology. The study used CORRONA registry data from 22,943 patients and about 22,000 RA treatment regimens with a mean duration between 1.5 and 2.4 years.
Dr. Lillegraven and her colleagues found an adjusted hazard ratio for type 2 diabetes of 0.35 for TNF inhibitors (95% confidence interval, 0.13-0.91), compared with a reference group of non-methotrexate, non-hydroxychloroquine, nonbiologic disease-modifying antirheumatic drugs such as cyclosporine, sulfasalazine, and leflunomide. The DMARDs hydroxychloroquine and methotrexate were separately compared with this reference group.
"It was a statistically significant finding, and the model was adjusted for differences between patients who received TNF inhibitors and the patients who received the comparator drugs," Dr. Lillegraven said in an interview.
One of Dr. Lillegraven’s coauthors on the study, Dr. Daniel Solomon of Brigham and Women’s Hospital in Boston earlier reported a lower risk of type 2 diabetes for individuals taking TNF inhibitors or hydroxychloroquine, compared with nonbiologic DMARDs (JAMA 2011;305:2525-31).
In that study, which enrolled about 14,000 patients and evaluated about 22,000 treatment episodes, the multivariate adjusted hazard ratio for diabetes was 0.62 (95% CI, 0.42-0.91) for TNF inhibitors, compared with other nonbiologic DMARDs. The effect was even greater for hydroxychloroquine, compared with other nonbiologics (hazard ratio, 0.54; 95% CI, 0.36-0.80).
Dr. Lillegraven and her colleagues saw a similar effect size for hydroxychloroquine, compared with the nonbiologic DMARDs, but this did not reach statistical significance.
As both studies were observational in design, Dr. Lillegraven noted, the results do not carry the weight of randomized, controlled trial findings. "We would have loved to have a clinical trial that confirmed the findings," she said, adding that designing such a trial would be difficult. "The outcome is relatively rare, and you will not likely get enough diabetes outcomes to be able to conclude whether an exposure had an effect." In Dr. Lillegraven and her colleagues’ study, for example, only 84 incident cases of diabetes occurred.
Last year, investigators reported that TNF inhibitors were associated with a halving of diabetes risk, compared with RA patients who had never used them (HR, 0.49; 95% CI 0.24-0.99), in a cohort of 1,587 RA patients without diabetes at enrollment who were followed for 3-4 years (Arthritis Care Res. 2012;64:215-21), and several studies have suggested a relationship between the biologic pathways that TNF inhibitors affect and diabetes.
Dr. Lillegraven also analyzed the impact of body-mass index (BMI) and steroid dosage on diabetes incidence in these patients. Those with a BMI of more than 30 kg/m2 had a statistically significant sixfold increased rate of incident diabetes, compared with patients with a BMI of less than 25 kg/m2. Patients with a BMI of 25-30 kg/m2 had a significant, nearly twofold increased rate. Patients who received a steroid dose of at least 7.5 mg/day had a statistically significant, twofold increased diabetes incidence, compared with patients who did not receive any steroid treatment.
Dr. Lillegraven said that her study’s findings, added to the earlier findings, support "a potential for tailoring treatment in high-risk individuals." But it is still too early to draw any definite conclusions regarding how this should be carried out in the clinic, she cautioned.
Dr. Lillegraven declared no conflicts of interest relevant to her study. Dr. Solomon declared unpaid consultancies for Pfizer and Novartis. Three other coauthors reported financial relationships with pharmaceutical firms and CORRONA, a database registry for rheumatologic diseases; one is an employee of CORRONA.
Recent research has suggested that tumor necrosis factor inhibitors can significantly reduce diabetes risk in people with rheumatoid arthritis.
Dr. Siri Lillegraven of Diakonhjemmet Hospital in Oslo presented results from the CORRONA (Consortium of Rheumatology Researchers of North America) study, which Dr. Lillegraven, its lead author, called "the first large study to find the same association" at the annual European Congress of Rheumatology. The study used CORRONA registry data from 22,943 patients and about 22,000 RA treatment regimens with a mean duration between 1.5 and 2.4 years.
Dr. Lillegraven and her colleagues found an adjusted hazard ratio for type 2 diabetes of 0.35 for TNF inhibitors (95% confidence interval, 0.13-0.91), compared with a reference group of non-methotrexate, non-hydroxychloroquine, nonbiologic disease-modifying antirheumatic drugs such as cyclosporine, sulfasalazine, and leflunomide. The DMARDs hydroxychloroquine and methotrexate were separately compared with this reference group.
"It was a statistically significant finding, and the model was adjusted for differences between patients who received TNF inhibitors and the patients who received the comparator drugs," Dr. Lillegraven said in an interview.
One of Dr. Lillegraven’s coauthors on the study, Dr. Daniel Solomon of Brigham and Women’s Hospital in Boston earlier reported a lower risk of type 2 diabetes for individuals taking TNF inhibitors or hydroxychloroquine, compared with nonbiologic DMARDs (JAMA 2011;305:2525-31).
In that study, which enrolled about 14,000 patients and evaluated about 22,000 treatment episodes, the multivariate adjusted hazard ratio for diabetes was 0.62 (95% CI, 0.42-0.91) for TNF inhibitors, compared with other nonbiologic DMARDs. The effect was even greater for hydroxychloroquine, compared with other nonbiologics (hazard ratio, 0.54; 95% CI, 0.36-0.80).
Dr. Lillegraven and her colleagues saw a similar effect size for hydroxychloroquine, compared with the nonbiologic DMARDs, but this did not reach statistical significance.
As both studies were observational in design, Dr. Lillegraven noted, the results do not carry the weight of randomized, controlled trial findings. "We would have loved to have a clinical trial that confirmed the findings," she said, adding that designing such a trial would be difficult. "The outcome is relatively rare, and you will not likely get enough diabetes outcomes to be able to conclude whether an exposure had an effect." In Dr. Lillegraven and her colleagues’ study, for example, only 84 incident cases of diabetes occurred.
Last year, investigators reported that TNF inhibitors were associated with a halving of diabetes risk, compared with RA patients who had never used them (HR, 0.49; 95% CI 0.24-0.99), in a cohort of 1,587 RA patients without diabetes at enrollment who were followed for 3-4 years (Arthritis Care Res. 2012;64:215-21), and several studies have suggested a relationship between the biologic pathways that TNF inhibitors affect and diabetes.
Dr. Lillegraven also analyzed the impact of body-mass index (BMI) and steroid dosage on diabetes incidence in these patients. Those with a BMI of more than 30 kg/m2 had a statistically significant sixfold increased rate of incident diabetes, compared with patients with a BMI of less than 25 kg/m2. Patients with a BMI of 25-30 kg/m2 had a significant, nearly twofold increased rate. Patients who received a steroid dose of at least 7.5 mg/day had a statistically significant, twofold increased diabetes incidence, compared with patients who did not receive any steroid treatment.
Dr. Lillegraven said that her study’s findings, added to the earlier findings, support "a potential for tailoring treatment in high-risk individuals." But it is still too early to draw any definite conclusions regarding how this should be carried out in the clinic, she cautioned.
Dr. Lillegraven declared no conflicts of interest relevant to her study. Dr. Solomon declared unpaid consultancies for Pfizer and Novartis. Three other coauthors reported financial relationships with pharmaceutical firms and CORRONA, a database registry for rheumatologic diseases; one is an employee of CORRONA.
FROM THE EULAR CONGRESS 2013
More evidence TNF inhibitors slash diabetes risk
Recent research has suggested that tumor necrosis factor inhibitors can significantly reduce diabetes risk in people with rheumatoid arthritis.
Dr. Siri Lillegraven of Diakonhjemmet Hospital in Oslo presented results from the CORRONA (Consortium of Rheumatology Researchers of North America) study, which Dr. Lillegraven, its lead author, called "the first large study to find the same association" at the annual European Congress of Rheumatology. The study used CORRONA registry data from 22,943 patients and about 22,000 RA treatment regimens with a mean duration between 1.5 and 2.4 years.
Dr. Lillegraven and her colleagues found an adjusted hazard ratio for type 2 diabetes of 0.35 for TNF inhibitors (95% confidence interval, 0.13-0.91), compared with a reference group of non-methotrexate, non-hydroxychloroquine, nonbiologic disease-modifying antirheumatic drugs such as cyclosporine, sulfasalazine, and leflunomide. The DMARDs hydroxychloroquine and methotrexate were separately compared with this reference group.
"It was a statistically significant finding, and the model was adjusted for differences between patients who received TNF inhibitors and the patients who received the comparator drugs," Dr. Lillegraven said in an interview.
One of Dr. Lillegraven’s coauthors on the study, Dr. Daniel Solomon of Brigham and Women’s Hospital in Boston earlier reported a lower risk of type 2 diabetes for individuals taking TNF inhibitors or hydroxychloroquine, compared with nonbiologic DMARDs (JAMA 2011;305:2525-31).
In that study, which enrolled about 14,000 patients and evaluated about 22,000 treatment episodes, the multivariate adjusted hazard ratio for diabetes was 0.62 (95% CI, 0.42-0.91) for TNF inhibitors, compared with other nonbiologic DMARDs. The effect was even greater for hydroxychloroquine, compared with other nonbiologics (hazard ratio, 0.54; 95% CI, 0.36-0.80).
Dr. Lillegraven and her colleagues saw a similar effect size for hydroxychloroquine, compared with the nonbiologic DMARDs, but this did not reach statistical significance.
As both studies were observational in design, Dr. Lillegraven noted, the results do not carry the weight of randomized, controlled trial findings. "We would have loved to have a clinical trial that confirmed the findings," she said, adding that designing such a trial would be difficult. "The outcome is relatively rare, and you will not likely get enough diabetes outcomes to be able to conclude whether an exposure had an effect." In Dr. Lillegraven and her colleagues’ study, for example, only 84 incident cases of diabetes occurred.
Last year, investigators reported that TNF inhibitors were associated with a halving of diabetes risk, compared with RA patients who had never used them (HR, 0.49; 95% CI 0.24-0.99), in a cohort of 1,587 RA patients without diabetes at enrollment who were followed for 3-4 years (Arthritis Care Res. 2012;64:215-21), and several studies have suggested a relationship between the biologic pathways that TNF inhibitors affect and diabetes.
Dr. Lillegraven also analyzed the impact of body-mass index (BMI) and steroid dosage on diabetes incidence in these patients. Those with a BMI of more than 30 kg/m2 had a statistically significant sixfold increased rate of incident diabetes, compared with patients with a BMI of less than 25 kg/m2. Patients with a BMI of 25-30 kg/m2 had a significant, nearly twofold increased rate. Patients who received a steroid dose of at least 7.5 mg/day had a statistically significant, twofold increased diabetes incidence, compared with patients who did not receive any steroid treatment.
Dr. Lillegraven said that her study’s findings, added to the earlier findings, support "a potential for tailoring treatment in high-risk individuals." But it is still too early to draw any definite conclusions regarding how this should be carried out in the clinic, she cautioned.
Dr. Lillegraven declared no conflicts of interest relevant to her study. Dr. Solomon declared unpaid consultancies for Pfizer and Novartis. Three other coauthors reported financial relationships with pharmaceutical firms and CORRONA, a database registry for rheumatologic diseases; one is an employee of CORRONA.
Recent research has suggested that tumor necrosis factor inhibitors can significantly reduce diabetes risk in people with rheumatoid arthritis.
Dr. Siri Lillegraven of Diakonhjemmet Hospital in Oslo presented results from the CORRONA (Consortium of Rheumatology Researchers of North America) study, which Dr. Lillegraven, its lead author, called "the first large study to find the same association" at the annual European Congress of Rheumatology. The study used CORRONA registry data from 22,943 patients and about 22,000 RA treatment regimens with a mean duration between 1.5 and 2.4 years.
Dr. Lillegraven and her colleagues found an adjusted hazard ratio for type 2 diabetes of 0.35 for TNF inhibitors (95% confidence interval, 0.13-0.91), compared with a reference group of non-methotrexate, non-hydroxychloroquine, nonbiologic disease-modifying antirheumatic drugs such as cyclosporine, sulfasalazine, and leflunomide. The DMARDs hydroxychloroquine and methotrexate were separately compared with this reference group.
"It was a statistically significant finding, and the model was adjusted for differences between patients who received TNF inhibitors and the patients who received the comparator drugs," Dr. Lillegraven said in an interview.
One of Dr. Lillegraven’s coauthors on the study, Dr. Daniel Solomon of Brigham and Women’s Hospital in Boston earlier reported a lower risk of type 2 diabetes for individuals taking TNF inhibitors or hydroxychloroquine, compared with nonbiologic DMARDs (JAMA 2011;305:2525-31).
In that study, which enrolled about 14,000 patients and evaluated about 22,000 treatment episodes, the multivariate adjusted hazard ratio for diabetes was 0.62 (95% CI, 0.42-0.91) for TNF inhibitors, compared with other nonbiologic DMARDs. The effect was even greater for hydroxychloroquine, compared with other nonbiologics (hazard ratio, 0.54; 95% CI, 0.36-0.80).
Dr. Lillegraven and her colleagues saw a similar effect size for hydroxychloroquine, compared with the nonbiologic DMARDs, but this did not reach statistical significance.
As both studies were observational in design, Dr. Lillegraven noted, the results do not carry the weight of randomized, controlled trial findings. "We would have loved to have a clinical trial that confirmed the findings," she said, adding that designing such a trial would be difficult. "The outcome is relatively rare, and you will not likely get enough diabetes outcomes to be able to conclude whether an exposure had an effect." In Dr. Lillegraven and her colleagues’ study, for example, only 84 incident cases of diabetes occurred.
Last year, investigators reported that TNF inhibitors were associated with a halving of diabetes risk, compared with RA patients who had never used them (HR, 0.49; 95% CI 0.24-0.99), in a cohort of 1,587 RA patients without diabetes at enrollment who were followed for 3-4 years (Arthritis Care Res. 2012;64:215-21), and several studies have suggested a relationship between the biologic pathways that TNF inhibitors affect and diabetes.
Dr. Lillegraven also analyzed the impact of body-mass index (BMI) and steroid dosage on diabetes incidence in these patients. Those with a BMI of more than 30 kg/m2 had a statistically significant sixfold increased rate of incident diabetes, compared with patients with a BMI of less than 25 kg/m2. Patients with a BMI of 25-30 kg/m2 had a significant, nearly twofold increased rate. Patients who received a steroid dose of at least 7.5 mg/day had a statistically significant, twofold increased diabetes incidence, compared with patients who did not receive any steroid treatment.
Dr. Lillegraven said that her study’s findings, added to the earlier findings, support "a potential for tailoring treatment in high-risk individuals." But it is still too early to draw any definite conclusions regarding how this should be carried out in the clinic, she cautioned.
Dr. Lillegraven declared no conflicts of interest relevant to her study. Dr. Solomon declared unpaid consultancies for Pfizer and Novartis. Three other coauthors reported financial relationships with pharmaceutical firms and CORRONA, a database registry for rheumatologic diseases; one is an employee of CORRONA.
Recent research has suggested that tumor necrosis factor inhibitors can significantly reduce diabetes risk in people with rheumatoid arthritis.
Dr. Siri Lillegraven of Diakonhjemmet Hospital in Oslo presented results from the CORRONA (Consortium of Rheumatology Researchers of North America) study, which Dr. Lillegraven, its lead author, called "the first large study to find the same association" at the annual European Congress of Rheumatology. The study used CORRONA registry data from 22,943 patients and about 22,000 RA treatment regimens with a mean duration between 1.5 and 2.4 years.
Dr. Lillegraven and her colleagues found an adjusted hazard ratio for type 2 diabetes of 0.35 for TNF inhibitors (95% confidence interval, 0.13-0.91), compared with a reference group of non-methotrexate, non-hydroxychloroquine, nonbiologic disease-modifying antirheumatic drugs such as cyclosporine, sulfasalazine, and leflunomide. The DMARDs hydroxychloroquine and methotrexate were separately compared with this reference group.
"It was a statistically significant finding, and the model was adjusted for differences between patients who received TNF inhibitors and the patients who received the comparator drugs," Dr. Lillegraven said in an interview.
One of Dr. Lillegraven’s coauthors on the study, Dr. Daniel Solomon of Brigham and Women’s Hospital in Boston earlier reported a lower risk of type 2 diabetes for individuals taking TNF inhibitors or hydroxychloroquine, compared with nonbiologic DMARDs (JAMA 2011;305:2525-31).
In that study, which enrolled about 14,000 patients and evaluated about 22,000 treatment episodes, the multivariate adjusted hazard ratio for diabetes was 0.62 (95% CI, 0.42-0.91) for TNF inhibitors, compared with other nonbiologic DMARDs. The effect was even greater for hydroxychloroquine, compared with other nonbiologics (hazard ratio, 0.54; 95% CI, 0.36-0.80).
Dr. Lillegraven and her colleagues saw a similar effect size for hydroxychloroquine, compared with the nonbiologic DMARDs, but this did not reach statistical significance.
As both studies were observational in design, Dr. Lillegraven noted, the results do not carry the weight of randomized, controlled trial findings. "We would have loved to have a clinical trial that confirmed the findings," she said, adding that designing such a trial would be difficult. "The outcome is relatively rare, and you will not likely get enough diabetes outcomes to be able to conclude whether an exposure had an effect." In Dr. Lillegraven and her colleagues’ study, for example, only 84 incident cases of diabetes occurred.
Last year, investigators reported that TNF inhibitors were associated with a halving of diabetes risk, compared with RA patients who had never used them (HR, 0.49; 95% CI 0.24-0.99), in a cohort of 1,587 RA patients without diabetes at enrollment who were followed for 3-4 years (Arthritis Care Res. 2012;64:215-21), and several studies have suggested a relationship between the biologic pathways that TNF inhibitors affect and diabetes.
Dr. Lillegraven also analyzed the impact of body-mass index (BMI) and steroid dosage on diabetes incidence in these patients. Those with a BMI of more than 30 kg/m2 had a statistically significant sixfold increased rate of incident diabetes, compared with patients with a BMI of less than 25 kg/m2. Patients with a BMI of 25-30 kg/m2 had a significant, nearly twofold increased rate. Patients who received a steroid dose of at least 7.5 mg/day had a statistically significant, twofold increased diabetes incidence, compared with patients who did not receive any steroid treatment.
Dr. Lillegraven said that her study’s findings, added to the earlier findings, support "a potential for tailoring treatment in high-risk individuals." But it is still too early to draw any definite conclusions regarding how this should be carried out in the clinic, she cautioned.
Dr. Lillegraven declared no conflicts of interest relevant to her study. Dr. Solomon declared unpaid consultancies for Pfizer and Novartis. Three other coauthors reported financial relationships with pharmaceutical firms and CORRONA, a database registry for rheumatologic diseases; one is an employee of CORRONA.
FROM THE EULAR CONGRESS 2013
Antimalarials in SLE: high hopes, new benefits, and caution
BUENOS AIRES – The antimalarial drug hydroxychloroquine is now standard first-line therapy in systemic lupus erythematosus, with most SLE patients taking it indefinitely alone or in addition to other medications.
It was not always this way. The past 15 years have seen what was long regarded as a mild drug, one commonly withdrawn after evidence of disease improvement, become more often compared to a miracle drug. Hydroxychloroquine (HCQ) is now considered indispensible in lupus, and is thought to confer a host of previously unrecognized benefits, with new ones being discovered every year.
Prospective and retrospective observational studies have found HCQ use associated with the prevention of lupus flares, less damage accrual, prolonged survival, less vascular damage, fewer thrombolic and cardiovascular events, better renal outcomes, and skin and joint improvement (J. Rheumatol. 2012;39:1769-71). One team of investigators has hypothesized that HCQ decreases cancer risk in people with lupus (Ann. Rheum. Dis. 2007;66:815-17). But other researchers have challenged some of these studies as potentially biased and not in keeping with observed clinical outcomes.
At the international congress on systemic lupus erythematosus, researchers discussed the latest findings related to HCQ in lupus, and shared thoughts on their implications for clinical practice.
Dr. Murray Urowitz, a senior scientist at the Toronto Western Research Institute, referred to results from a large multicenter cohort study (n = 1,631) that showed SLE patients taking antimalarial drugs in the absence of immunosuppressant medicines had significantly lower risk of seizures (Ann. Rheum. Dis. 2012;71:1502-9), possibly because HCQ is protective against flares, and seizures are thought to be caused by active neuropsychiatric lupus.
"We’ve heard this antimalarials story over and over again," Dr. Urowitz said, in commenting on the seizure findings. "Why aren’t all of our patients on antimalarials?"
HCQ use was seen as protective against cardiovascular disease (odds ratio 0.34, 95% confidence interval 0.16-0.71; P = .003) in a cohort of 306 SLE patients in Turkey, according to findings presented at the conference by Dr. Murat Inanc of Istanbul University (Lupus 2013;22[Suppl.]:O07).
In a separate presentation, Dr. Jill Buyon, director of the Lupus Center at New York University, reported encouraging preliminary data from a small, open-label study (n = 19) of HCQ in pregnant women with anti-SSA/Ro antibodies who previously had a child with cardiac manifestations of neonatal lupus, or cardiac-NL.
The major manifestation of cardiac-NL is heart block, an abnormality in which the heart beats too slowly. It is seen in about 2% of pregnancies in mothers with anti-SSA/Ro and anti-SSB/La serology, and the risk is 17.4% for those who have previously given birth to a child with cardiac-NL. Thus far, third degree heart block has been seen in only 1 of 17 pregnancies in women with a previous child with cardiac-NL taking 400 mg hydroxychloroquine daily, Dr. Buyon reported, suggesting a protective effect.
Dr. Bevra Hahn, chief of rheumatology at UCLA David Geffen School of Medicine, Los Angeles, discussed her own approach to HCQ in the clinic. When faced with patients whose serology or symptoms are suggestive of lupus yet insufficient to fulfill criteria for a lupus diagnosis, Dr. Hahn said she initiates treatment with HCQ. "Can we prevent, delay, or make disease milder with [HCQ]? My answer to that is yes, and we do it a lot," Dr. Hahn said, citing a retrospective study that showed lupus onset to be delayed in people treated with HCQ (Lupus 2007;16:401-9).
Another recent case-control study (n = 481) bolstered the case for early use of HCQ. Investigators found that prompt use of HCQ after SLE diagnosis protected against cumulative damage after 3 years (J. Rheumatol. 2013 April 15 [doi:10.3899/jrheum.120572]).
Dr. Guillermo Ruiz-Irastorza of the University of the Basque Country, Barakaldo, Spain, gave an update at the congress on current approaches to antimalarials. "I am absolutely convinced that HCQ has a very wide range of good effects in lupus, and that the longer it is used, the better it works," he said in a later interview. "Our patients are now almost 100% on HCQ, and the outcome of most of them is amazing – obviously not only because of HCQ, but I am sure it plays a main role. We have seen very severe flares in patients stopping HCQ monotherapy. HCQ is also a crucial part of therapy in renal disease – along with lower prednisone doses, pulse methylprednisolone, and low-dose cyclophosphamide. That is our protocol, with excellent results."
A better understanding of the way HCQ works in lupus has only increased the perception of its clinical importance. In recent years, HCQ was found to have activity against antiphospholipid antibodies (Lupus 2010;19:460-9), which helps to explain its protective effect against pregnancy loss and thrombosis in SLE. More recently, HCQ has been found to antagonize toll-like receptors (TLR) 7 and 9, which are components of innate immunity erroneously activated in lupus. They are a target for new drug development in SLE (Curr. Allergy Asthma Rep. 2012;12:1-7).
Dr. David Pisetsky, professor of immunology at Duke University, Durham, N.C., discussed the implications of HCQ’s anti-TLR activity at the congress. "This relatively benign drug has powerful immunological effects, even though we don’t really think of it that way," he said. "When we’re talking about strategies to block TLR, we’ve already been probably doing it unbeknownst to us rather effectively."
Dr. Buyon, who was moderating Dr. Pisetsky’s talk, noted: "Maybe we’re really underselling ourselves [with HCQ]. Most of us confine ourselves to 6.5 mg/kg," she said, referring to the well-known risk of ocular toxicity and retinal changes associated with long-term HCQ treatment, requiring patients on HCQ to get eye exams yearly. Dr. Pisetsky agreed: "To me it would seem very worthwhile to push the dose to get more out of it."
Dr. Pisetsky and Dr. Buyon both expressed hope that manufacturers would seek to create an HCQ-like compound without the ocular risk, allowing the administration of higher doses with presumably more clinical effect. "But so far there’s been a very limited effort," Dr. Pisetsky said.
Another lupus researcher, rheumatologist and epidemiologist Dr. Sasha Bernatsky of McGill University, Montreal, expressed cautious optimism about some of the recent findings. Like Dr. Urowitz, Dr. Inanc, Dr. Buyon, Dr. Ruiz-Irastorz, and many other international scientists, Dr. Bernatsky is a member of the Systemic Lupus International Collaborating Clinics research group, which studies long-term outcomes in SLE.
"The exact possibilities, in terms of disease modification, remain a matter for further study," Dr. Bernatsky said in an interview, adding that while she strongly endorses HCQ for its many benefits, and recommends the drug in almost all SLE patients, she doesn’t fully understand the extremely strong effects that recent studies have suggested, related to nephritis, central nervous system manifestations, cancer, and overall survival.
Dr. Bernatsky struggles with the findings of a study that found HCQ associated with a 70% reduction in renal damage in lupus patients (Arthritis Rheum. 2009;61:830-9; Arthritis Rheum. 2009;61:1614-5). "I am amazed by that degree of disease-modifying effect in terms of active kidney disease, with [HCQ]," she said.
The recent finding of reduced seizures in lupus patients taking HCQ also surprised her. "A hazards ratio of 0.07 suggests that antimalarials reduce 93% of the risk of seizures, which is an incredibly large effect size."
One area of particular debate in HCQ and lupus concerns cancer risk. While Dr. Ruiz-Irastorza and his colleagues found a protective effect associated with HCQ in a cohort study of 235 patients (Ann. Rheum. Dis. 2007;66:815-7), "I did not believe the results at first," Dr. Ruiz-Irastorza said. "However, after discovering several papers showing biological plausibility for such an effect, I changed my mind. It seems to work by a number of different mechanisms, including inhibition of autophagy and sensitization of tumor cells to chemotherapy."
Dr. Bernatsky and SLICC investigators have studied malignancy risk and medication exposures in a large cohort (n = 16,409) of SLE patients (J. Autoimmun. 2013;42:130-5) without finding a protective effect associated with HCQ. "While I would not rule out some beneficial effects for cancer risk in the rheumatic diseases, I think the jury is still out," she said.
Nonetheless, Dr. Bernatsky said, "At our clinic, we keep most of our patients on antimalarials for years, and I hope it is similar in the United States and Europe. I’m happy for almost all SLE patients to be on HCQ because I think it’s a great drug."
None of the investigators mentioned have financial disclosures related to HCQ.
BUENOS AIRES – The antimalarial drug hydroxychloroquine is now standard first-line therapy in systemic lupus erythematosus, with most SLE patients taking it indefinitely alone or in addition to other medications.
It was not always this way. The past 15 years have seen what was long regarded as a mild drug, one commonly withdrawn after evidence of disease improvement, become more often compared to a miracle drug. Hydroxychloroquine (HCQ) is now considered indispensible in lupus, and is thought to confer a host of previously unrecognized benefits, with new ones being discovered every year.
Prospective and retrospective observational studies have found HCQ use associated with the prevention of lupus flares, less damage accrual, prolonged survival, less vascular damage, fewer thrombolic and cardiovascular events, better renal outcomes, and skin and joint improvement (J. Rheumatol. 2012;39:1769-71). One team of investigators has hypothesized that HCQ decreases cancer risk in people with lupus (Ann. Rheum. Dis. 2007;66:815-17). But other researchers have challenged some of these studies as potentially biased and not in keeping with observed clinical outcomes.
At the international congress on systemic lupus erythematosus, researchers discussed the latest findings related to HCQ in lupus, and shared thoughts on their implications for clinical practice.
Dr. Murray Urowitz, a senior scientist at the Toronto Western Research Institute, referred to results from a large multicenter cohort study (n = 1,631) that showed SLE patients taking antimalarial drugs in the absence of immunosuppressant medicines had significantly lower risk of seizures (Ann. Rheum. Dis. 2012;71:1502-9), possibly because HCQ is protective against flares, and seizures are thought to be caused by active neuropsychiatric lupus.
"We’ve heard this antimalarials story over and over again," Dr. Urowitz said, in commenting on the seizure findings. "Why aren’t all of our patients on antimalarials?"
HCQ use was seen as protective against cardiovascular disease (odds ratio 0.34, 95% confidence interval 0.16-0.71; P = .003) in a cohort of 306 SLE patients in Turkey, according to findings presented at the conference by Dr. Murat Inanc of Istanbul University (Lupus 2013;22[Suppl.]:O07).
In a separate presentation, Dr. Jill Buyon, director of the Lupus Center at New York University, reported encouraging preliminary data from a small, open-label study (n = 19) of HCQ in pregnant women with anti-SSA/Ro antibodies who previously had a child with cardiac manifestations of neonatal lupus, or cardiac-NL.
The major manifestation of cardiac-NL is heart block, an abnormality in which the heart beats too slowly. It is seen in about 2% of pregnancies in mothers with anti-SSA/Ro and anti-SSB/La serology, and the risk is 17.4% for those who have previously given birth to a child with cardiac-NL. Thus far, third degree heart block has been seen in only 1 of 17 pregnancies in women with a previous child with cardiac-NL taking 400 mg hydroxychloroquine daily, Dr. Buyon reported, suggesting a protective effect.
Dr. Bevra Hahn, chief of rheumatology at UCLA David Geffen School of Medicine, Los Angeles, discussed her own approach to HCQ in the clinic. When faced with patients whose serology or symptoms are suggestive of lupus yet insufficient to fulfill criteria for a lupus diagnosis, Dr. Hahn said she initiates treatment with HCQ. "Can we prevent, delay, or make disease milder with [HCQ]? My answer to that is yes, and we do it a lot," Dr. Hahn said, citing a retrospective study that showed lupus onset to be delayed in people treated with HCQ (Lupus 2007;16:401-9).
Another recent case-control study (n = 481) bolstered the case for early use of HCQ. Investigators found that prompt use of HCQ after SLE diagnosis protected against cumulative damage after 3 years (J. Rheumatol. 2013 April 15 [doi:10.3899/jrheum.120572]).
Dr. Guillermo Ruiz-Irastorza of the University of the Basque Country, Barakaldo, Spain, gave an update at the congress on current approaches to antimalarials. "I am absolutely convinced that HCQ has a very wide range of good effects in lupus, and that the longer it is used, the better it works," he said in a later interview. "Our patients are now almost 100% on HCQ, and the outcome of most of them is amazing – obviously not only because of HCQ, but I am sure it plays a main role. We have seen very severe flares in patients stopping HCQ monotherapy. HCQ is also a crucial part of therapy in renal disease – along with lower prednisone doses, pulse methylprednisolone, and low-dose cyclophosphamide. That is our protocol, with excellent results."
A better understanding of the way HCQ works in lupus has only increased the perception of its clinical importance. In recent years, HCQ was found to have activity against antiphospholipid antibodies (Lupus 2010;19:460-9), which helps to explain its protective effect against pregnancy loss and thrombosis in SLE. More recently, HCQ has been found to antagonize toll-like receptors (TLR) 7 and 9, which are components of innate immunity erroneously activated in lupus. They are a target for new drug development in SLE (Curr. Allergy Asthma Rep. 2012;12:1-7).
Dr. David Pisetsky, professor of immunology at Duke University, Durham, N.C., discussed the implications of HCQ’s anti-TLR activity at the congress. "This relatively benign drug has powerful immunological effects, even though we don’t really think of it that way," he said. "When we’re talking about strategies to block TLR, we’ve already been probably doing it unbeknownst to us rather effectively."
Dr. Buyon, who was moderating Dr. Pisetsky’s talk, noted: "Maybe we’re really underselling ourselves [with HCQ]. Most of us confine ourselves to 6.5 mg/kg," she said, referring to the well-known risk of ocular toxicity and retinal changes associated with long-term HCQ treatment, requiring patients on HCQ to get eye exams yearly. Dr. Pisetsky agreed: "To me it would seem very worthwhile to push the dose to get more out of it."
Dr. Pisetsky and Dr. Buyon both expressed hope that manufacturers would seek to create an HCQ-like compound without the ocular risk, allowing the administration of higher doses with presumably more clinical effect. "But so far there’s been a very limited effort," Dr. Pisetsky said.
Another lupus researcher, rheumatologist and epidemiologist Dr. Sasha Bernatsky of McGill University, Montreal, expressed cautious optimism about some of the recent findings. Like Dr. Urowitz, Dr. Inanc, Dr. Buyon, Dr. Ruiz-Irastorz, and many other international scientists, Dr. Bernatsky is a member of the Systemic Lupus International Collaborating Clinics research group, which studies long-term outcomes in SLE.
"The exact possibilities, in terms of disease modification, remain a matter for further study," Dr. Bernatsky said in an interview, adding that while she strongly endorses HCQ for its many benefits, and recommends the drug in almost all SLE patients, she doesn’t fully understand the extremely strong effects that recent studies have suggested, related to nephritis, central nervous system manifestations, cancer, and overall survival.
Dr. Bernatsky struggles with the findings of a study that found HCQ associated with a 70% reduction in renal damage in lupus patients (Arthritis Rheum. 2009;61:830-9; Arthritis Rheum. 2009;61:1614-5). "I am amazed by that degree of disease-modifying effect in terms of active kidney disease, with [HCQ]," she said.
The recent finding of reduced seizures in lupus patients taking HCQ also surprised her. "A hazards ratio of 0.07 suggests that antimalarials reduce 93% of the risk of seizures, which is an incredibly large effect size."
One area of particular debate in HCQ and lupus concerns cancer risk. While Dr. Ruiz-Irastorza and his colleagues found a protective effect associated with HCQ in a cohort study of 235 patients (Ann. Rheum. Dis. 2007;66:815-7), "I did not believe the results at first," Dr. Ruiz-Irastorza said. "However, after discovering several papers showing biological plausibility for such an effect, I changed my mind. It seems to work by a number of different mechanisms, including inhibition of autophagy and sensitization of tumor cells to chemotherapy."
Dr. Bernatsky and SLICC investigators have studied malignancy risk and medication exposures in a large cohort (n = 16,409) of SLE patients (J. Autoimmun. 2013;42:130-5) without finding a protective effect associated with HCQ. "While I would not rule out some beneficial effects for cancer risk in the rheumatic diseases, I think the jury is still out," she said.
Nonetheless, Dr. Bernatsky said, "At our clinic, we keep most of our patients on antimalarials for years, and I hope it is similar in the United States and Europe. I’m happy for almost all SLE patients to be on HCQ because I think it’s a great drug."
None of the investigators mentioned have financial disclosures related to HCQ.
BUENOS AIRES – The antimalarial drug hydroxychloroquine is now standard first-line therapy in systemic lupus erythematosus, with most SLE patients taking it indefinitely alone or in addition to other medications.
It was not always this way. The past 15 years have seen what was long regarded as a mild drug, one commonly withdrawn after evidence of disease improvement, become more often compared to a miracle drug. Hydroxychloroquine (HCQ) is now considered indispensible in lupus, and is thought to confer a host of previously unrecognized benefits, with new ones being discovered every year.
Prospective and retrospective observational studies have found HCQ use associated with the prevention of lupus flares, less damage accrual, prolonged survival, less vascular damage, fewer thrombolic and cardiovascular events, better renal outcomes, and skin and joint improvement (J. Rheumatol. 2012;39:1769-71). One team of investigators has hypothesized that HCQ decreases cancer risk in people with lupus (Ann. Rheum. Dis. 2007;66:815-17). But other researchers have challenged some of these studies as potentially biased and not in keeping with observed clinical outcomes.
At the international congress on systemic lupus erythematosus, researchers discussed the latest findings related to HCQ in lupus, and shared thoughts on their implications for clinical practice.
Dr. Murray Urowitz, a senior scientist at the Toronto Western Research Institute, referred to results from a large multicenter cohort study (n = 1,631) that showed SLE patients taking antimalarial drugs in the absence of immunosuppressant medicines had significantly lower risk of seizures (Ann. Rheum. Dis. 2012;71:1502-9), possibly because HCQ is protective against flares, and seizures are thought to be caused by active neuropsychiatric lupus.
"We’ve heard this antimalarials story over and over again," Dr. Urowitz said, in commenting on the seizure findings. "Why aren’t all of our patients on antimalarials?"
HCQ use was seen as protective against cardiovascular disease (odds ratio 0.34, 95% confidence interval 0.16-0.71; P = .003) in a cohort of 306 SLE patients in Turkey, according to findings presented at the conference by Dr. Murat Inanc of Istanbul University (Lupus 2013;22[Suppl.]:O07).
In a separate presentation, Dr. Jill Buyon, director of the Lupus Center at New York University, reported encouraging preliminary data from a small, open-label study (n = 19) of HCQ in pregnant women with anti-SSA/Ro antibodies who previously had a child with cardiac manifestations of neonatal lupus, or cardiac-NL.
The major manifestation of cardiac-NL is heart block, an abnormality in which the heart beats too slowly. It is seen in about 2% of pregnancies in mothers with anti-SSA/Ro and anti-SSB/La serology, and the risk is 17.4% for those who have previously given birth to a child with cardiac-NL. Thus far, third degree heart block has been seen in only 1 of 17 pregnancies in women with a previous child with cardiac-NL taking 400 mg hydroxychloroquine daily, Dr. Buyon reported, suggesting a protective effect.
Dr. Bevra Hahn, chief of rheumatology at UCLA David Geffen School of Medicine, Los Angeles, discussed her own approach to HCQ in the clinic. When faced with patients whose serology or symptoms are suggestive of lupus yet insufficient to fulfill criteria for a lupus diagnosis, Dr. Hahn said she initiates treatment with HCQ. "Can we prevent, delay, or make disease milder with [HCQ]? My answer to that is yes, and we do it a lot," Dr. Hahn said, citing a retrospective study that showed lupus onset to be delayed in people treated with HCQ (Lupus 2007;16:401-9).
Another recent case-control study (n = 481) bolstered the case for early use of HCQ. Investigators found that prompt use of HCQ after SLE diagnosis protected against cumulative damage after 3 years (J. Rheumatol. 2013 April 15 [doi:10.3899/jrheum.120572]).
Dr. Guillermo Ruiz-Irastorza of the University of the Basque Country, Barakaldo, Spain, gave an update at the congress on current approaches to antimalarials. "I am absolutely convinced that HCQ has a very wide range of good effects in lupus, and that the longer it is used, the better it works," he said in a later interview. "Our patients are now almost 100% on HCQ, and the outcome of most of them is amazing – obviously not only because of HCQ, but I am sure it plays a main role. We have seen very severe flares in patients stopping HCQ monotherapy. HCQ is also a crucial part of therapy in renal disease – along with lower prednisone doses, pulse methylprednisolone, and low-dose cyclophosphamide. That is our protocol, with excellent results."
A better understanding of the way HCQ works in lupus has only increased the perception of its clinical importance. In recent years, HCQ was found to have activity against antiphospholipid antibodies (Lupus 2010;19:460-9), which helps to explain its protective effect against pregnancy loss and thrombosis in SLE. More recently, HCQ has been found to antagonize toll-like receptors (TLR) 7 and 9, which are components of innate immunity erroneously activated in lupus. They are a target for new drug development in SLE (Curr. Allergy Asthma Rep. 2012;12:1-7).
Dr. David Pisetsky, professor of immunology at Duke University, Durham, N.C., discussed the implications of HCQ’s anti-TLR activity at the congress. "This relatively benign drug has powerful immunological effects, even though we don’t really think of it that way," he said. "When we’re talking about strategies to block TLR, we’ve already been probably doing it unbeknownst to us rather effectively."
Dr. Buyon, who was moderating Dr. Pisetsky’s talk, noted: "Maybe we’re really underselling ourselves [with HCQ]. Most of us confine ourselves to 6.5 mg/kg," she said, referring to the well-known risk of ocular toxicity and retinal changes associated with long-term HCQ treatment, requiring patients on HCQ to get eye exams yearly. Dr. Pisetsky agreed: "To me it would seem very worthwhile to push the dose to get more out of it."
Dr. Pisetsky and Dr. Buyon both expressed hope that manufacturers would seek to create an HCQ-like compound without the ocular risk, allowing the administration of higher doses with presumably more clinical effect. "But so far there’s been a very limited effort," Dr. Pisetsky said.
Another lupus researcher, rheumatologist and epidemiologist Dr. Sasha Bernatsky of McGill University, Montreal, expressed cautious optimism about some of the recent findings. Like Dr. Urowitz, Dr. Inanc, Dr. Buyon, Dr. Ruiz-Irastorz, and many other international scientists, Dr. Bernatsky is a member of the Systemic Lupus International Collaborating Clinics research group, which studies long-term outcomes in SLE.
"The exact possibilities, in terms of disease modification, remain a matter for further study," Dr. Bernatsky said in an interview, adding that while she strongly endorses HCQ for its many benefits, and recommends the drug in almost all SLE patients, she doesn’t fully understand the extremely strong effects that recent studies have suggested, related to nephritis, central nervous system manifestations, cancer, and overall survival.
Dr. Bernatsky struggles with the findings of a study that found HCQ associated with a 70% reduction in renal damage in lupus patients (Arthritis Rheum. 2009;61:830-9; Arthritis Rheum. 2009;61:1614-5). "I am amazed by that degree of disease-modifying effect in terms of active kidney disease, with [HCQ]," she said.
The recent finding of reduced seizures in lupus patients taking HCQ also surprised her. "A hazards ratio of 0.07 suggests that antimalarials reduce 93% of the risk of seizures, which is an incredibly large effect size."
One area of particular debate in HCQ and lupus concerns cancer risk. While Dr. Ruiz-Irastorza and his colleagues found a protective effect associated with HCQ in a cohort study of 235 patients (Ann. Rheum. Dis. 2007;66:815-7), "I did not believe the results at first," Dr. Ruiz-Irastorza said. "However, after discovering several papers showing biological plausibility for such an effect, I changed my mind. It seems to work by a number of different mechanisms, including inhibition of autophagy and sensitization of tumor cells to chemotherapy."
Dr. Bernatsky and SLICC investigators have studied malignancy risk and medication exposures in a large cohort (n = 16,409) of SLE patients (J. Autoimmun. 2013;42:130-5) without finding a protective effect associated with HCQ. "While I would not rule out some beneficial effects for cancer risk in the rheumatic diseases, I think the jury is still out," she said.
Nonetheless, Dr. Bernatsky said, "At our clinic, we keep most of our patients on antimalarials for years, and I hope it is similar in the United States and Europe. I’m happy for almost all SLE patients to be on HCQ because I think it’s a great drug."
None of the investigators mentioned have financial disclosures related to HCQ.
AT THE SLE INTERNATIONAL CONGRESS
Strategy outlined for treating severe refractory cutaneous lupus
BUENOS AIRES – Clinicians facing cases of severe refractory cutaneous lupus erythematosus – including in patients who smoke – have several treatment options, according to a prominent CLE researcher.
Dr. Victoria P. Werth, professor of dermatology at the Hospital of the University of Pennsylvania, Philadelphia, and chief of dermatology at the Philadelphia Veterans Affairs Medical Center, shared clinical strategies for treating CLE that is resistant to topical or intralesional treatments, and even systemic therapy with antimalarials.
"In terms of systemic therapy there are very few randomized placebo-controlled trials, and recommendations are based on expert opinion and retrospective case series. However, this is beginning to change," Dr. Werth said at an international congress on systemic lupus erythematosus. With the validated CLASI (CLE Disease Area and Severity Index) measure, which Dr. Werth and her colleagues introduced in 2005, "it’s been possible to prospectively follow patients who are being put on treatment."
Antimalarials are the established first-line systemic treatment for CLE, with studies showing hydroxychloroquine to be effective in 50%-70% of patients (Curr. Rheumatol. Rep. 2011;13: 300-7). "It’s worth it to give antimalarials to smokers," Dr. Werth said, citing findings from a prospective cohort study she coauthored (n = 218). She and her colleagues found that even though smoking was associated with more severe disease activity, current smokers requiring treatment with antimalarial agents alone actually improved more than nonsmokers treated with only these agents (Arch. Dermatol. 2012;148:317-21). When skin disease was refractory to antimalarials, the smokers responded less well than nonsmokers to additional therapies such as immunosuppressants.
Dr. Werth noted that patients who do not respond to hydroxychloroquine tend to be those with generalized discoid lupus. In her clinic, she said, patients are started with hydroxychloroquine at less than 6.5 mg/kg per day and given 6-8 weeks to respond. If they do not, quinacrine 100 mg/day is added. At another 6-8 weeks, if no improvement is seen, "stop the hydroxychloroquine and consider starting chloroquine at a dose of less than 3.5 mg/kg per day," Dr. Werth advised, noting that chloroquine has more eye toxicity than hydroxychloroquine.
Immunosuppressants are the usual next step after treatment failure with antimalarials; mycophenolate mofetil (MMF) has been shown in small, uncontrolled studies to be effective in CLE. Dr. Werth discussed a yet-unpublished open-label study (n = 13) that her group conducted in which azathioprine tended to be less effective than MMF in patients who had failed antimalarials.
Thalidomide is effective for refractory CLE, Dr. Werth noted, citing a Spanish study (n = 60) in which nearly all patients treated with 100 mg daily achieved a clinical response, as assessed by CLASI scores, with a complete response seen in 85% (Br. J. Dermatol. 2012;166:616-23).
"Many patients not responsive to antimalarials do respond to thalidomide, and sometimes a lower maintenance dose – as much as 25-50 mg/day or even once a week – can be helpful," she said. Patients, particularly those with discoid forms of CLE, can relapse when taken off thalidomide, but do respond when started again, she said, and kept on low-dose aspirin or hydroxychloroquine to prevent thrombotic events.
Thalidomide is used cautiously in CLE because of its serious adverse effect profile, which includes teratogenicity, amenorrhea, stroke, and peripheral neuropathy. And about 10% of patients, mostly smokers, prove refractory to immunosuppressives and/or thalidomide. For severely refractory patients, the thalidomide analog lenalidomide may have a role.
In Dr. Werth and her colleagues’ case series of lenalidomide in five severely refractory CLE patients, four improved, but one developed systemic lupus erythematosus, leading to speculation that the drug could activate T cells and trigger systemic disease (J. Am. Acad. Dermatol. 2012;66:571-82). In a Spanish open-label study evaluating 5-10 mg/day of lenalidomide in 15 patients, a complete response occurred in 12, and there were no reports of systemic lupus developing after a mean 15 months’ follow-up (Arthritis Res. Ther. 2012;14:R265). Dr. Werth called the lenalidomide findings "encouraging," but warned that the thalidomide derivatives "have complex mechanisms that need to be studied."
The biologic agents belimumab and rituximab offer other options for patients who fail thalidomide. Post-hoc analyses of randomized clinical trials of belimumab "showed that there seemed to be dose-dependent improvement in rash in patients relative to baseline – so there’s hope that further study will demonstrate that skin may benefit from treatment with belimumab," Dr. Werth said.
Rituximab also may be indicated for patients with bullous lupus that is unresponsive to treatment with dapsone or steroids. "It would make sense because this is clearly an autoantibody-driven process," Dr. Werth said. "There have been a number of reports of rituximab helping patients with refractory bullous lupus."
The CLASI copyright is owned by the University of Pennsylvania, Dr. Werth’s institution. Dr. Werth disclosed financial relationships with Pfizer, Novartis, Cephalon, Rigel, and Medimmune, and grant support from Celgene and Amgen.
BUENOS AIRES – Clinicians facing cases of severe refractory cutaneous lupus erythematosus – including in patients who smoke – have several treatment options, according to a prominent CLE researcher.
Dr. Victoria P. Werth, professor of dermatology at the Hospital of the University of Pennsylvania, Philadelphia, and chief of dermatology at the Philadelphia Veterans Affairs Medical Center, shared clinical strategies for treating CLE that is resistant to topical or intralesional treatments, and even systemic therapy with antimalarials.
"In terms of systemic therapy there are very few randomized placebo-controlled trials, and recommendations are based on expert opinion and retrospective case series. However, this is beginning to change," Dr. Werth said at an international congress on systemic lupus erythematosus. With the validated CLASI (CLE Disease Area and Severity Index) measure, which Dr. Werth and her colleagues introduced in 2005, "it’s been possible to prospectively follow patients who are being put on treatment."
Antimalarials are the established first-line systemic treatment for CLE, with studies showing hydroxychloroquine to be effective in 50%-70% of patients (Curr. Rheumatol. Rep. 2011;13: 300-7). "It’s worth it to give antimalarials to smokers," Dr. Werth said, citing findings from a prospective cohort study she coauthored (n = 218). She and her colleagues found that even though smoking was associated with more severe disease activity, current smokers requiring treatment with antimalarial agents alone actually improved more than nonsmokers treated with only these agents (Arch. Dermatol. 2012;148:317-21). When skin disease was refractory to antimalarials, the smokers responded less well than nonsmokers to additional therapies such as immunosuppressants.
Dr. Werth noted that patients who do not respond to hydroxychloroquine tend to be those with generalized discoid lupus. In her clinic, she said, patients are started with hydroxychloroquine at less than 6.5 mg/kg per day and given 6-8 weeks to respond. If they do not, quinacrine 100 mg/day is added. At another 6-8 weeks, if no improvement is seen, "stop the hydroxychloroquine and consider starting chloroquine at a dose of less than 3.5 mg/kg per day," Dr. Werth advised, noting that chloroquine has more eye toxicity than hydroxychloroquine.
Immunosuppressants are the usual next step after treatment failure with antimalarials; mycophenolate mofetil (MMF) has been shown in small, uncontrolled studies to be effective in CLE. Dr. Werth discussed a yet-unpublished open-label study (n = 13) that her group conducted in which azathioprine tended to be less effective than MMF in patients who had failed antimalarials.
Thalidomide is effective for refractory CLE, Dr. Werth noted, citing a Spanish study (n = 60) in which nearly all patients treated with 100 mg daily achieved a clinical response, as assessed by CLASI scores, with a complete response seen in 85% (Br. J. Dermatol. 2012;166:616-23).
"Many patients not responsive to antimalarials do respond to thalidomide, and sometimes a lower maintenance dose – as much as 25-50 mg/day or even once a week – can be helpful," she said. Patients, particularly those with discoid forms of CLE, can relapse when taken off thalidomide, but do respond when started again, she said, and kept on low-dose aspirin or hydroxychloroquine to prevent thrombotic events.
Thalidomide is used cautiously in CLE because of its serious adverse effect profile, which includes teratogenicity, amenorrhea, stroke, and peripheral neuropathy. And about 10% of patients, mostly smokers, prove refractory to immunosuppressives and/or thalidomide. For severely refractory patients, the thalidomide analog lenalidomide may have a role.
In Dr. Werth and her colleagues’ case series of lenalidomide in five severely refractory CLE patients, four improved, but one developed systemic lupus erythematosus, leading to speculation that the drug could activate T cells and trigger systemic disease (J. Am. Acad. Dermatol. 2012;66:571-82). In a Spanish open-label study evaluating 5-10 mg/day of lenalidomide in 15 patients, a complete response occurred in 12, and there were no reports of systemic lupus developing after a mean 15 months’ follow-up (Arthritis Res. Ther. 2012;14:R265). Dr. Werth called the lenalidomide findings "encouraging," but warned that the thalidomide derivatives "have complex mechanisms that need to be studied."
The biologic agents belimumab and rituximab offer other options for patients who fail thalidomide. Post-hoc analyses of randomized clinical trials of belimumab "showed that there seemed to be dose-dependent improvement in rash in patients relative to baseline – so there’s hope that further study will demonstrate that skin may benefit from treatment with belimumab," Dr. Werth said.
Rituximab also may be indicated for patients with bullous lupus that is unresponsive to treatment with dapsone or steroids. "It would make sense because this is clearly an autoantibody-driven process," Dr. Werth said. "There have been a number of reports of rituximab helping patients with refractory bullous lupus."
The CLASI copyright is owned by the University of Pennsylvania, Dr. Werth’s institution. Dr. Werth disclosed financial relationships with Pfizer, Novartis, Cephalon, Rigel, and Medimmune, and grant support from Celgene and Amgen.
BUENOS AIRES – Clinicians facing cases of severe refractory cutaneous lupus erythematosus – including in patients who smoke – have several treatment options, according to a prominent CLE researcher.
Dr. Victoria P. Werth, professor of dermatology at the Hospital of the University of Pennsylvania, Philadelphia, and chief of dermatology at the Philadelphia Veterans Affairs Medical Center, shared clinical strategies for treating CLE that is resistant to topical or intralesional treatments, and even systemic therapy with antimalarials.
"In terms of systemic therapy there are very few randomized placebo-controlled trials, and recommendations are based on expert opinion and retrospective case series. However, this is beginning to change," Dr. Werth said at an international congress on systemic lupus erythematosus. With the validated CLASI (CLE Disease Area and Severity Index) measure, which Dr. Werth and her colleagues introduced in 2005, "it’s been possible to prospectively follow patients who are being put on treatment."
Antimalarials are the established first-line systemic treatment for CLE, with studies showing hydroxychloroquine to be effective in 50%-70% of patients (Curr. Rheumatol. Rep. 2011;13: 300-7). "It’s worth it to give antimalarials to smokers," Dr. Werth said, citing findings from a prospective cohort study she coauthored (n = 218). She and her colleagues found that even though smoking was associated with more severe disease activity, current smokers requiring treatment with antimalarial agents alone actually improved more than nonsmokers treated with only these agents (Arch. Dermatol. 2012;148:317-21). When skin disease was refractory to antimalarials, the smokers responded less well than nonsmokers to additional therapies such as immunosuppressants.
Dr. Werth noted that patients who do not respond to hydroxychloroquine tend to be those with generalized discoid lupus. In her clinic, she said, patients are started with hydroxychloroquine at less than 6.5 mg/kg per day and given 6-8 weeks to respond. If they do not, quinacrine 100 mg/day is added. At another 6-8 weeks, if no improvement is seen, "stop the hydroxychloroquine and consider starting chloroquine at a dose of less than 3.5 mg/kg per day," Dr. Werth advised, noting that chloroquine has more eye toxicity than hydroxychloroquine.
Immunosuppressants are the usual next step after treatment failure with antimalarials; mycophenolate mofetil (MMF) has been shown in small, uncontrolled studies to be effective in CLE. Dr. Werth discussed a yet-unpublished open-label study (n = 13) that her group conducted in which azathioprine tended to be less effective than MMF in patients who had failed antimalarials.
Thalidomide is effective for refractory CLE, Dr. Werth noted, citing a Spanish study (n = 60) in which nearly all patients treated with 100 mg daily achieved a clinical response, as assessed by CLASI scores, with a complete response seen in 85% (Br. J. Dermatol. 2012;166:616-23).
"Many patients not responsive to antimalarials do respond to thalidomide, and sometimes a lower maintenance dose – as much as 25-50 mg/day or even once a week – can be helpful," she said. Patients, particularly those with discoid forms of CLE, can relapse when taken off thalidomide, but do respond when started again, she said, and kept on low-dose aspirin or hydroxychloroquine to prevent thrombotic events.
Thalidomide is used cautiously in CLE because of its serious adverse effect profile, which includes teratogenicity, amenorrhea, stroke, and peripheral neuropathy. And about 10% of patients, mostly smokers, prove refractory to immunosuppressives and/or thalidomide. For severely refractory patients, the thalidomide analog lenalidomide may have a role.
In Dr. Werth and her colleagues’ case series of lenalidomide in five severely refractory CLE patients, four improved, but one developed systemic lupus erythematosus, leading to speculation that the drug could activate T cells and trigger systemic disease (J. Am. Acad. Dermatol. 2012;66:571-82). In a Spanish open-label study evaluating 5-10 mg/day of lenalidomide in 15 patients, a complete response occurred in 12, and there were no reports of systemic lupus developing after a mean 15 months’ follow-up (Arthritis Res. Ther. 2012;14:R265). Dr. Werth called the lenalidomide findings "encouraging," but warned that the thalidomide derivatives "have complex mechanisms that need to be studied."
The biologic agents belimumab and rituximab offer other options for patients who fail thalidomide. Post-hoc analyses of randomized clinical trials of belimumab "showed that there seemed to be dose-dependent improvement in rash in patients relative to baseline – so there’s hope that further study will demonstrate that skin may benefit from treatment with belimumab," Dr. Werth said.
Rituximab also may be indicated for patients with bullous lupus that is unresponsive to treatment with dapsone or steroids. "It would make sense because this is clearly an autoantibody-driven process," Dr. Werth said. "There have been a number of reports of rituximab helping patients with refractory bullous lupus."
The CLASI copyright is owned by the University of Pennsylvania, Dr. Werth’s institution. Dr. Werth disclosed financial relationships with Pfizer, Novartis, Cephalon, Rigel, and Medimmune, and grant support from Celgene and Amgen.
AT THE SLE INTERNATIONAL CONGRESS