Jennie Smith

Smoking is implicated in over a third of cases of the most severe and common form of rheumatoid arthritis, researchers in Sweden have found, and in one in five cases of RA overall.

Results from a population-based study strengthened the growing body of evidence that links smoking with development of anti-cyclic citrullinated peptide (anti-CCP) antibody–positive rheumatoid arthritis. In a dose-response manner, the link became stronger with heavier smoking, regardless of allele status.

The investigators, led by Henrik Källberg, Ph.D., of the Karolinska Institute in Stockholm, determined the excess fraction of RA cases attributable to smoking to be 20%, regardless of the presence of known genetic risk factors, which comprise single or dual copies of the HLA-DRB1 shared epitope. Smoking was estimated to be responsible for 35% of anti-CCP–positive cases (31% for women and 42% for men) and for each copy of the HLA-DRB1 shared epitope (SE) that was found, smoking was dose-dependently associated with an increased risk of anti-CCP–positive RA. In people with two copies of the HLA-DRB1 SE, 55% of anti-CCP–positive RA was attributable to smoking.

They also found an increased risk of developing RA (OR, 1.9; 95% confidence interval, 1.1-3.5) among heavy smokers without any genetic risk factors. “That was one really interesting finding,” Dr. Källberg said in an interview. “As a heavy smoker, you are almost two times more likely to develop RA” even without the HLA-DRB1 SE alleles.

For their research, Dr. Källberg and colleagues collected blood samples and questionnaire information from 1,205 people who were diagnosed with RA according to the American College of Rheumatology's 1987 criteria, as well as 872 healthy controls matched for age, sex, and geographic location. The cases were part of the Swedish EIRA (Epidemiological Investigation of Rheumatoid Arthritis) cohort study.

The questionnaires solicited information on past and current smoking, thereby allowing investigators to classify each subject by smoking history (current and former smokers of 0-9, 10-19, and 20 pack-years, with 1 pack-year defined as equaling 20 cigarettes per day for 1 year). The investigators tested blood samples for anti-CCP antibody status and the presence of genotyped SE alleles.

The investigators calculated the odds ratios of developing RA associated with different smoking levels and SE alleles, together with 95% confidence intervals, by using logistic regression models. The interaction between smoking and the presence of SE alleles was evaluated as a departure from additive effects, and was estimated by calculating the attributable proportion due to interaction.

For former light and moderate smokers, the risk of developing RA declined and approached never-smoker levels the longer the person had not smoked since quitting. Former heavy smokers, however, continued to see elevated risk, even decades after quitting.

The dose-dependent association with smoking was “not a total surprise. We knew from earlier studies that there was some sort of relationship with the amount,” Dr. Källberg said. “We just didn't expect it to be so clear cut.”

The fact that ex–heavy smokers continued to see elevated risk does not mean that smokers shouldn't quit, Dr. Källberg said. “To some degree, the damage may be done, but we actually find that you gain something by quitting smoking. Quitting smoking can affect how well you respond to treatment.”

Although smoking's presence in RA is smaller than in lung cancer, it is “similar to that seen for ischemic heart disease,” the investigators wrote in their analysis. Furthermore, cardiovascular disease is associated with RA and is the major cause of premature death in people with RA (Ann. Rheum. Dis. 2010 [doi:10.1136/ard.2009.120899]).

Dr. Källberg and colleagues' study was funded by grants from the Swedish government; the insurance company AFA; the European Union; the Flight Attendant Medical Research Institute; National Institutes of Health; and the COMBINE (Controlling Chronic Inflammatory Diseases With Combined Efforts) project. Neither Dr. Källberg nor any of his colleagues declared conflicts of interest.

Smoking is implicated in over a third of cases of the most severe and common form of rheumatoid arthritis, researchers in Sweden have found, and in one in five cases of RA overall.

Results from a population-based study strengthened the growing body of evidence that links smoking with development of anti-cyclic citrullinated peptide (anti-CCP) antibody–positive rheumatoid arthritis. In a dose-response manner, the link became stronger with heavier smoking, regardless of allele status.

The investigators, led by Henrik Källberg, Ph.D., of the Karolinska Institute in Stockholm, determined the excess fraction of RA cases attributable to smoking to be 20%, regardless of the presence of known genetic risk factors, which comprise single or dual copies of the HLA-DRB1 shared epitope. Smoking was estimated to be responsible for 35% of anti-CCP–positive cases (31% for women and 42% for men) and for each copy of the HLA-DRB1 shared epitope (SE) that was found, smoking was dose-dependently associated with an increased risk of anti-CCP–positive RA. In people with two copies of the HLA-DRB1 SE, 55% of anti-CCP–positive RA was attributable to smoking.

They also found an increased risk of developing RA (OR, 1.9; 95% confidence interval, 1.1-3.5) among heavy smokers without any genetic risk factors. “That was one really interesting finding,” Dr. Källberg said in an interview. “As a heavy smoker, you are almost two times more likely to develop RA” even without the HLA-DRB1 SE alleles.

For their research, Dr. Källberg and colleagues collected blood samples and questionnaire information from 1,205 people who were diagnosed with RA according to the American College of Rheumatology's 1987 criteria, as well as 872 healthy controls matched for age, sex, and geographic location. The cases were part of the Swedish EIRA (Epidemiological Investigation of Rheumatoid Arthritis) cohort study.

The questionnaires solicited information on past and current smoking, thereby allowing investigators to classify each subject by smoking history (current and former smokers of 0-9, 10-19, and 20 pack-years, with 1 pack-year defined as equaling 20 cigarettes per day for 1 year). The investigators tested blood samples for anti-CCP antibody status and the presence of genotyped SE alleles.

The investigators calculated the odds ratios of developing RA associated with different smoking levels and SE alleles, together with 95% confidence intervals, by using logistic regression models. The interaction between smoking and the presence of SE alleles was evaluated as a departure from additive effects, and was estimated by calculating the attributable proportion due to interaction.

For former light and moderate smokers, the risk of developing RA declined and approached never-smoker levels the longer the person had not smoked since quitting. Former heavy smokers, however, continued to see elevated risk, even decades after quitting.

The dose-dependent association with smoking was “not a total surprise. We knew from earlier studies that there was some sort of relationship with the amount,” Dr. Källberg said. “We just didn't expect it to be so clear cut.”

The fact that ex–heavy smokers continued to see elevated risk does not mean that smokers shouldn't quit, Dr. Källberg said. “To some degree, the damage may be done, but we actually find that you gain something by quitting smoking. Quitting smoking can affect how well you respond to treatment.”

Although smoking's presence in RA is smaller than in lung cancer, it is “similar to that seen for ischemic heart disease,” the investigators wrote in their analysis. Furthermore, cardiovascular disease is associated with RA and is the major cause of premature death in people with RA (Ann. Rheum. Dis. 2010 [doi:10.1136/ard.2009.120899]).

Dr. Källberg and colleagues' study was funded by grants from the Swedish government; the insurance company AFA; the European Union; the Flight Attendant Medical Research Institute; National Institutes of Health; and the COMBINE (Controlling Chronic Inflammatory Diseases With Combined Efforts) project. Neither Dr. Källberg nor any of his colleagues declared conflicts of interest.

Smoking is implicated in over a third of cases of the most severe and common form of rheumatoid arthritis, researchers in Sweden have found, and in one in five cases of RA overall.

Results from a population-based study strengthened the growing body of evidence that links smoking with development of anti-cyclic citrullinated peptide (anti-CCP) antibody–positive rheumatoid arthritis. In a dose-response manner, the link became stronger with heavier smoking, regardless of allele status.

The investigators, led by Henrik Källberg, Ph.D., of the Karolinska Institute in Stockholm, determined the excess fraction of RA cases attributable to smoking to be 20%, regardless of the presence of known genetic risk factors, which comprise single or dual copies of the HLA-DRB1 shared epitope. Smoking was estimated to be responsible for 35% of anti-CCP–positive cases (31% for women and 42% for men) and for each copy of the HLA-DRB1 shared epitope (SE) that was found, smoking was dose-dependently associated with an increased risk of anti-CCP–positive RA. In people with two copies of the HLA-DRB1 SE, 55% of anti-CCP–positive RA was attributable to smoking.

They also found an increased risk of developing RA (OR, 1.9; 95% confidence interval, 1.1-3.5) among heavy smokers without any genetic risk factors. “That was one really interesting finding,” Dr. Källberg said in an interview. “As a heavy smoker, you are almost two times more likely to develop RA” even without the HLA-DRB1 SE alleles.

For their research, Dr. Källberg and colleagues collected blood samples and questionnaire information from 1,205 people who were diagnosed with RA according to the American College of Rheumatology's 1987 criteria, as well as 872 healthy controls matched for age, sex, and geographic location. The cases were part of the Swedish EIRA (Epidemiological Investigation of Rheumatoid Arthritis) cohort study.

The questionnaires solicited information on past and current smoking, thereby allowing investigators to classify each subject by smoking history (current and former smokers of 0-9, 10-19, and 20 pack-years, with 1 pack-year defined as equaling 20 cigarettes per day for 1 year). The investigators tested blood samples for anti-CCP antibody status and the presence of genotyped SE alleles.

The investigators calculated the odds ratios of developing RA associated with different smoking levels and SE alleles, together with 95% confidence intervals, by using logistic regression models. The interaction between smoking and the presence of SE alleles was evaluated as a departure from additive effects, and was estimated by calculating the attributable proportion due to interaction.

For former light and moderate smokers, the risk of developing RA declined and approached never-smoker levels the longer the person had not smoked since quitting. Former heavy smokers, however, continued to see elevated risk, even decades after quitting.

The dose-dependent association with smoking was “not a total surprise. We knew from earlier studies that there was some sort of relationship with the amount,” Dr. Källberg said. “We just didn't expect it to be so clear cut.”

The fact that ex–heavy smokers continued to see elevated risk does not mean that smokers shouldn't quit, Dr. Källberg said. “To some degree, the damage may be done, but we actually find that you gain something by quitting smoking. Quitting smoking can affect how well you respond to treatment.”

Although smoking's presence in RA is smaller than in lung cancer, it is “similar to that seen for ischemic heart disease,” the investigators wrote in their analysis. Furthermore, cardiovascular disease is associated with RA and is the major cause of premature death in people with RA (Ann. Rheum. Dis. 2010 [doi:10.1136/ard.2009.120899]).

Dr. Källberg and colleagues' study was funded by grants from the Swedish government; the insurance company AFA; the European Union; the Flight Attendant Medical Research Institute; National Institutes of Health; and the COMBINE (Controlling Chronic Inflammatory Diseases With Combined Efforts) project. Neither Dr. Källberg nor any of his colleagues declared conflicts of interest.

Two publicly funded studies from the United States and England show that the proportion of seasonal influenza A viruses resistant to two types of antiviral drugs has risen in recent years, and that drug-resistant pandemic influenza A was transmitted person-to-person during one 2009 outbreak.

Both studies, published online Dec. 7 in the journal, highlight concerns about how easily influenza A(H1N1) viruses can develop mutations for resistance, about the paucity of treatment options available for resistant infections, and the risks of using potentially ineffective agents.

For the first study, Tiffany G. Sheu and Dr. Larisa Gubareva of the Centers for Disease Control and Prevention in Atlanta, and their colleagues, tested seasonal H1N1 viruses collected between 2008 and 2010 for resistance to two types of antivirals: oseltamivir and adamantane drugs. The researchers noted that resistance-conferring mutations in an influenza A virus can occur as a result of drug selection, spontaneous mutation, or genetic reassortment with another drug-resistant influenza A virus (J. Infect. Dis. 2011;203[1]:13-7).

Of the nearly 1,500 virus samples submitted by surveillance programs around the world, 28 viruses from five countries in North America, Africa, and Asia, exhibited both adamantane and oseltamivir resistance, the investigators reported. The proportion of resistant viruses increased from 0.06% (1 of 1,753) of those for 2007-2008, to 1.5% in samples for 2008-2009 (21 of 1,426), and to 28% in a smaller number of samples from the 2009-2010 season (7 of 25), when fewer seasonal A strains were circulating. The dual-resistant viruses represented four different genotypes.

“Although dual-resistant viruses are still rare,” the researchers wrote, “the increase in prevalence among seasonal influenza A(H1N1) viruses was notable during the last three seasons.” Also, the detection of dual-resistant seasonal A(H1N1) viruses from five countries “warrants concern,” they wrote, “because of the limited treatment options currently available for dual-resistant influenza A viruses.”

In the U.K. study, clinical virologist Catherine Moore and Dr. Elori Davies of the Public Health Wales NHS Trust in Cardiff, and their colleagues, described the first molecularly confirmed person-to-person transmission of oseltamivir-resistant pandemic influenza A(H1N1) 2009 virus. After an outbreak of 11 cases in the hematology wing of a public hospital in October and November 2009, 10 were shown by sequencing to be virologically related, 8 were oseltamivir-resistant, and 4 of the 8 infections occurred by direct transmission of resistant virus.

Though the infected patients had considerable underlying disease, including leukemia, multiple myeloma, and lymphoma, influenza symptoms were generally manageable during the outbreak, and none of the patients died as a result of their resistant infections, Ms. Moore and colleagues reported (J. Infect. Dis. 2011; 203[1]:18-24).

Dual treatment with oseltamivir and zanamivir was used when resistant virus was suspected or confirmed. However, Ms. Moore and colleagues noted that “recent data suggest there is possibly no synergy to be gained from this approach.”

In an editorial comment accompanying the two studies, Dr. Frederick G. Hayden of the University of Virginia, Charlottesville, and Dr. Menno D. de Jong of the University of Amsterdam, the Netherlands, saw cautions in both. “Together, these findings illustrate that single reassortment events or mutations can lead to the emergence of transmissible variants of pandemic 2009 or seasonal A(H1N1) viruses unresponsive to most, if not all, of our currently available drugs,” they wrote (J. Infect. Dis. 2011; 203[1]6-10).

The study by Ms. Sheu and Dr. Gubareva was funded by the Centers for Disease Control and Prevention. The study by Ms. Moore and Dr. Davies was funded by their public institutions; one coauthor acknowledged funding from the Wellcome Trust for a virus-sequencing pipeline project and another received funding from Roche for an influenza virus shedding study in oseltamivir-treated patients.

Dr. Hayden reported that he has received no research grants or personal honoraria from industry since 2006, but that he has served as an unpaid adviser to multiple companies involved in the development of influenza antivirals since 2008, and is member of the Neuraminidase Inhibitor Susceptibility Network, which has received funds from GlaxoSmithKline and Roche.

Two publicly funded studies from the United States and England show that the proportion of seasonal influenza A viruses resistant to two types of antiviral drugs has risen in recent years, and that drug-resistant pandemic influenza A was transmitted person-to-person during one 2009 outbreak.

Both studies, published online Dec. 7 in the journal, highlight concerns about how easily influenza A(H1N1) viruses can develop mutations for resistance, about the paucity of treatment options available for resistant infections, and the risks of using potentially ineffective agents.

For the first study, Tiffany G. Sheu and Dr. Larisa Gubareva of the Centers for Disease Control and Prevention in Atlanta, and their colleagues, tested seasonal H1N1 viruses collected between 2008 and 2010 for resistance to two types of antivirals: oseltamivir and adamantane drugs. The researchers noted that resistance-conferring mutations in an influenza A virus can occur as a result of drug selection, spontaneous mutation, or genetic reassortment with another drug-resistant influenza A virus (J. Infect. Dis. 2011;203[1]:13-7).

Of the nearly 1,500 virus samples submitted by surveillance programs around the world, 28 viruses from five countries in North America, Africa, and Asia, exhibited both adamantane and oseltamivir resistance, the investigators reported. The proportion of resistant viruses increased from 0.06% (1 of 1,753) of those for 2007-2008, to 1.5% in samples for 2008-2009 (21 of 1,426), and to 28% in a smaller number of samples from the 2009-2010 season (7 of 25), when fewer seasonal A strains were circulating. The dual-resistant viruses represented four different genotypes.

“Although dual-resistant viruses are still rare,” the researchers wrote, “the increase in prevalence among seasonal influenza A(H1N1) viruses was notable during the last three seasons.” Also, the detection of dual-resistant seasonal A(H1N1) viruses from five countries “warrants concern,” they wrote, “because of the limited treatment options currently available for dual-resistant influenza A viruses.”

In the U.K. study, clinical virologist Catherine Moore and Dr. Elori Davies of the Public Health Wales NHS Trust in Cardiff, and their colleagues, described the first molecularly confirmed person-to-person transmission of oseltamivir-resistant pandemic influenza A(H1N1) 2009 virus. After an outbreak of 11 cases in the hematology wing of a public hospital in October and November 2009, 10 were shown by sequencing to be virologically related, 8 were oseltamivir-resistant, and 4 of the 8 infections occurred by direct transmission of resistant virus.

Though the infected patients had considerable underlying disease, including leukemia, multiple myeloma, and lymphoma, influenza symptoms were generally manageable during the outbreak, and none of the patients died as a result of their resistant infections, Ms. Moore and colleagues reported (J. Infect. Dis. 2011; 203[1]:18-24).

Dual treatment with oseltamivir and zanamivir was used when resistant virus was suspected or confirmed. However, Ms. Moore and colleagues noted that “recent data suggest there is possibly no synergy to be gained from this approach.”

In an editorial comment accompanying the two studies, Dr. Frederick G. Hayden of the University of Virginia, Charlottesville, and Dr. Menno D. de Jong of the University of Amsterdam, the Netherlands, saw cautions in both. “Together, these findings illustrate that single reassortment events or mutations can lead to the emergence of transmissible variants of pandemic 2009 or seasonal A(H1N1) viruses unresponsive to most, if not all, of our currently available drugs,” they wrote (J. Infect. Dis. 2011; 203[1]6-10).

The study by Ms. Sheu and Dr. Gubareva was funded by the Centers for Disease Control and Prevention. The study by Ms. Moore and Dr. Davies was funded by their public institutions; one coauthor acknowledged funding from the Wellcome Trust for a virus-sequencing pipeline project and another received funding from Roche for an influenza virus shedding study in oseltamivir-treated patients.

Dr. Hayden reported that he has received no research grants or personal honoraria from industry since 2006, but that he has served as an unpaid adviser to multiple companies involved in the development of influenza antivirals since 2008, and is member of the Neuraminidase Inhibitor Susceptibility Network, which has received funds from GlaxoSmithKline and Roche.

Two publicly funded studies from the United States and England show that the proportion of seasonal influenza A viruses resistant to two types of antiviral drugs has risen in recent years, and that drug-resistant pandemic influenza A was transmitted person-to-person during one 2009 outbreak.

Both studies, published online Dec. 7 in the journal, highlight concerns about how easily influenza A(H1N1) viruses can develop mutations for resistance, about the paucity of treatment options available for resistant infections, and the risks of using potentially ineffective agents.

For the first study, Tiffany G. Sheu and Dr. Larisa Gubareva of the Centers for Disease Control and Prevention in Atlanta, and their colleagues, tested seasonal H1N1 viruses collected between 2008 and 2010 for resistance to two types of antivirals: oseltamivir and adamantane drugs. The researchers noted that resistance-conferring mutations in an influenza A virus can occur as a result of drug selection, spontaneous mutation, or genetic reassortment with another drug-resistant influenza A virus (J. Infect. Dis. 2011;203[1]:13-7).

Of the nearly 1,500 virus samples submitted by surveillance programs around the world, 28 viruses from five countries in North America, Africa, and Asia, exhibited both adamantane and oseltamivir resistance, the investigators reported. The proportion of resistant viruses increased from 0.06% (1 of 1,753) of those for 2007-2008, to 1.5% in samples for 2008-2009 (21 of 1,426), and to 28% in a smaller number of samples from the 2009-2010 season (7 of 25), when fewer seasonal A strains were circulating. The dual-resistant viruses represented four different genotypes.

“Although dual-resistant viruses are still rare,” the researchers wrote, “the increase in prevalence among seasonal influenza A(H1N1) viruses was notable during the last three seasons.” Also, the detection of dual-resistant seasonal A(H1N1) viruses from five countries “warrants concern,” they wrote, “because of the limited treatment options currently available for dual-resistant influenza A viruses.”

In the U.K. study, clinical virologist Catherine Moore and Dr. Elori Davies of the Public Health Wales NHS Trust in Cardiff, and their colleagues, described the first molecularly confirmed person-to-person transmission of oseltamivir-resistant pandemic influenza A(H1N1) 2009 virus. After an outbreak of 11 cases in the hematology wing of a public hospital in October and November 2009, 10 were shown by sequencing to be virologically related, 8 were oseltamivir-resistant, and 4 of the 8 infections occurred by direct transmission of resistant virus.

Though the infected patients had considerable underlying disease, including leukemia, multiple myeloma, and lymphoma, influenza symptoms were generally manageable during the outbreak, and none of the patients died as a result of their resistant infections, Ms. Moore and colleagues reported (J. Infect. Dis. 2011; 203[1]:18-24).

Dual treatment with oseltamivir and zanamivir was used when resistant virus was suspected or confirmed. However, Ms. Moore and colleagues noted that “recent data suggest there is possibly no synergy to be gained from this approach.”

In an editorial comment accompanying the two studies, Dr. Frederick G. Hayden of the University of Virginia, Charlottesville, and Dr. Menno D. de Jong of the University of Amsterdam, the Netherlands, saw cautions in both. “Together, these findings illustrate that single reassortment events or mutations can lead to the emergence of transmissible variants of pandemic 2009 or seasonal A(H1N1) viruses unresponsive to most, if not all, of our currently available drugs,” they wrote (J. Infect. Dis. 2011; 203[1]6-10).

The study by Ms. Sheu and Dr. Gubareva was funded by the Centers for Disease Control and Prevention. The study by Ms. Moore and Dr. Davies was funded by their public institutions; one coauthor acknowledged funding from the Wellcome Trust for a virus-sequencing pipeline project and another received funding from Roche for an influenza virus shedding study in oseltamivir-treated patients.

Dr. Hayden reported that he has received no research grants or personal honoraria from industry since 2006, but that he has served as an unpaid adviser to multiple companies involved in the development of influenza antivirals since 2008, and is member of the Neuraminidase Inhibitor Susceptibility Network, which has received funds from GlaxoSmithKline and Roche.

Smoking is implicated in over a third of cases of the most severe and common form of rheumatoid arthritis, researchers in Sweden have found, and in one in five cases of RA overall.

Results from a population-based study published online Dec. 14 in the Annals of the Rheumatic Diseases strengthened the growing body of evidence that links smoking with development of anti–citrullinated protein/peptide antibody (ACPA)–positive rheumatoid arthritis. In a dose-response manner, the link became stronger with heavier smoking, regardless of allele status.

The investigators, led by Henrik Källberg, Ph.D., of the Karolinska Institute in Stockholm, determined the excess fraction of RA cases attributable to smoking to be 20%, regardless of the presence of known genetic risk factors, which comprise single or dual copies of the HLA-DRB1 shared epitope.

Smoking was estimated to be responsible for 35% of ACPA-positive cases (31% for women and 42% for men), and for each copy of the HLA-DRB1 shared epitope (SE) that was found, smoking was dose-dependently associated with an increased risk of ACPA-positive RA. In people with two copies of the HLA-DRB1 SE, 55% of ACPA-positive RA was attributable to smoking, Dr. Källberg and colleagues determined.

Dr. Källberg and colleagues also found an increased risk of developing RA (OR, 1.9; 95% confidence interval, 1.1-3.5) among heavy smokers without any genetic risk factors. "That was one really interesting finding," Dr. Källberg said in an interview. "As a heavy smoker, you are almost two times more likely to develop RA" even without the HLA-DRB1 SE alleles, he said.

For their research, Dr. Källberg and colleagues collected blood samples and questionnaire information from 1,205 people who were diagnosed with RA according to the American College of Rheumatology’s 1987 criteria, as well as 872 healthy controls matched for age, sex, and geographic location. The cases were part of the Swedish EIRA (Epidemiological Investigation of Rheumatoid Arthritis) cohort study.

The questionnaires solicited information on past and current smoking, thereby allowing investigators to classify each subject by smoking history (current and former smokers of 0-9, 10-19, and 20 pack-years, with 1 pack-year defined as equaling 20 cigarettes per day for 1 year). The investigators tested blood samples for ACPA status and the presence of genotyped SE alleles.

The investigators calculated the odds ratios of developing RA associated with different smoking levels and SE alleles, together with 95% confidence intervals, by using logistic regression models. The interaction between smoking and the presence of SE alleles was evaluated as a departure from additive effects, and was estimated by calculating the attributable proportion due to interaction.

For former light and moderate smokers, the risk of developing RA declined and approached never-smoker levels the longer the person had not smoked since quitting. Former heavy smokers, however, continued to see elevated risk, even decades after quitting.

The dose-dependent association with smoking was "not a total surprise. We knew from earlier studies that there was some sort of relationship with the amount," Dr. Källberg said. "We just didn’t expect it to be so clear cut."

The fact that ex–heavy smokers continued to see elevated risk does not mean that smokers shouldn’t quit, Dr. Källberg said. "To some degree, the damage may be done, but we actually find that you gain something by quitting smoking. Quitting smoking can affect how well you respond to treatment."

Although smoking’s presence in RA is smaller than in lung cancer, it is "similar to that seen for ischemic heart disease," the investigators wrote in their analysis. Furthermore, cardiovascular disease is associated with RA and is the major cause of premature death in people with RA, according to the investigators (Ann. Rheum. Dis. 2010 Dec. 14 [doi:10.1136/ard.2009.120899]).

Dr. Källberg and colleagues noted that some other factors, such as air pollution, alcohol consumption, and hormonal differences could affect the smoking-RA interaction among populations. However, they wrote, they were confident – based on the age, sex, and residential matching of controls and cases within the same population – that their methodology was strong.

Dr. Källberg and colleagues’ study was funded by grants from the Swedish government; the insurance company AFA; the European Union; the Flight Attendant Medical Research Institute; National Institutes of Health; and the COMBINE (Controlling Chronic Inflammatory Diseases With Combined Efforts) project. Neither Dr. Källberg nor any of his colleagues declared conflicts of interest.

Smoking is implicated in over a third of cases of the most severe and common form of rheumatoid arthritis, researchers in Sweden have found, and in one in five cases of RA overall.

Results from a population-based study published online Dec. 14 in the Annals of the Rheumatic Diseases strengthened the growing body of evidence that links smoking with development of anti–citrullinated protein/peptide antibody (ACPA)–positive rheumatoid arthritis. In a dose-response manner, the link became stronger with heavier smoking, regardless of allele status.

The investigators, led by Henrik Källberg, Ph.D., of the Karolinska Institute in Stockholm, determined the excess fraction of RA cases attributable to smoking to be 20%, regardless of the presence of known genetic risk factors, which comprise single or dual copies of the HLA-DRB1 shared epitope.

Smoking was estimated to be responsible for 35% of ACPA-positive cases (31% for women and 42% for men), and for each copy of the HLA-DRB1 shared epitope (SE) that was found, smoking was dose-dependently associated with an increased risk of ACPA-positive RA. In people with two copies of the HLA-DRB1 SE, 55% of ACPA-positive RA was attributable to smoking, Dr. Källberg and colleagues determined.

Dr. Källberg and colleagues also found an increased risk of developing RA (OR, 1.9; 95% confidence interval, 1.1-3.5) among heavy smokers without any genetic risk factors. "That was one really interesting finding," Dr. Källberg said in an interview. "As a heavy smoker, you are almost two times more likely to develop RA" even without the HLA-DRB1 SE alleles, he said.

For their research, Dr. Källberg and colleagues collected blood samples and questionnaire information from 1,205 people who were diagnosed with RA according to the American College of Rheumatology’s 1987 criteria, as well as 872 healthy controls matched for age, sex, and geographic location. The cases were part of the Swedish EIRA (Epidemiological Investigation of Rheumatoid Arthritis) cohort study.

The questionnaires solicited information on past and current smoking, thereby allowing investigators to classify each subject by smoking history (current and former smokers of 0-9, 10-19, and 20 pack-years, with 1 pack-year defined as equaling 20 cigarettes per day for 1 year). The investigators tested blood samples for ACPA status and the presence of genotyped SE alleles.

The investigators calculated the odds ratios of developing RA associated with different smoking levels and SE alleles, together with 95% confidence intervals, by using logistic regression models. The interaction between smoking and the presence of SE alleles was evaluated as a departure from additive effects, and was estimated by calculating the attributable proportion due to interaction.

For former light and moderate smokers, the risk of developing RA declined and approached never-smoker levels the longer the person had not smoked since quitting. Former heavy smokers, however, continued to see elevated risk, even decades after quitting.

The dose-dependent association with smoking was "not a total surprise. We knew from earlier studies that there was some sort of relationship with the amount," Dr. Källberg said. "We just didn’t expect it to be so clear cut."

The fact that ex–heavy smokers continued to see elevated risk does not mean that smokers shouldn’t quit, Dr. Källberg said. "To some degree, the damage may be done, but we actually find that you gain something by quitting smoking. Quitting smoking can affect how well you respond to treatment."

Although smoking’s presence in RA is smaller than in lung cancer, it is "similar to that seen for ischemic heart disease," the investigators wrote in their analysis. Furthermore, cardiovascular disease is associated with RA and is the major cause of premature death in people with RA, according to the investigators (Ann. Rheum. Dis. 2010 Dec. 14 [doi:10.1136/ard.2009.120899]).

Dr. Källberg and colleagues noted that some other factors, such as air pollution, alcohol consumption, and hormonal differences could affect the smoking-RA interaction among populations. However, they wrote, they were confident – based on the age, sex, and residential matching of controls and cases within the same population – that their methodology was strong.

Dr. Källberg and colleagues’ study was funded by grants from the Swedish government; the insurance company AFA; the European Union; the Flight Attendant Medical Research Institute; National Institutes of Health; and the COMBINE (Controlling Chronic Inflammatory Diseases With Combined Efforts) project. Neither Dr. Källberg nor any of his colleagues declared conflicts of interest.

Smoking is implicated in over a third of cases of the most severe and common form of rheumatoid arthritis, researchers in Sweden have found, and in one in five cases of RA overall.

Results from a population-based study published online Dec. 14 in the Annals of the Rheumatic Diseases strengthened the growing body of evidence that links smoking with development of anti–citrullinated protein/peptide antibody (ACPA)–positive rheumatoid arthritis. In a dose-response manner, the link became stronger with heavier smoking, regardless of allele status.

The investigators, led by Henrik Källberg, Ph.D., of the Karolinska Institute in Stockholm, determined the excess fraction of RA cases attributable to smoking to be 20%, regardless of the presence of known genetic risk factors, which comprise single or dual copies of the HLA-DRB1 shared epitope.

Smoking was estimated to be responsible for 35% of ACPA-positive cases (31% for women and 42% for men), and for each copy of the HLA-DRB1 shared epitope (SE) that was found, smoking was dose-dependently associated with an increased risk of ACPA-positive RA. In people with two copies of the HLA-DRB1 SE, 55% of ACPA-positive RA was attributable to smoking, Dr. Källberg and colleagues determined.

Dr. Källberg and colleagues also found an increased risk of developing RA (OR, 1.9; 95% confidence interval, 1.1-3.5) among heavy smokers without any genetic risk factors. "That was one really interesting finding," Dr. Källberg said in an interview. "As a heavy smoker, you are almost two times more likely to develop RA" even without the HLA-DRB1 SE alleles, he said.

For their research, Dr. Källberg and colleagues collected blood samples and questionnaire information from 1,205 people who were diagnosed with RA according to the American College of Rheumatology’s 1987 criteria, as well as 872 healthy controls matched for age, sex, and geographic location. The cases were part of the Swedish EIRA (Epidemiological Investigation of Rheumatoid Arthritis) cohort study.

The questionnaires solicited information on past and current smoking, thereby allowing investigators to classify each subject by smoking history (current and former smokers of 0-9, 10-19, and 20 pack-years, with 1 pack-year defined as equaling 20 cigarettes per day for 1 year). The investigators tested blood samples for ACPA status and the presence of genotyped SE alleles.

The investigators calculated the odds ratios of developing RA associated with different smoking levels and SE alleles, together with 95% confidence intervals, by using logistic regression models. The interaction between smoking and the presence of SE alleles was evaluated as a departure from additive effects, and was estimated by calculating the attributable proportion due to interaction.

For former light and moderate smokers, the risk of developing RA declined and approached never-smoker levels the longer the person had not smoked since quitting. Former heavy smokers, however, continued to see elevated risk, even decades after quitting.

The dose-dependent association with smoking was "not a total surprise. We knew from earlier studies that there was some sort of relationship with the amount," Dr. Källberg said. "We just didn’t expect it to be so clear cut."

The fact that ex–heavy smokers continued to see elevated risk does not mean that smokers shouldn’t quit, Dr. Källberg said. "To some degree, the damage may be done, but we actually find that you gain something by quitting smoking. Quitting smoking can affect how well you respond to treatment."

Although smoking’s presence in RA is smaller than in lung cancer, it is "similar to that seen for ischemic heart disease," the investigators wrote in their analysis. Furthermore, cardiovascular disease is associated with RA and is the major cause of premature death in people with RA, according to the investigators (Ann. Rheum. Dis. 2010 Dec. 14 [doi:10.1136/ard.2009.120899]).

Dr. Källberg and colleagues noted that some other factors, such as air pollution, alcohol consumption, and hormonal differences could affect the smoking-RA interaction among populations. However, they wrote, they were confident – based on the age, sex, and residential matching of controls and cases within the same population – that their methodology was strong.

Dr. Källberg and colleagues’ study was funded by grants from the Swedish government; the insurance company AFA; the European Union; the Flight Attendant Medical Research Institute; National Institutes of Health; and the COMBINE (Controlling Chronic Inflammatory Diseases With Combined Efforts) project. Neither Dr. Källberg nor any of his colleagues declared conflicts of interest.

The European Medicines Agency said Dec. 10 that it was reviewing the safety of somatropin-containing medicines, following reports linking these to increased mortality in people treated with them as children.

Somatropin is a recombinant human growth hormone used to counter very short stature in growing children. The EMA said it had launched the review in response to preliminary results from an observational study of over 10,000 French patients begun in 2007. The EMA said that AFSSAPS, the French Agency for the Safety of Health Products, brought the issue to its attention.

Approximately 40,000 European children are treated with daily injections of somatropin-containing medicines, according to the official Web site of the Safety and Appropriateness of Growth hormone treatments in Europe, or SAGhE study, which is funded by the European Community and health agencies in eight European countries.

The SAGhE study, which began in France in 2007, last year expanded recruitment to Belgium, Germany, Italy, the Netherlands, Sweden, Switzerland, and the United Kingdom, and intends to evaluate 30,000 patients. The study is looking into overall and cancer-related mortality in relation to treatment with somatropin-containing medicines. It is scheduled to end on May 31, 2012.

The preliminary French results, the EMA said on Dec. 10, "suggest an increased risk of mortality with somatropin therapy compared to the general population. The risk appears to be particularly increased when high doses are used (beyond doses as recommended in the Summary of Product Characteristics)." The agency did not detail or publish the results, however, and cautioned that they need to be confirmed through further analysis.

The three somatropin-containing medicines licensed throughout the European Union are NutropinAq, Omnitrope, and Valtropin. Other somatropin-containing medicines are licensed by individual EU countries.

The European Medicines Agency said Dec. 10 that it was reviewing the safety of somatropin-containing medicines, following reports linking these to increased mortality in people treated with them as children.

Somatropin is a recombinant human growth hormone used to counter very short stature in growing children. The EMA said it had launched the review in response to preliminary results from an observational study of over 10,000 French patients begun in 2007. The EMA said that AFSSAPS, the French Agency for the Safety of Health Products, brought the issue to its attention.

Approximately 40,000 European children are treated with daily injections of somatropin-containing medicines, according to the official Web site of the Safety and Appropriateness of Growth hormone treatments in Europe, or SAGhE study, which is funded by the European Community and health agencies in eight European countries.

The SAGhE study, which began in France in 2007, last year expanded recruitment to Belgium, Germany, Italy, the Netherlands, Sweden, Switzerland, and the United Kingdom, and intends to evaluate 30,000 patients. The study is looking into overall and cancer-related mortality in relation to treatment with somatropin-containing medicines. It is scheduled to end on May 31, 2012.

The preliminary French results, the EMA said on Dec. 10, "suggest an increased risk of mortality with somatropin therapy compared to the general population. The risk appears to be particularly increased when high doses are used (beyond doses as recommended in the Summary of Product Characteristics)." The agency did not detail or publish the results, however, and cautioned that they need to be confirmed through further analysis.

The three somatropin-containing medicines licensed throughout the European Union are NutropinAq, Omnitrope, and Valtropin. Other somatropin-containing medicines are licensed by individual EU countries.

The European Medicines Agency said Dec. 10 that it was reviewing the safety of somatropin-containing medicines, following reports linking these to increased mortality in people treated with them as children.

Somatropin is a recombinant human growth hormone used to counter very short stature in growing children. The EMA said it had launched the review in response to preliminary results from an observational study of over 10,000 French patients begun in 2007. The EMA said that AFSSAPS, the French Agency for the Safety of Health Products, brought the issue to its attention.

Approximately 40,000 European children are treated with daily injections of somatropin-containing medicines, according to the official Web site of the Safety and Appropriateness of Growth hormone treatments in Europe, or SAGhE study, which is funded by the European Community and health agencies in eight European countries.

The SAGhE study, which began in France in 2007, last year expanded recruitment to Belgium, Germany, Italy, the Netherlands, Sweden, Switzerland, and the United Kingdom, and intends to evaluate 30,000 patients. The study is looking into overall and cancer-related mortality in relation to treatment with somatropin-containing medicines. It is scheduled to end on May 31, 2012.

The preliminary French results, the EMA said on Dec. 10, "suggest an increased risk of mortality with somatropin therapy compared to the general population. The risk appears to be particularly increased when high doses are used (beyond doses as recommended in the Summary of Product Characteristics)." The agency did not detail or publish the results, however, and cautioned that they need to be confirmed through further analysis.

The three somatropin-containing medicines licensed throughout the European Union are NutropinAq, Omnitrope, and Valtropin. Other somatropin-containing medicines are licensed by individual EU countries.

The European Medicines Agency said Dec. 10 that it was reviewing the safety of somatropin-containing medicines, following reports linking these to increased mortality in people treated with them as children.

Somatropin is a recombinant human growth hormone used to counter very short stature in growing children. The EMA said it had launched the review in response to preliminary results from an observational study of over 10,000 French patients begun in 2007. The EMA said that AFSSAPS, the French Agency for the Safety of Health Products, brought the issue to its attention.

Approximately 40,000 European children are treated with daily injections of somatropin-containing medicines, according to the official Web site of the Safety and Appropriateness of Growth hormone treatments in Europe, or SAGhE study, which is funded by the European Community and health agencies in eight European countries.

The SAGhE study, which began in France in 2007, last year expanded recruitment to Belgium, Germany, Italy, the Netherlands, Sweden, Switzerland, and the United Kingdom, and intends to evaluate 30,000 patients. The study is looking into overall and cancer-related mortality in relation to treatment with somatropin-containing medicines. It is scheduled to end on May 31, 2012.

The preliminary French results, the EMA said on Dec. 10, "suggest an increased risk of mortality with somatropin therapy compared to the general population. The risk appears to be particularly increased when high doses are used (beyond doses as recommended in the Summary of Product Characteristics)." The agency did not detail or publish the results, however, and cautioned that they need to be confirmed through further analysis.

The three somatropin-containing medicines licensed throughout the European Union are NutropinAq, Omnitrope, and Valtropin. Other somatropin-containing medicines are licensed by individual EU countries.

The European Medicines Agency said Dec. 10 that it was reviewing the safety of somatropin-containing medicines, following reports linking these to increased mortality in people treated with them as children.

Somatropin is a recombinant human growth hormone used to counter very short stature in growing children. The EMA said it had launched the review in response to preliminary results from an observational study of over 10,000 French patients begun in 2007. The EMA said that AFSSAPS, the French Agency for the Safety of Health Products, brought the issue to its attention.

Approximately 40,000 European children are treated with daily injections of somatropin-containing medicines, according to the official Web site of the Safety and Appropriateness of Growth hormone treatments in Europe, or SAGhE study, which is funded by the European Community and health agencies in eight European countries.

The SAGhE study, which began in France in 2007, last year expanded recruitment to Belgium, Germany, Italy, the Netherlands, Sweden, Switzerland, and the United Kingdom, and intends to evaluate 30,000 patients. The study is looking into overall and cancer-related mortality in relation to treatment with somatropin-containing medicines. It is scheduled to end on May 31, 2012.

The preliminary French results, the EMA said on Dec. 10, "suggest an increased risk of mortality with somatropin therapy compared to the general population. The risk appears to be particularly increased when high doses are used (beyond doses as recommended in the Summary of Product Characteristics)." The agency did not detail or publish the results, however, and cautioned that they need to be confirmed through further analysis.

The three somatropin-containing medicines licensed throughout the European Union are NutropinAq, Omnitrope, and Valtropin. Other somatropin-containing medicines are licensed by individual EU countries.

The European Medicines Agency said Dec. 10 that it was reviewing the safety of somatropin-containing medicines, following reports linking these to increased mortality in people treated with them as children.

Somatropin is a recombinant human growth hormone used to counter very short stature in growing children. The EMA said it had launched the review in response to preliminary results from an observational study of over 10,000 French patients begun in 2007. The EMA said that AFSSAPS, the French Agency for the Safety of Health Products, brought the issue to its attention.

Approximately 40,000 European children are treated with daily injections of somatropin-containing medicines, according to the official Web site of the Safety and Appropriateness of Growth hormone treatments in Europe, or SAGhE study, which is funded by the European Community and health agencies in eight European countries.

The SAGhE study, which began in France in 2007, last year expanded recruitment to Belgium, Germany, Italy, the Netherlands, Sweden, Switzerland, and the United Kingdom, and intends to evaluate 30,000 patients. The study is looking into overall and cancer-related mortality in relation to treatment with somatropin-containing medicines. It is scheduled to end on May 31, 2012.

The preliminary French results, the EMA said on Dec. 10, "suggest an increased risk of mortality with somatropin therapy compared to the general population. The risk appears to be particularly increased when high doses are used (beyond doses as recommended in the Summary of Product Characteristics)." The agency did not detail or publish the results, however, and cautioned that they need to be confirmed through further analysis.

The three somatropin-containing medicines licensed throughout the European Union are NutropinAq, Omnitrope, and Valtropin. Other somatropin-containing medicines are licensed by individual EU countries.

Two publicly funded studies from the United States and England show that the proportion of seasonal influenza A viruses resistant to two types of antiviral drugs has risen in recent years, and that drug-resistant pandemic influenza A was transmitted person-to-person during one 2009 outbreak.

Both studies, published online Dec. 7 in the Journal of Infectious Diseases, highlight concerns about how easily influenza A(H1N1) viruses can develop mutations for resistance, about the paucity of treatment options available for resistant infections, and the risks of using potentially ineffective agents.

For the first study, Tiffany G. Sheu and Dr. Larisa Gubareva of the Centers for Disease Control and Prevention in Atlanta, and their colleagues, tested seasonal H1N1 viruses collected between 2008 and 2010 for resistance to two types of antivirals: oseltamivir and adamantane drugs. The investigators noted that resistance-conferring mutations in an influenza A virus can occur as a result of drug selection, spontaneous mutation, or genetic reassortment with another drug-resistant influenza A virus (J. Infect. Dis. 2011;203:13-7).

Of the nearly 1,500 virus samples submitted by surveillance programs around the world, 28 viruses from 5 countries in North America, Africa, and Asia, exhibited both adamantane and oseltamivir resistance, the investigators reported. The proportion of resistant viruses increased from .06% (1 of 1,753) of those from 2007-2008, to 1.5% in samples from 2008-2009 (21 of 1,426), and to 28% in a smaller number of samples from the 2009-2010 season (7 of 25), when fewer seasonal A strains were circulating. The dual-resistant viruses represented 4 different genotypes.

"Although dual-resistant viruses are still rare," the researchers wrote, "the increase in prevalence among seasonal influenza A(H1N1) viruses was notable during the last 3 seasons." Also, the detection of dual-resistant seasonal A(H1N1) viruses from 5 countries "warrants concern," they wrote, "because of the limited treatment options currently available for dual-resistant influenza A viruses."

In the U.K. study, clinical virologist Catherine Moore and Dr. Elori Davies of the Public Health Wales NHS Trust in Cardiff, and their colleagues, described the first molecularly confirmed person-to-person transmission of oseltamivir-resistant pandemic influenza A(H1N1) 2009 virus. After an outbreak of 11 cases in the hematology wing of a public hospital in October and November 2009, 10 were shown by sequencing to be virologically related, 8 were oseltamivir-resistant, and 4 of the 8 infections occurred by direct transmission of resistant virus.

Though the infected patients had considerable underlying disease, including leukemia, multiple myeloma, and lymphoma, influenza symptoms were generally manageable during the outbreak, and none of the patients died as a result of their resistant infections, Moore and colleagues reported (J. Infect. Dis. 2011;203:18-24).

Dual treatment with oseltamivir and zanamivir was used when resistant virus was suspected or confirmed. However, Moore and colleagues noted, "recent data suggest there is possibly no synergy to be gained from this approach," and "zanamivir alone therefore would be preferable as a frontline treatment in particularly high-risk groups."

Two publicly funded studies from the United States and England show that the proportion of seasonal influenza A viruses resistant to two types of antiviral drugs has risen in recent years, and that drug-resistant pandemic influenza A was transmitted person-to-person during one 2009 outbreak.

Both studies, published online Dec. 7 in the Journal of Infectious Diseases, highlight concerns about how easily influenza A(H1N1) viruses can develop mutations for resistance, about the paucity of treatment options available for resistant infections, and the risks of using potentially ineffective agents.

For the first study, Tiffany G. Sheu and Dr. Larisa Gubareva of the Centers for Disease Control and Prevention in Atlanta, and their colleagues, tested seasonal H1N1 viruses collected between 2008 and 2010 for resistance to two types of antivirals: oseltamivir and adamantane drugs. The investigators noted that resistance-conferring mutations in an influenza A virus can occur as a result of drug selection, spontaneous mutation, or genetic reassortment with another drug-resistant influenza A virus (J. Infect. Dis. 2011;203:13-7).

Of the nearly 1,500 virus samples submitted by surveillance programs around the world, 28 viruses from 5 countries in North America, Africa, and Asia, exhibited both adamantane and oseltamivir resistance, the investigators reported. The proportion of resistant viruses increased from .06% (1 of 1,753) of those from 2007-2008, to 1.5% in samples from 2008-2009 (21 of 1,426), and to 28% in a smaller number of samples from the 2009-2010 season (7 of 25), when fewer seasonal A strains were circulating. The dual-resistant viruses represented 4 different genotypes.

"Although dual-resistant viruses are still rare," the researchers wrote, "the increase in prevalence among seasonal influenza A(H1N1) viruses was notable during the last 3 seasons." Also, the detection of dual-resistant seasonal A(H1N1) viruses from 5 countries "warrants concern," they wrote, "because of the limited treatment options currently available for dual-resistant influenza A viruses."

In the U.K. study, clinical virologist Catherine Moore and Dr. Elori Davies of the Public Health Wales NHS Trust in Cardiff, and their colleagues, described the first molecularly confirmed person-to-person transmission of oseltamivir-resistant pandemic influenza A(H1N1) 2009 virus. After an outbreak of 11 cases in the hematology wing of a public hospital in October and November 2009, 10 were shown by sequencing to be virologically related, 8 were oseltamivir-resistant, and 4 of the 8 infections occurred by direct transmission of resistant virus.

Though the infected patients had considerable underlying disease, including leukemia, multiple myeloma, and lymphoma, influenza symptoms were generally manageable during the outbreak, and none of the patients died as a result of their resistant infections, Moore and colleagues reported (J. Infect. Dis. 2011;203:18-24).

Dual treatment with oseltamivir and zanamivir was used when resistant virus was suspected or confirmed. However, Moore and colleagues noted, "recent data suggest there is possibly no synergy to be gained from this approach," and "zanamivir alone therefore would be preferable as a frontline treatment in particularly high-risk groups."

Two publicly funded studies from the United States and England show that the proportion of seasonal influenza A viruses resistant to two types of antiviral drugs has risen in recent years, and that drug-resistant pandemic influenza A was transmitted person-to-person during one 2009 outbreak.

Both studies, published online Dec. 7 in the Journal of Infectious Diseases, highlight concerns about how easily influenza A(H1N1) viruses can develop mutations for resistance, about the paucity of treatment options available for resistant infections, and the risks of using potentially ineffective agents.

For the first study, Tiffany G. Sheu and Dr. Larisa Gubareva of the Centers for Disease Control and Prevention in Atlanta, and their colleagues, tested seasonal H1N1 viruses collected between 2008 and 2010 for resistance to two types of antivirals: oseltamivir and adamantane drugs. The investigators noted that resistance-conferring mutations in an influenza A virus can occur as a result of drug selection, spontaneous mutation, or genetic reassortment with another drug-resistant influenza A virus (J. Infect. Dis. 2011;203:13-7).

Of the nearly 1,500 virus samples submitted by surveillance programs around the world, 28 viruses from 5 countries in North America, Africa, and Asia, exhibited both adamantane and oseltamivir resistance, the investigators reported. The proportion of resistant viruses increased from .06% (1 of 1,753) of those from 2007-2008, to 1.5% in samples from 2008-2009 (21 of 1,426), and to 28% in a smaller number of samples from the 2009-2010 season (7 of 25), when fewer seasonal A strains were circulating. The dual-resistant viruses represented 4 different genotypes.

"Although dual-resistant viruses are still rare," the researchers wrote, "the increase in prevalence among seasonal influenza A(H1N1) viruses was notable during the last 3 seasons." Also, the detection of dual-resistant seasonal A(H1N1) viruses from 5 countries "warrants concern," they wrote, "because of the limited treatment options currently available for dual-resistant influenza A viruses."

In the U.K. study, clinical virologist Catherine Moore and Dr. Elori Davies of the Public Health Wales NHS Trust in Cardiff, and their colleagues, described the first molecularly confirmed person-to-person transmission of oseltamivir-resistant pandemic influenza A(H1N1) 2009 virus. After an outbreak of 11 cases in the hematology wing of a public hospital in October and November 2009, 10 were shown by sequencing to be virologically related, 8 were oseltamivir-resistant, and 4 of the 8 infections occurred by direct transmission of resistant virus.

Though the infected patients had considerable underlying disease, including leukemia, multiple myeloma, and lymphoma, influenza symptoms were generally manageable during the outbreak, and none of the patients died as a result of their resistant infections, Moore and colleagues reported (J. Infect. Dis. 2011;203:18-24).

Dual treatment with oseltamivir and zanamivir was used when resistant virus was suspected or confirmed. However, Moore and colleagues noted, "recent data suggest there is possibly no synergy to be gained from this approach," and "zanamivir alone therefore would be preferable as a frontline treatment in particularly high-risk groups."

Two publicly funded studies from the United States and England show that the proportion of seasonal influenza A viruses resistant to two types of antiviral drugs has risen in recent years, and that drug-resistant pandemic influenza A was transmitted person-to-person during one 2009 outbreak.

Both studies, published online Dec. 7 in the Journal of Infectious Diseases, highlight concerns about how easily influenza A/H1N1 viruses can develop mutations for resistance, about the paucity of treatment options available for resistant infections, and the risks of using potentially ineffective agents.

For the first study, Tiffany G. Sheu and Dr. Larisa Gubareva of the Centers for Disease Control and Prevention in Atlanta, and their colleagues, tested seasonal H1N1 viruses collected between 2008 and 2010 for resistance to two types of antivirals: oseltamivir and adamantane drugs. The investigators noted that resistance-conferring mutations in an influenza A virus can occur as a result of drug selection, spontaneous mutation, or genetic reassortment with another drug-resistant influenza A virus (J. Infect. Dis. 2011;203[1]:13-7).

Of the nearly 1,500 virus samples submitted by surveillance programs around the world, 28 viruses from 5 countries in North America, Africa, and Asia, exhibited both adamantane and oseltamivir resistance, the investigators reported. The proportion of resistant viruses increased from .06% (1 of 1,753) of those from 2007-2008, to 1.5% in samples from 2008-2009 (21 of 1,426), and to 28% in a smaller number of samples from the 2009-2010 season (7 of 25), when fewer seasonal A strains were circulating. The dual-resistant viruses represented 4 different genotypes.

"Although dual-resistant viruses are still rare," the researchers wrote, "the increase in prevalence among seasonal influenza A(H1N1) viruses was notable during the last 3 seasons." Also, the detection of dual-resistant seasonal A(H1N1) viruses from 5 countries "warrants concern," they wrote, "because of the limited treatment options currently available for dual-resistant influenza A viruses."

In the U.K. study, clinical virologist Catherine Moore and Dr. Elori Davies of the Public Health Wales NHS Trust in Cardiff, and their colleagues, described the first molecularly confirmed person-to-person transmission of oseltamivir-resistant pandemic influenza A(H1N1) 2009 virus. After an outbreak of 11 cases in the hematology wing of a public hospital in October and November 2009, 10 were shown by sequencing to be virologically related, 8 were oseltamivir-resistant, and 4 of the 8 infections occurred by direct transmission of resistant virus.

Though the infected patients had considerable underlying disease, including leukemia, multiple myeloma, and lymphoma, influenza symptoms were generally manageable during the outbreak, and none of the patients died as a result of their resistant infections, Moore and colleagues reported (J. Infect. Dis. 2011;203[1]:18-24).

Dual treatment with oseltamivir and zanamivir was used when resistant virus was suspected or confirmed. However, Moore and colleagues noted, "recent data suggest there is possibly no synergy to be gained from this approach," and "zanamivir alone therefore would be preferable as a frontline treatment in particularly high-risk groups."

In an editorial comment accompanying the two studies, Dr. Frederick G. Hayden of the University of Virginia, Charlottesville, and Dr. Menno D. de Jong of the University of Amsterdam, the Netherlands, saw cautions in both. "Together, these findings illustrate that single reassortment events or mutations can lead to the emergence of transmissible variants of pandemic 2009 or seasonal A(H1N1) viruses unresponsive to most, if not all, of our currently available drugs. This raises multiple questions regarding patient management and preparations for future influenza outbreaks," they wrote (J. Infect. Dis. 2011;203[1]6-10).

The study by Ms. Sheu and Dr. Gubareva was funded by the Centers for Disease Control and Prevention. The study by Ms. Moore and Dr. Davies was funded by their public institutions; one coauthors acknowledged funding from the Wellcome Trust for a virus-sequencing pipeline project and another received funding from Roche for an influenza virus shedding study in oseltamivir-treated patients.

Dr. Hayden reported that he has received no research grants or personal honoraria from industry since 2006, but that he has served as an unpaid adviser to multiple companies involved in the development of influenza antivirals since 2008, and is member of the Neuraminidase Inhibitor Susceptibility Network, which has received funds from GlaxoSmithKline and Roche.

Two publicly funded studies from the United States and England show that the proportion of seasonal influenza A viruses resistant to two types of antiviral drugs has risen in recent years, and that drug-resistant pandemic influenza A was transmitted person-to-person during one 2009 outbreak.

Both studies, published online Dec. 7 in the Journal of Infectious Diseases, highlight concerns about how easily influenza A/H1N1 viruses can develop mutations for resistance, about the paucity of treatment options available for resistant infections, and the risks of using potentially ineffective agents.

For the first study, Tiffany G. Sheu and Dr. Larisa Gubareva of the Centers for Disease Control and Prevention in Atlanta, and their colleagues, tested seasonal H1N1 viruses collected between 2008 and 2010 for resistance to two types of antivirals: oseltamivir and adamantane drugs. The investigators noted that resistance-conferring mutations in an influenza A virus can occur as a result of drug selection, spontaneous mutation, or genetic reassortment with another drug-resistant influenza A virus (J. Infect. Dis. 2011;203[1]:13-7).

Of the nearly 1,500 virus samples submitted by surveillance programs around the world, 28 viruses from 5 countries in North America, Africa, and Asia, exhibited both adamantane and oseltamivir resistance, the investigators reported. The proportion of resistant viruses increased from .06% (1 of 1,753) of those from 2007-2008, to 1.5% in samples from 2008-2009 (21 of 1,426), and to 28% in a smaller number of samples from the 2009-2010 season (7 of 25), when fewer seasonal A strains were circulating. The dual-resistant viruses represented 4 different genotypes.

"Although dual-resistant viruses are still rare," the researchers wrote, "the increase in prevalence among seasonal influenza A(H1N1) viruses was notable during the last 3 seasons." Also, the detection of dual-resistant seasonal A(H1N1) viruses from 5 countries "warrants concern," they wrote, "because of the limited treatment options currently available for dual-resistant influenza A viruses."

In the U.K. study, clinical virologist Catherine Moore and Dr. Elori Davies of the Public Health Wales NHS Trust in Cardiff, and their colleagues, described the first molecularly confirmed person-to-person transmission of oseltamivir-resistant pandemic influenza A(H1N1) 2009 virus. After an outbreak of 11 cases in the hematology wing of a public hospital in October and November 2009, 10 were shown by sequencing to be virologically related, 8 were oseltamivir-resistant, and 4 of the 8 infections occurred by direct transmission of resistant virus.

Though the infected patients had considerable underlying disease, including leukemia, multiple myeloma, and lymphoma, influenza symptoms were generally manageable during the outbreak, and none of the patients died as a result of their resistant infections, Moore and colleagues reported (J. Infect. Dis. 2011;203[1]:18-24).

Dual treatment with oseltamivir and zanamivir was used when resistant virus was suspected or confirmed. However, Moore and colleagues noted, "recent data suggest there is possibly no synergy to be gained from this approach," and "zanamivir alone therefore would be preferable as a frontline treatment in particularly high-risk groups."

In an editorial comment accompanying the two studies, Dr. Frederick G. Hayden of the University of Virginia, Charlottesville, and Dr. Menno D. de Jong of the University of Amsterdam, the Netherlands, saw cautions in both. "Together, these findings illustrate that single reassortment events or mutations can lead to the emergence of transmissible variants of pandemic 2009 or seasonal A(H1N1) viruses unresponsive to most, if not all, of our currently available drugs. This raises multiple questions regarding patient management and preparations for future influenza outbreaks," they wrote (J. Infect. Dis. 2011;203[1]6-10).

The study by Ms. Sheu and Dr. Gubareva was funded by the Centers for Disease Control and Prevention. The study by Ms. Moore and Dr. Davies was funded by their public institutions; one coauthors acknowledged funding from the Wellcome Trust for a virus-sequencing pipeline project and another received funding from Roche for an influenza virus shedding study in oseltamivir-treated patients.

Dr. Hayden reported that he has received no research grants or personal honoraria from industry since 2006, but that he has served as an unpaid adviser to multiple companies involved in the development of influenza antivirals since 2008, and is member of the Neuraminidase Inhibitor Susceptibility Network, which has received funds from GlaxoSmithKline and Roche.

Two publicly funded studies from the United States and England show that the proportion of seasonal influenza A viruses resistant to two types of antiviral drugs has risen in recent years, and that drug-resistant pandemic influenza A was transmitted person-to-person during one 2009 outbreak.

Both studies, published online Dec. 7 in the Journal of Infectious Diseases, highlight concerns about how easily influenza A/H1N1 viruses can develop mutations for resistance, about the paucity of treatment options available for resistant infections, and the risks of using potentially ineffective agents.

For the first study, Tiffany G. Sheu and Dr. Larisa Gubareva of the Centers for Disease Control and Prevention in Atlanta, and their colleagues, tested seasonal H1N1 viruses collected between 2008 and 2010 for resistance to two types of antivirals: oseltamivir and adamantane drugs. The investigators noted that resistance-conferring mutations in an influenza A virus can occur as a result of drug selection, spontaneous mutation, or genetic reassortment with another drug-resistant influenza A virus (J. Infect. Dis. 2011;203[1]:13-7).

Of the nearly 1,500 virus samples submitted by surveillance programs around the world, 28 viruses from 5 countries in North America, Africa, and Asia, exhibited both adamantane and oseltamivir resistance, the investigators reported. The proportion of resistant viruses increased from .06% (1 of 1,753) of those from 2007-2008, to 1.5% in samples from 2008-2009 (21 of 1,426), and to 28% in a smaller number of samples from the 2009-2010 season (7 of 25), when fewer seasonal A strains were circulating. The dual-resistant viruses represented 4 different genotypes.

"Although dual-resistant viruses are still rare," the researchers wrote, "the increase in prevalence among seasonal influenza A(H1N1) viruses was notable during the last 3 seasons." Also, the detection of dual-resistant seasonal A(H1N1) viruses from 5 countries "warrants concern," they wrote, "because of the limited treatment options currently available for dual-resistant influenza A viruses."

In the U.K. study, clinical virologist Catherine Moore and Dr. Elori Davies of the Public Health Wales NHS Trust in Cardiff, and their colleagues, described the first molecularly confirmed person-to-person transmission of oseltamivir-resistant pandemic influenza A(H1N1) 2009 virus. After an outbreak of 11 cases in the hematology wing of a public hospital in October and November 2009, 10 were shown by sequencing to be virologically related, 8 were oseltamivir-resistant, and 4 of the 8 infections occurred by direct transmission of resistant virus.

Though the infected patients had considerable underlying disease, including leukemia, multiple myeloma, and lymphoma, influenza symptoms were generally manageable during the outbreak, and none of the patients died as a result of their resistant infections, Moore and colleagues reported (J. Infect. Dis. 2011;203[1]:18-24).

Dual treatment with oseltamivir and zanamivir was used when resistant virus was suspected or confirmed. However, Moore and colleagues noted, "recent data suggest there is possibly no synergy to be gained from this approach," and "zanamivir alone therefore would be preferable as a frontline treatment in particularly high-risk groups."

In an editorial comment accompanying the two studies, Dr. Frederick G. Hayden of the University of Virginia, Charlottesville, and Dr. Menno D. de Jong of the University of Amsterdam, the Netherlands, saw cautions in both. "Together, these findings illustrate that single reassortment events or mutations can lead to the emergence of transmissible variants of pandemic 2009 or seasonal A(H1N1) viruses unresponsive to most, if not all, of our currently available drugs. This raises multiple questions regarding patient management and preparations for future influenza outbreaks," they wrote (J. Infect. Dis. 2011;203[1]6-10).

The study by Ms. Sheu and Dr. Gubareva was funded by the Centers for Disease Control and Prevention. The study by Ms. Moore and Dr. Davies was funded by their public institutions; one coauthors acknowledged funding from the Wellcome Trust for a virus-sequencing pipeline project and another received funding from Roche for an influenza virus shedding study in oseltamivir-treated patients.

Dr. Hayden reported that he has received no research grants or personal honoraria from industry since 2006, but that he has served as an unpaid adviser to multiple companies involved in the development of influenza antivirals since 2008, and is member of the Neuraminidase Inhibitor Susceptibility Network, which has received funds from GlaxoSmithKline and Roche.

Two publicly funded studies from the United States and England show that the proportion of seasonal influenza A viruses resistant to two types of antiviral drugs has risen in recent years, and that drug-resistant pandemic influenza A was transmitted person-to-person during one 2009 outbreak.

Both studies, published online Dec. 7 in the Journal of Infectious Diseases, highlight concerns about how easily influenza A/H1N1 viruses can develop mutations for resistance, about the paucity of treatment options available for resistant infections, and the risks of using potentially ineffective agents.

For the first study, Tiffany G. Sheu and Dr. Larisa Gubareva of the Centers for Disease Control and Prevention in Atlanta, and their colleagues, tested seasonal H1N1 viruses collected between 2008 and 2010 for resistance to two types of antivirals: oseltamivir and adamantane drugs. The investigators noted that resistance-conferring mutations in an influenza A virus can occur as a result of drug selection, spontaneous mutation, or genetic reassortment with another drug-resistant influenza A virus (J. Infect. Dis. 2011;203[1]:13-7).

Of the nearly 1,500 virus samples submitted by surveillance programs around the world, 28 viruses from 5 countries in North America, Africa, and Asia, exhibited both adamantane and oseltamivir resistance, the investigators reported. The proportion of resistant viruses increased from .06% (1 of 1,753) of those from 2007-2008, to 1.5% in samples from 2008-2009 (21 of 1,426), and to 28% in a smaller number of samples from the 2009-2010 season (7 of 25), when fewer seasonal A strains were circulating. The dual-resistant viruses represented 4 different genotypes.

"Although dual-resistant viruses are still rare," the researchers wrote, "the increase in prevalence among seasonal influenza A(H1N1) viruses was notable during the last 3 seasons." Also, the detection of dual-resistant seasonal A(H1N1) viruses from 5 countries "warrants concern," they wrote, "because of the limited treatment options currently available for dual-resistant influenza A viruses."

In the U.K. study, clinical virologist Catherine Moore and Dr. Elori Davies of the Public Health Wales NHS Trust in Cardiff, and their colleagues, described the first molecularly confirmed person-to-person transmission of oseltamivir-resistant pandemic influenza A(H1N1) 2009 virus. After an outbreak of 11 cases in the hematology wing of a public hospital in October and November 2009, 10 were shown by sequencing to be virologically related, 8 were oseltamivir-resistant, and 4 of the 8 infections occurred by direct transmission of resistant virus.

Though the infected patients had considerable underlying disease, including leukemia, multiple myeloma, and lymphoma, influenza symptoms were generally manageable during the outbreak, and none of the patients died as a result of their resistant infections, Moore and colleagues reported (J. Infect. Dis. 2011;203[1]:18-24).

Dual treatment with oseltamivir and zanamivir was used when resistant virus was suspected or confirmed. However, Moore and colleagues noted, "recent data suggest there is possibly no synergy to be gained from this approach," and "zanamivir alone therefore would be preferable as a frontline treatment in particularly high-risk groups."

In an editorial comment accompanying the two studies, Dr. Frederick G. Hayden of the University of Virginia, Charlottesville, and Dr. Menno D. de Jong of the University of Amsterdam, the Netherlands, saw cautions in both. "Together, these findings illustrate that single reassortment events or mutations can lead to the emergence of transmissible variants of pandemic 2009 or seasonal A(H1N1) viruses unresponsive to most, if not all, of our currently available drugs. This raises multiple questions regarding patient management and preparations for future influenza outbreaks," they wrote (J. Infect. Dis. 2011;203[1]6-10).

The study by Ms. Sheu and Dr. Gubareva was funded by the Centers for Disease Control and Prevention. The study by Ms. Moore and Dr. Davies was funded by their public institutions; one coauthors acknowledged funding from the Wellcome Trust for a virus-sequencing pipeline project and another received funding from Roche for an influenza virus shedding study in oseltamivir-treated patients.

Dr. Hayden reported that he has received no research grants or personal honoraria from industry since 2006, but that he has served as an unpaid adviser to multiple companies involved in the development of influenza antivirals since 2008, and is member of the Neuraminidase Inhibitor Susceptibility Network, which has received funds from GlaxoSmithKline and Roche.

Two publicly funded studies from the United States and England show that the proportion of seasonal influenza A viruses resistant to two types of antiviral drugs has risen in recent years, and that drug-resistant pandemic influenza A was transmitted person-to-person during one 2009 outbreak.

Both studies, published online Dec. 7 in the Journal of Infectious Diseases, highlight concerns about how easily influenza A/H1N1 viruses can develop mutations for resistance, about the paucity of treatment options available for resistant infections, and the risks of using potentially ineffective agents.

For the first study, Tiffany G. Sheu and Dr. Larisa Gubareva of the Centers for Disease Control and Prevention in Atlanta, and their colleagues, tested seasonal H1N1 viruses collected between 2008 and 2010 for resistance to two types of antivirals: oseltamivir and adamantane drugs. The investigators noted that resistance-conferring mutations in an influenza A virus can occur as a result of drug selection, spontaneous mutation, or genetic reassortment with another drug-resistant influenza A virus (J. Infect. Dis. 2011;203[1]:13-7).

Of the nearly 1,500 virus samples submitted by surveillance programs around the world, 28 viruses from 5 countries in North America, Africa, and Asia, exhibited both adamantane and oseltamivir resistance, the investigators reported. The proportion of resistant viruses increased from .06% (1 of 1,753) of those from 2007-2008, to 1.5% in samples from 2008-2009 (21 of 1,426), and to 28% in a smaller number of samples from the 2009-2010 season (7 of 25), when fewer seasonal A strains were circulating. The dual-resistant viruses represented 4 different genotypes.

"Although dual-resistant viruses are still rare," the researchers wrote, "the increase in prevalence among seasonal influenza A(H1N1) viruses was notable during the last 3 seasons." Also, the detection of dual-resistant seasonal A(H1N1) viruses from 5 countries "warrants concern," they wrote, "because of the limited treatment options currently available for dual-resistant influenza A viruses."

In the U.K. study, clinical virologist Catherine Moore and Dr. Elori Davies of the Public Health Wales NHS Trust in Cardiff, and their colleagues, described the first molecularly confirmed person-to-person transmission of oseltamivir-resistant pandemic influenza A(H1N1) 2009 virus. After an outbreak of 11 cases in the hematology wing of a public hospital in October and November 2009, 10 were shown by sequencing to be virologically related, 8 were oseltamivir-resistant, and 4 of the 8 infections occurred by direct transmission of resistant virus.

Though the infected patients had considerable underlying disease, including leukemia, multiple myeloma, and lymphoma, influenza symptoms were generally manageable during the outbreak, and none of the patients died as a result of their resistant infections, Moore and colleagues reported (J. Infect. Dis. 2011;203[1]:18-24).

Dual treatment with oseltamivir and zanamivir was used when resistant virus was suspected or confirmed. However, Moore and colleagues noted, "recent data suggest there is possibly no synergy to be gained from this approach," and "zanamivir alone therefore would be preferable as a frontline treatment in particularly high-risk groups."

In an editorial comment accompanying the two studies, Dr. Frederick G. Hayden of the University of Virginia, Charlottesville, and Dr. Menno D. de Jong of the University of Amsterdam, the Netherlands, saw cautions in both. "Together, these findings illustrate that single reassortment events or mutations can lead to the emergence of transmissible variants of pandemic 2009 or seasonal A(H1N1) viruses unresponsive to most, if not all, of our currently available drugs. This raises multiple questions regarding patient management and preparations for future influenza outbreaks," they wrote (J. Infect. Dis. 2011;203[1]6-10).

The study by Ms. Sheu and Dr. Gubareva was funded by the Centers for Disease Control and Prevention. The study by Ms. Moore and Dr. Davies was funded by their public institutions; one coauthors acknowledged funding from the Wellcome Trust for a virus-sequencing pipeline project and another received funding from Roche for an influenza virus shedding study in oseltamivir-treated patients.

Dr. Hayden reported that he has received no research grants or personal honoraria from industry since 2006, but that he has served as an unpaid adviser to multiple companies involved in the development of influenza antivirals since 2008, and is member of the Neuraminidase Inhibitor Susceptibility Network, which has received funds from GlaxoSmithKline and Roche.

Two publicly funded studies from the United States and England show that the proportion of seasonal influenza A viruses resistant to two types of antiviral drugs has risen in recent years, and that drug-resistant pandemic influenza A was transmitted person-to-person during one 2009 outbreak.

Both studies, published online Dec. 7 in the Journal of Infectious Diseases, highlight concerns about how easily influenza A/H1N1 viruses can develop mutations for resistance, about the paucity of treatment options available for resistant infections, and the risks of using potentially ineffective agents.

For the first study, Tiffany G. Sheu and Dr. Larisa Gubareva of the Centers for Disease Control and Prevention in Atlanta, and their colleagues, tested seasonal H1N1 viruses collected between 2008 and 2010 for resistance to two types of antivirals: oseltamivir and adamantane drugs. The investigators noted that resistance-conferring mutations in an influenza A virus can occur as a result of drug selection, spontaneous mutation, or genetic reassortment with another drug-resistant influenza A virus (J. Infect. Dis. 2011;203[1]:13-7).

Of the nearly 1,500 virus samples submitted by surveillance programs around the world, 28 viruses from 5 countries in North America, Africa, and Asia, exhibited both adamantane and oseltamivir resistance, the investigators reported. The proportion of resistant viruses increased from .06% (1 of 1,753) of those from 2007-2008, to 1.5% in samples from 2008-2009 (21 of 1,426), and to 28% in a smaller number of samples from the 2009-2010 season (7 of 25), when fewer seasonal A strains were circulating. The dual-resistant viruses represented 4 different genotypes.

"Although dual-resistant viruses are still rare," the researchers wrote, "the increase in prevalence among seasonal influenza A(H1N1) viruses was notable during the last 3 seasons." Also, the detection of dual-resistant seasonal A(H1N1) viruses from 5 countries "warrants concern," they wrote, "because of the limited treatment options currently available for dual-resistant influenza A viruses."

In the U.K. study, clinical virologist Catherine Moore and Dr. Elori Davies of the Public Health Wales NHS Trust in Cardiff, and their colleagues, described the first molecularly confirmed person-to-person transmission of oseltamivir-resistant pandemic influenza A(H1N1) 2009 virus. After an outbreak of 11 cases in the hematology wing of a public hospital in October and November 2009, 10 were shown by sequencing to be virologically related, 8 were oseltamivir-resistant, and 4 of the 8 infections occurred by direct transmission of resistant virus.

Though the infected patients had considerable underlying disease, including leukemia, multiple myeloma, and lymphoma, influenza symptoms were generally manageable during the outbreak, and none of the patients died as a result of their resistant infections, Moore and colleagues reported (J. Infect. Dis. 2011;203[1]:18-24).

Dual treatment with oseltamivir and zanamivir was used when resistant virus was suspected or confirmed. However, Moore and colleagues noted, "recent data suggest there is possibly no synergy to be gained from this approach," and "zanamivir alone therefore would be preferable as a frontline treatment in particularly high-risk groups."

In an editorial comment accompanying the two studies, Dr. Frederick G. Hayden of the University of Virginia, Charlottesville, and Dr. Menno D. de Jong of the University of Amsterdam, the Netherlands, saw cautions in both. "Together, these findings illustrate that single reassortment events or mutations can lead to the emergence of transmissible variants of pandemic 2009 or seasonal A(H1N1) viruses unresponsive to most, if not all, of our currently available drugs. This raises multiple questions regarding patient management and preparations for future influenza outbreaks," they wrote (J. Infect. Dis. 2011;203[1]6-10).

The study by Ms. Sheu and Dr. Gubareva was funded by the Centers for Disease Control and Prevention. The study by Ms. Moore and Dr. Davies was funded by their public institutions; one coauthors acknowledged funding from the Wellcome Trust for a virus-sequencing pipeline project and another received funding from Roche for an influenza virus shedding study in oseltamivir-treated patients.

Dr. Hayden reported that he has received no research grants or personal honoraria from industry since 2006, but that he has served as an unpaid adviser to multiple companies involved in the development of influenza antivirals since 2008, and is member of the Neuraminidase Inhibitor Susceptibility Network, which has received funds from GlaxoSmithKline and Roche.

The clinical effectiveness agency for England and Wales says that it will recommend the atypical antipsychotic drug aripiprazole for people aged 15-17 years with schizophrenia.

The National Institute for Health and Clinical Effectiveness had said in September that it was unlikely to recommend Bristol-Myers Squibb Co.’s and Otsuka Pharmaceutical Co.’s aripiprazole (Abilify) for people aged 15-17 years, citing a paucity of data comparing it to three similar drugs that it already recommends for that age group.

However, the agency said on Dec. 1 that it had been persuaded by information later submitted by aripiprazole’s manufacturer comparing the drug to each of three other atypical antipsychotics – risperidone, quetiapine, and olanzapine – that are routinely used in U.K. clinical practice to treat young people. NICE also heard from experts who advised that because of varying adverse effects, more choice was beneficial in this patient group.

The NICE reviewers decided that aripiprazole, which costs approximately as much as olanzapine and quetiapine, "should be available on equal terms with other antipsychotic comparators (apart from risperidone)." Risperidone, the cheapest option among the drugs, is still NICE’s first choice for young patients with schizophrenia. Therefore, aripiprazole, which has a "good side-effect profile," is recommended only when risperidone cannot be tolerated, the agency said.

The therapeutic dose of aripiprazole, an oral medication, is 10-30 mg/day. Tablets of 5 mg, 10 mg, and 15 mg cost ?97.67 for 28; aripiprazole 30-mg tablets cost ?195.33 for 28.

Although aripiprazole has marketing approval throughout the European Union for the treatment of people aged 15 years and older with schizophrenia, it has not yet been appraised by NICE as a treatment option for adults. Assessing the drug for adults, NICE said, was outside the scope of the current guidance.

In another reversal on Dec. 1, NICE said that it would recommend Amgen’s romiplostim (Nplate) for the treatment of idiopathic thrombocytopenic purpura (ITP), a bleeding disorder caused by low platelet counts, after issuing negative draft guidance on the drug in March. Recently, NICE rejected eltrombopag (Revolade) another drug to treat ITP, calling it too expensive. Both drugs work by increasing platelet production and platelet counts in the body.

NICE’s final recommendation on romiplostim will depend on whether its manufacturer agrees to a patient-access scheme, the details of which have not been disclosed, the agency said.

Romiplostim is an intravenous injection administered weekly at a minimum dose of 1 mcg/kg and a maximum dose of 10 mcg/kg. The annual cost of treatment for a person weighing 80 kg would be ?8,020 at a dosage of 1 mcg/kg weekly, and ?80,204 at a dosage of 10 mcg/kg weekly, NICE said.

The public comment period on romiplostim ends in January; final guidance on aripiprazole is also expected in January.

The clinical effectiveness agency for England and Wales says that it will recommend the atypical antipsychotic drug aripiprazole for people aged 15-17 years with schizophrenia.

The National Institute for Health and Clinical Effectiveness had said in September that it was unlikely to recommend Bristol-Myers Squibb Co.’s and Otsuka Pharmaceutical Co.’s aripiprazole (Abilify) for people aged 15-17 years, citing a paucity of data comparing it to three similar drugs that it already recommends for that age group.

However, the agency said on Dec. 1 that it had been persuaded by information later submitted by aripiprazole’s manufacturer comparing the drug to each of three other atypical antipsychotics – risperidone, quetiapine, and olanzapine – that are routinely used in U.K. clinical practice to treat young people. NICE also heard from experts who advised that because of varying adverse effects, more choice was beneficial in this patient group.

The NICE reviewers decided that aripiprazole, which costs approximately as much as olanzapine and quetiapine, "should be available on equal terms with other antipsychotic comparators (apart from risperidone)." Risperidone, the cheapest option among the drugs, is still NICE’s first choice for young patients with schizophrenia. Therefore, aripiprazole, which has a "good side-effect profile," is recommended only when risperidone cannot be tolerated, the agency said.

The therapeutic dose of aripiprazole, an oral medication, is 10-30 mg/day. Tablets of 5 mg, 10 mg, and 15 mg cost ?97.67 for 28; aripiprazole 30-mg tablets cost ?195.33 for 28.

Although aripiprazole has marketing approval throughout the European Union for the treatment of people aged 15 years and older with schizophrenia, it has not yet been appraised by NICE as a treatment option for adults. Assessing the drug for adults, NICE said, was outside the scope of the current guidance.

In another reversal on Dec. 1, NICE said that it would recommend Amgen’s romiplostim (Nplate) for the treatment of idiopathic thrombocytopenic purpura (ITP), a bleeding disorder caused by low platelet counts, after issuing negative draft guidance on the drug in March. Recently, NICE rejected eltrombopag (Revolade) another drug to treat ITP, calling it too expensive. Both drugs work by increasing platelet production and platelet counts in the body.

NICE’s final recommendation on romiplostim will depend on whether its manufacturer agrees to a patient-access scheme, the details of which have not been disclosed, the agency said.

Romiplostim is an intravenous injection administered weekly at a minimum dose of 1 mcg/kg and a maximum dose of 10 mcg/kg. The annual cost of treatment for a person weighing 80 kg would be ?8,020 at a dosage of 1 mcg/kg weekly, and ?80,204 at a dosage of 10 mcg/kg weekly, NICE said.

The public comment period on romiplostim ends in January; final guidance on aripiprazole is also expected in January.

The clinical effectiveness agency for England and Wales says that it will recommend the atypical antipsychotic drug aripiprazole for people aged 15-17 years with schizophrenia.

The National Institute for Health and Clinical Effectiveness had said in September that it was unlikely to recommend Bristol-Myers Squibb Co.’s and Otsuka Pharmaceutical Co.’s aripiprazole (Abilify) for people aged 15-17 years, citing a paucity of data comparing it to three similar drugs that it already recommends for that age group.

However, the agency said on Dec. 1 that it had been persuaded by information later submitted by aripiprazole’s manufacturer comparing the drug to each of three other atypical antipsychotics – risperidone, quetiapine, and olanzapine – that are routinely used in U.K. clinical practice to treat young people. NICE also heard from experts who advised that because of varying adverse effects, more choice was beneficial in this patient group.

The NICE reviewers decided that aripiprazole, which costs approximately as much as olanzapine and quetiapine, "should be available on equal terms with other antipsychotic comparators (apart from risperidone)." Risperidone, the cheapest option among the drugs, is still NICE’s first choice for young patients with schizophrenia. Therefore, aripiprazole, which has a "good side-effect profile," is recommended only when risperidone cannot be tolerated, the agency said.

The therapeutic dose of aripiprazole, an oral medication, is 10-30 mg/day. Tablets of 5 mg, 10 mg, and 15 mg cost ?97.67 for 28; aripiprazole 30-mg tablets cost ?195.33 for 28.

Although aripiprazole has marketing approval throughout the European Union for the treatment of people aged 15 years and older with schizophrenia, it has not yet been appraised by NICE as a treatment option for adults. Assessing the drug for adults, NICE said, was outside the scope of the current guidance.

In another reversal on Dec. 1, NICE said that it would recommend Amgen’s romiplostim (Nplate) for the treatment of idiopathic thrombocytopenic purpura (ITP), a bleeding disorder caused by low platelet counts, after issuing negative draft guidance on the drug in March. Recently, NICE rejected eltrombopag (Revolade) another drug to treat ITP, calling it too expensive. Both drugs work by increasing platelet production and platelet counts in the body.

NICE’s final recommendation on romiplostim will depend on whether its manufacturer agrees to a patient-access scheme, the details of which have not been disclosed, the agency said.

Romiplostim is an intravenous injection administered weekly at a minimum dose of 1 mcg/kg and a maximum dose of 10 mcg/kg. The annual cost of treatment for a person weighing 80 kg would be ?8,020 at a dosage of 1 mcg/kg weekly, and ?80,204 at a dosage of 10 mcg/kg weekly, NICE said.

The public comment period on romiplostim ends in January; final guidance on aripiprazole is also expected in January.

Women who take over-the-counter painkillers during pregnancy have an increased risk of having sons born with undescended testes, according to a study that also incorporates rat models to show why this might be.

Using data from a birth cohort study of singleton sons born to 1,463 women in Finland and 834 in Denmark, all of whom either completed written questionnaires or telephone interviews or both, the researchers, led by Henrik Leffers, Ph.D., of Rigshospitalet in Copenhagen, found the risk of cryptorchidism to increase sevenfold in boys born to women who used more then one of three over-the-counter painkillers – aspirin (acetylsalicylic acid), acetaminophen (paracetamol), or ibuprofen – simultaneously during their pregnancies.

Exact doses of the painkillers were not recorded.

The findings, published online Nov. 8 in the journal Human Reproduction (doi:10.1093/humrep/deq323), also showed that any of these painkillers that were used for any duration during the second trimester more than doubled the risk of cryptorchidism, although the association for acetaminophen did not reach statistical significance.

The highest risk was observed, Dr. Leffers and his colleagues reported, among women who used more than one compound simultaneously for more than 2 weeks in the second trimester (adjusted odds ratio, 21.7 [1.83-258]).

A possible mechanism for this effect, Dr. Leffers and his colleagues hypothesized, was demonstrated by some of the study's coauthors, who found in a linked investigation that intrauterine exposure to acetaminophen, at three times the recommended dose for humans, led to a reduction in anogenital distance among fetal rats, and also reduced testosterone production by about half in fetal rat testes.

Aspirin was also tested in rats, but the results were not conclusive.

“A particular strength of this study is the use of two complementary rat models to support the contention that the association between analgesic use and cryptorchidism seen in our cohort study may result from a reduction in androgen production,” Dr. Leffers and his colleagues wrote.

Their study adds to findings published earlier this month (Epidemiology 2010;21:779-85) from a cohort of 47,000 boys born in Denmark, 980 of whom were identified in childhood as having cryptorchidism. That study, which also looked at acetaminophen, ibuprofen, and acetylsalicylic acid during pregnancy through telephone interviews and questionnaires with mothers, saw exposure to acetaminophen during both the first and second trimesters associated with increased cryptorchidism (hazard ratio, 1.33).

Acetaminophen exposure of more than 4 weeks between the 8th and 14th gestational weeks was associated with an HR of 1.38. However no association was found for either ibuprofen or aspirin.

Dr. Leffers and his colleagues' study found all but one of their statistically significant associations in the Danish part of their cohort, and speculated that differences in design of the Finnish and Danish cohort studies may have been partly responsible.

Although the Finnish questionnaire asked respondents to list only which medications were taken and when, the Danish telephone interviews asked the most pointed questions about over-the-counter and prescription pain medications, including which products were used in which weeks of pregnancy.

Although just more than a quarter (26%) of the Danish mothers who responded to the written questionnaire said that they had used mild analgesics, more than half (56%) of those interviewed by telephone said the same.

“These findings indicated that many mothers did not consider mild analgesics as medication and hence strongly underreported their use unless specifically asked. We therefore only included the data from the computer-assisted telephone interview from the Danish part of the study,” the investigators wrote.

In a press release accompanying the study, Dr. Leffers said that a “single paracetamol tablet (500 mg) contains more endocrine disruptor potency than the combined exposure to the 10 most prevalent of the currently known environmental endocrine disruptors during the whole pregnancy.”

Men who are born with cryptorchidism, the researchers noted, see an increased risk of having poor semen quality and testicular germ cell cancer.

Dr. Leffers and his colleagues' study was funded by European Commission and French government grants, the Villum Kann Rasmussen Foundation, and Novo Nordisk.

None of its authors declared conflicts of interest.

Women who take over-the-counter painkillers during pregnancy have an increased risk of having sons born with undescended testes, according to a study that also incorporates rat models to show why this might be.

Using data from a birth cohort study of singleton sons born to 1,463 women in Finland and 834 in Denmark, all of whom either completed written questionnaires or telephone interviews or both, the researchers, led by Henrik Leffers, Ph.D., of Rigshospitalet in Copenhagen, found the risk of cryptorchidism to increase sevenfold in boys born to women who used more then one of three over-the-counter painkillers – aspirin (acetylsalicylic acid), acetaminophen (paracetamol), or ibuprofen – simultaneously during their pregnancies.

Exact doses of the painkillers were not recorded.

The findings, published online Nov. 8 in the journal Human Reproduction (doi:10.1093/humrep/deq323), also showed that any of these painkillers that were used for any duration during the second trimester more than doubled the risk of cryptorchidism, although the association for acetaminophen did not reach statistical significance.

The highest risk was observed, Dr. Leffers and his colleagues reported, among women who used more than one compound simultaneously for more than 2 weeks in the second trimester (adjusted odds ratio, 21.7 [1.83-258]).

A possible mechanism for this effect, Dr. Leffers and his colleagues hypothesized, was demonstrated by some of the study's coauthors, who found in a linked investigation that intrauterine exposure to acetaminophen, at three times the recommended dose for humans, led to a reduction in anogenital distance among fetal rats, and also reduced testosterone production by about half in fetal rat testes.

Aspirin was also tested in rats, but the results were not conclusive.

“A particular strength of this study is the use of two complementary rat models to support the contention that the association between analgesic use and cryptorchidism seen in our cohort study may result from a reduction in androgen production,” Dr. Leffers and his colleagues wrote.

Their study adds to findings published earlier this month (Epidemiology 2010;21:779-85) from a cohort of 47,000 boys born in Denmark, 980 of whom were identified in childhood as having cryptorchidism. That study, which also looked at acetaminophen, ibuprofen, and acetylsalicylic acid during pregnancy through telephone interviews and questionnaires with mothers, saw exposure to acetaminophen during both the first and second trimesters associated with increased cryptorchidism (hazard ratio, 1.33).

Acetaminophen exposure of more than 4 weeks between the 8th and 14th gestational weeks was associated with an HR of 1.38. However no association was found for either ibuprofen or aspirin.

Dr. Leffers and his colleagues' study found all but one of their statistically significant associations in the Danish part of their cohort, and speculated that differences in design of the Finnish and Danish cohort studies may have been partly responsible.

Although the Finnish questionnaire asked respondents to list only which medications were taken and when, the Danish telephone interviews asked the most pointed questions about over-the-counter and prescription pain medications, including which products were used in which weeks of pregnancy.

Although just more than a quarter (26%) of the Danish mothers who responded to the written questionnaire said that they had used mild analgesics, more than half (56%) of those interviewed by telephone said the same.

“These findings indicated that many mothers did not consider mild analgesics as medication and hence strongly underreported their use unless specifically asked. We therefore only included the data from the computer-assisted telephone interview from the Danish part of the study,” the investigators wrote.

In a press release accompanying the study, Dr. Leffers said that a “single paracetamol tablet (500 mg) contains more endocrine disruptor potency than the combined exposure to the 10 most prevalent of the currently known environmental endocrine disruptors during the whole pregnancy.”

Men who are born with cryptorchidism, the researchers noted, see an increased risk of having poor semen quality and testicular germ cell cancer.

Dr. Leffers and his colleagues' study was funded by European Commission and French government grants, the Villum Kann Rasmussen Foundation, and Novo Nordisk.

None of its authors declared conflicts of interest.

Women who take over-the-counter painkillers during pregnancy have an increased risk of having sons born with undescended testes, according to a study that also incorporates rat models to show why this might be.

Using data from a birth cohort study of singleton sons born to 1,463 women in Finland and 834 in Denmark, all of whom either completed written questionnaires or telephone interviews or both, the researchers, led by Henrik Leffers, Ph.D., of Rigshospitalet in Copenhagen, found the risk of cryptorchidism to increase sevenfold in boys born to women who used more then one of three over-the-counter painkillers – aspirin (acetylsalicylic acid), acetaminophen (paracetamol), or ibuprofen – simultaneously during their pregnancies.

Exact doses of the painkillers were not recorded.

The findings, published online Nov. 8 in the journal Human Reproduction (doi:10.1093/humrep/deq323), also showed that any of these painkillers that were used for any duration during the second trimester more than doubled the risk of cryptorchidism, although the association for acetaminophen did not reach statistical significance.

The highest risk was observed, Dr. Leffers and his colleagues reported, among women who used more than one compound simultaneously for more than 2 weeks in the second trimester (adjusted odds ratio, 21.7 [1.83-258]).

A possible mechanism for this effect, Dr. Leffers and his colleagues hypothesized, was demonstrated by some of the study's coauthors, who found in a linked investigation that intrauterine exposure to acetaminophen, at three times the recommended dose for humans, led to a reduction in anogenital distance among fetal rats, and also reduced testosterone production by about half in fetal rat testes.

Aspirin was also tested in rats, but the results were not conclusive.

“A particular strength of this study is the use of two complementary rat models to support the contention that the association between analgesic use and cryptorchidism seen in our cohort study may result from a reduction in androgen production,” Dr. Leffers and his colleagues wrote.

Their study adds to findings published earlier this month (Epidemiology 2010;21:779-85) from a cohort of 47,000 boys born in Denmark, 980 of whom were identified in childhood as having cryptorchidism. That study, which also looked at acetaminophen, ibuprofen, and acetylsalicylic acid during pregnancy through telephone interviews and questionnaires with mothers, saw exposure to acetaminophen during both the first and second trimesters associated with increased cryptorchidism (hazard ratio, 1.33).

Acetaminophen exposure of more than 4 weeks between the 8th and 14th gestational weeks was associated with an HR of 1.38. However no association was found for either ibuprofen or aspirin.

Dr. Leffers and his colleagues' study found all but one of their statistically significant associations in the Danish part of their cohort, and speculated that differences in design of the Finnish and Danish cohort studies may have been partly responsible.

Although the Finnish questionnaire asked respondents to list only which medications were taken and when, the Danish telephone interviews asked the most pointed questions about over-the-counter and prescription pain medications, including which products were used in which weeks of pregnancy.

Although just more than a quarter (26%) of the Danish mothers who responded to the written questionnaire said that they had used mild analgesics, more than half (56%) of those interviewed by telephone said the same.

“These findings indicated that many mothers did not consider mild analgesics as medication and hence strongly underreported their use unless specifically asked. We therefore only included the data from the computer-assisted telephone interview from the Danish part of the study,” the investigators wrote.

In a press release accompanying the study, Dr. Leffers said that a “single paracetamol tablet (500 mg) contains more endocrine disruptor potency than the combined exposure to the 10 most prevalent of the currently known environmental endocrine disruptors during the whole pregnancy.”

Men who are born with cryptorchidism, the researchers noted, see an increased risk of having poor semen quality and testicular germ cell cancer.

Dr. Leffers and his colleagues' study was funded by European Commission and French government grants, the Villum Kann Rasmussen Foundation, and Novo Nordisk.

None of its authors declared conflicts of interest.