Bruce Jancin

GOTHENBURG, SWEDEN – While the hygiene hypothesis is hands down the most popular explanation offered for the dramatic increase in atopic disease in developed countries in recent decades, it's not the only plausible explanation.

The hapten-atopy hypothesis holds that the 400% rise in atopic dermatitis, asthma, and hay fever during the past 50 years is caused at least in part by the revolutionary increase in exposure to chemical haptens in the personal environment during the same time frame, Dr. John P. McFadden said at the congress.

Haptens are low-molecular-weight organic chemicals that aren't allergenic on their own but can bind to a peptide or protein, thereby altering its configuration and rendering it foreign and allergenic. Examples of haptens include antibiotics and some other drugs, as well as chemicals present in toiletries, processed foods, powdered milk, preservatives used in vaccines, and metal jewelry, explained Dr. McFadden of St. John's Institute of Dermatology, St. Thomas' Hospital, London.

He noted that Scottish investigators have documented a relentless rise in cases of childhood asthma and eczema in that country from 1945 to 1997 occurring in parallel with an increasing prevalence of adult nickel allergy.

“Obviously, association doesn't prove causation. But there does seem to be a change, not just in nickel exposure, but in exposure to other haptens,” the dermatologist observed.

Indeed, exposure to haptens has exploded in modern life. For example, global sales of toiletries quadrupled during 1959-1976. Today more than 80% of baby skin care products contain chemical fragrances. Various brands of powdered milk contain a mean of 12 haptens each. In 1992, just 6% of young women living in Tokyo dyed their hair; by 2001, this figure had jumped to 89% – and meanwhile the incidence of atopic disease in the Tokyo area doubled. Antibiotics weren't in general use until the second half of the 20th century. And that's when pierced earrings took off in popularity as well, Dr. McFadden noted.

Also, epidemiologic studies show that certain maternal occupations predispose to the birth of atopic children. Among these occupations are hairdresser, beautician, cleaner, electroplater, bar staff, dental assistant, confectionary maker, and book binder. What these diverse occupations have in common is increased environmental exposure to haptens.

The cornerstone of the hygiene hypothesis is that major improvements in public health have led to a cleaner home environment, resulting in less microbial stimulation of immune function and a consequent predisposition to atopic disease. Under audience questioning, Dr. McFadden conceded the hygiene hypothesis “may have some validity,” but he added he finds it troubling that many adherents of the hypothesis have “a tendency to be slightly lazy in explaining away discrepancies.

“When you go back home,” Dr. McFadden continued, “I want you to ask your allergist colleagues three questions: One, the biggest reduction in infections came at the end of the 19th century, with improvements in sanitation and nutrition – not in the second half of the 20th century, when the greatest increase in atopic disease occurred – so why was there no reported increase in allergy back then? Two, they say our immune systems haven't met infections, but actually the vaccination programs mean our immune systems think we've met polio, tetanus, diphtheria, and measles, all by the age of 1 year – how does that fit with the hygiene hypothesis? And three, studies have repeatedly shown that respiratory infections are associated with the development of atopic disease, and we've all seen cases of eczema that are triggered by cutaneous infections – how does that fit in?”

The hapten hypothesis holds that persistent low-grade exposure to environmental haptens via the skin and oral routes at key times of Th2 cytokine immune dominance – namely, pregnancy and the first year of life – can lead to atopy.

Dietary hapten intake may interfere with oral immune tolerance mechanisms, while repeated cutaneous exposure to haptens could skew the innate immune system into promoting Th2 responses.

“We're postulating that all of this hapten exposure probably doesn't matter the rest of the time, but during these vulnerable periods it may be important,” Dr. McFadden said.

Last year he and his coworkers laid out in detail the proposed immunologic mechanisms driving the hapten-atopy hypothesis (Trends Immunol. 2009;30:67-74).

Consistent with their hypothesis, mouse studies have shown that repeated low-grade exposure to haptens can result in two types of nontolerogenic response: the classic one, namely, allergic contact dermatitis, but also atopic dermatitis.

In humans, it's well established that repeated exposure to haptens can cause allergic contact dermatitis, but it is as yet unknown if hapten exposure contributes in any way to atopic dermatitis. But it's an issue well worth pursuing, in Dr. McFadden's view.

“The question as to whether increases in environmental hapten exposure are contributing to atopy is a legitimate one,” he said.

Dr. McFadden disclosed that he has no relevant financial interests.

Exposure to haptens has exploded and may account in part for the 400% rise in atopic disease in the past 50 years.

Source DR. McFADDEN

GOTHENBURG, SWEDEN – While the hygiene hypothesis is hands down the most popular explanation offered for the dramatic increase in atopic disease in developed countries in recent decades, it's not the only plausible explanation.

The hapten-atopy hypothesis holds that the 400% rise in atopic dermatitis, asthma, and hay fever during the past 50 years is caused at least in part by the revolutionary increase in exposure to chemical haptens in the personal environment during the same time frame, Dr. John P. McFadden said at the congress.

Haptens are low-molecular-weight organic chemicals that aren't allergenic on their own but can bind to a peptide or protein, thereby altering its configuration and rendering it foreign and allergenic. Examples of haptens include antibiotics and some other drugs, as well as chemicals present in toiletries, processed foods, powdered milk, preservatives used in vaccines, and metal jewelry, explained Dr. McFadden of St. John's Institute of Dermatology, St. Thomas' Hospital, London.

He noted that Scottish investigators have documented a relentless rise in cases of childhood asthma and eczema in that country from 1945 to 1997 occurring in parallel with an increasing prevalence of adult nickel allergy.

“Obviously, association doesn't prove causation. But there does seem to be a change, not just in nickel exposure, but in exposure to other haptens,” the dermatologist observed.

Indeed, exposure to haptens has exploded in modern life. For example, global sales of toiletries quadrupled during 1959-1976. Today more than 80% of baby skin care products contain chemical fragrances. Various brands of powdered milk contain a mean of 12 haptens each. In 1992, just 6% of young women living in Tokyo dyed their hair; by 2001, this figure had jumped to 89% – and meanwhile the incidence of atopic disease in the Tokyo area doubled. Antibiotics weren't in general use until the second half of the 20th century. And that's when pierced earrings took off in popularity as well, Dr. McFadden noted.

Also, epidemiologic studies show that certain maternal occupations predispose to the birth of atopic children. Among these occupations are hairdresser, beautician, cleaner, electroplater, bar staff, dental assistant, confectionary maker, and book binder. What these diverse occupations have in common is increased environmental exposure to haptens.

The cornerstone of the hygiene hypothesis is that major improvements in public health have led to a cleaner home environment, resulting in less microbial stimulation of immune function and a consequent predisposition to atopic disease. Under audience questioning, Dr. McFadden conceded the hygiene hypothesis “may have some validity,” but he added he finds it troubling that many adherents of the hypothesis have “a tendency to be slightly lazy in explaining away discrepancies.

“When you go back home,” Dr. McFadden continued, “I want you to ask your allergist colleagues three questions: One, the biggest reduction in infections came at the end of the 19th century, with improvements in sanitation and nutrition – not in the second half of the 20th century, when the greatest increase in atopic disease occurred – so why was there no reported increase in allergy back then? Two, they say our immune systems haven't met infections, but actually the vaccination programs mean our immune systems think we've met polio, tetanus, diphtheria, and measles, all by the age of 1 year – how does that fit with the hygiene hypothesis? And three, studies have repeatedly shown that respiratory infections are associated with the development of atopic disease, and we've all seen cases of eczema that are triggered by cutaneous infections – how does that fit in?”

The hapten hypothesis holds that persistent low-grade exposure to environmental haptens via the skin and oral routes at key times of Th2 cytokine immune dominance – namely, pregnancy and the first year of life – can lead to atopy.

Dietary hapten intake may interfere with oral immune tolerance mechanisms, while repeated cutaneous exposure to haptens could skew the innate immune system into promoting Th2 responses.

“We're postulating that all of this hapten exposure probably doesn't matter the rest of the time, but during these vulnerable periods it may be important,” Dr. McFadden said.

Last year he and his coworkers laid out in detail the proposed immunologic mechanisms driving the hapten-atopy hypothesis (Trends Immunol. 2009;30:67-74).

Consistent with their hypothesis, mouse studies have shown that repeated low-grade exposure to haptens can result in two types of nontolerogenic response: the classic one, namely, allergic contact dermatitis, but also atopic dermatitis.

In humans, it's well established that repeated exposure to haptens can cause allergic contact dermatitis, but it is as yet unknown if hapten exposure contributes in any way to atopic dermatitis. But it's an issue well worth pursuing, in Dr. McFadden's view.

“The question as to whether increases in environmental hapten exposure are contributing to atopy is a legitimate one,” he said.

Dr. McFadden disclosed that he has no relevant financial interests.

Exposure to haptens has exploded and may account in part for the 400% rise in atopic disease in the past 50 years.

Source DR. McFADDEN

GOTHENBURG, SWEDEN – While the hygiene hypothesis is hands down the most popular explanation offered for the dramatic increase in atopic disease in developed countries in recent decades, it's not the only plausible explanation.

The hapten-atopy hypothesis holds that the 400% rise in atopic dermatitis, asthma, and hay fever during the past 50 years is caused at least in part by the revolutionary increase in exposure to chemical haptens in the personal environment during the same time frame, Dr. John P. McFadden said at the congress.

Haptens are low-molecular-weight organic chemicals that aren't allergenic on their own but can bind to a peptide or protein, thereby altering its configuration and rendering it foreign and allergenic. Examples of haptens include antibiotics and some other drugs, as well as chemicals present in toiletries, processed foods, powdered milk, preservatives used in vaccines, and metal jewelry, explained Dr. McFadden of St. John's Institute of Dermatology, St. Thomas' Hospital, London.

He noted that Scottish investigators have documented a relentless rise in cases of childhood asthma and eczema in that country from 1945 to 1997 occurring in parallel with an increasing prevalence of adult nickel allergy.

“Obviously, association doesn't prove causation. But there does seem to be a change, not just in nickel exposure, but in exposure to other haptens,” the dermatologist observed.

Indeed, exposure to haptens has exploded in modern life. For example, global sales of toiletries quadrupled during 1959-1976. Today more than 80% of baby skin care products contain chemical fragrances. Various brands of powdered milk contain a mean of 12 haptens each. In 1992, just 6% of young women living in Tokyo dyed their hair; by 2001, this figure had jumped to 89% – and meanwhile the incidence of atopic disease in the Tokyo area doubled. Antibiotics weren't in general use until the second half of the 20th century. And that's when pierced earrings took off in popularity as well, Dr. McFadden noted.

Also, epidemiologic studies show that certain maternal occupations predispose to the birth of atopic children. Among these occupations are hairdresser, beautician, cleaner, electroplater, bar staff, dental assistant, confectionary maker, and book binder. What these diverse occupations have in common is increased environmental exposure to haptens.

The cornerstone of the hygiene hypothesis is that major improvements in public health have led to a cleaner home environment, resulting in less microbial stimulation of immune function and a consequent predisposition to atopic disease. Under audience questioning, Dr. McFadden conceded the hygiene hypothesis “may have some validity,” but he added he finds it troubling that many adherents of the hypothesis have “a tendency to be slightly lazy in explaining away discrepancies.

“When you go back home,” Dr. McFadden continued, “I want you to ask your allergist colleagues three questions: One, the biggest reduction in infections came at the end of the 19th century, with improvements in sanitation and nutrition – not in the second half of the 20th century, when the greatest increase in atopic disease occurred – so why was there no reported increase in allergy back then? Two, they say our immune systems haven't met infections, but actually the vaccination programs mean our immune systems think we've met polio, tetanus, diphtheria, and measles, all by the age of 1 year – how does that fit with the hygiene hypothesis? And three, studies have repeatedly shown that respiratory infections are associated with the development of atopic disease, and we've all seen cases of eczema that are triggered by cutaneous infections – how does that fit in?”

The hapten hypothesis holds that persistent low-grade exposure to environmental haptens via the skin and oral routes at key times of Th2 cytokine immune dominance – namely, pregnancy and the first year of life – can lead to atopy.

Dietary hapten intake may interfere with oral immune tolerance mechanisms, while repeated cutaneous exposure to haptens could skew the innate immune system into promoting Th2 responses.

“We're postulating that all of this hapten exposure probably doesn't matter the rest of the time, but during these vulnerable periods it may be important,” Dr. McFadden said.

Last year he and his coworkers laid out in detail the proposed immunologic mechanisms driving the hapten-atopy hypothesis (Trends Immunol. 2009;30:67-74).

Consistent with their hypothesis, mouse studies have shown that repeated low-grade exposure to haptens can result in two types of nontolerogenic response: the classic one, namely, allergic contact dermatitis, but also atopic dermatitis.

In humans, it's well established that repeated exposure to haptens can cause allergic contact dermatitis, but it is as yet unknown if hapten exposure contributes in any way to atopic dermatitis. But it's an issue well worth pursuing, in Dr. McFadden's view.

“The question as to whether increases in environmental hapten exposure are contributing to atopy is a legitimate one,” he said.

Dr. McFadden disclosed that he has no relevant financial interests.

Exposure to haptens has exploded and may account in part for the 400% rise in atopic disease in the past 50 years.

Source DR. McFADDEN

GOTHENBURG, SWEDEN – The treatment regimens currently recommended for nongonococcal urethritis and cervicitis by the Centers for Disease Control and Prevention have significant drawbacks for infections caused by Mycoplasma genitalium, according to Dr. Carin Anagrius.

Multiple studies – reported since the Centers for Disease Control and Prevention's guidelines were released in 2006 – indicate that M. genitalium is the second most common cause of nongonococcal urethritis (NGU), with a prevalence about half that of Chlamydia trachomatis, Dr. Anagrius said at the congress.

The first-line treatment options recommended by the CDC for NGU and presumptive treatment of cervicitis (doxycycline and azithromycin) both have problems, said Dr. Anagrius of Falu Hospital in Falun, Sweden. Doxycycline at 100 mg twice daily for 7 days has an unacceptable eradication rate for M. genitalium, and azithromycin in a single 1-g dose promotes emergence of macrolide-resistant organisms.

For this reason, she said, a revision of the guidelines is in order. The best solution would be to elevate azithromycin given over 5 days to preferred first-line therapy status. This regimen consists of 500 mg of azithromycin on day 1 followed by 250 mg on days 2-5. Studies found it has a 95% M. genitalium eradication rate and a substantially lower risk of inducing azithromycin resistance than with a single 1-g dose, she said.

An observational study by Dr. Anagrius and coworkers showed that eradication rates in symptomatic M. genitalium NGU in Scandinavia were about 85% for azithromycin 1 g and less than 30% for doxycycline (Sex. Transm. Infect. 2008;84:72-6). Similar rates have been confirmed by other investigators, she noted.

For example, University of Mississippi investigators randomized men with known M. genitalium urethritis at a New Orleans STD clinic to doxycycline (100 mg twice a day for 7 days) or azithromycin (1 g as a single dose). The cure rates at the first follow-up visit were 87% with azithromycin, compared with 45% with doxycycline; 47% of those who were initially cured experienced clinical relapse in the next 2-6 weeks (Clin. Infect. Dis. 2009;48:1649-54).

The latest data from large population studies suggest M. genitalium causes about 15% of all NGU, noted Dr. Anagrius. Since there is as no commercially available diagnostic assay for M. genitalium infections, for every 1,000 patients with NGU who are treated with doxycycline, roughly 84 will return with persistent symptomatic M. genitalium urethritis. However, if the 1,000 patients were treated with single-dose azithromycin at 1 g, only 18 would return with persistent symptomatic M. genitalium urethritis.

Dr. Anagrius's studies indicate roughly 70% of these unsuccessfully treated patients would as a consequence of this unsuccessful treatment develop resistance to azithromycin in the form of a single base mutation in domain V of the 23S rRNA gene. Extended azithromycin as second-line therapy is unlikely to be successful in these patients. For them the only effective second-line antimicrobials are moxifloxacin and gatifloxacin. And there is as yet no third-line therapy.

If, on the other hand, 1,000 NGU patients were treated with 1.5 g of azithromycin over a 5-day period, only 6 would return because of persistent M. genitalium urethritis, she said. Thus, the number of individuals with azithromycin-resistant M. genitalium infections would be reduced by two-thirds, compared with the count if azithromycin 1 g were used.

The impact of using azithromycin 1 g as first-line therapy for NGU is illustrated by the markedly contrasting prevalence of macrolide-resistant M. genitalium in Sweden and neighboring Denmark. In Sweden, where using 1 g of azithromycin to treat NGU is uncommon, Dr. Anagrius and coworkers found the prevalence of azithromycin resistance to be only 1.6% among 181 patients presenting with new confirmed M. genitalium.

In Denmark, where azithromycin 1 g is widely prescribed as first-line therapy, Dr. Anagrius's Danish collaborators found a 40% prevalence of macrolide resistance in 415 patients presenting with new confirmed M. genitalium urethritis.

Dr. Anagrius noted that discussion about screening for M. genitalium infection in asymptomatic individuals in high-prevalence settings is starting to occur among venereologists and public health officials. The problem is the lack of a commercial polymerase chain reaction assay, which must be a high developmental priority. In the meantime, Dr. Anagrius urged physicians to “think M. genitalium” in patients with repeated urinary tract infections, abnormal bleeding, lower abdominal pain, persistent discharge, epididymitis, prostatitis, and what is often labeled treatment-resistant candidiasis.

And since M. genitalium NGU and cervicitis are sexually transmitted infections, optimal care includes treatment of the patient's partner or partners, she stressed.

Dr. Anagrius said she had no financial conflicts of interest.

The best solution would be to elevate azithromycin given over 5 days to preferred first-line therapy status.

Source DR. ANAGRIUS

GOTHENBURG, SWEDEN – The treatment regimens currently recommended for nongonococcal urethritis and cervicitis by the Centers for Disease Control and Prevention have significant drawbacks for infections caused by Mycoplasma genitalium, according to Dr. Carin Anagrius.

Multiple studies – reported since the Centers for Disease Control and Prevention's guidelines were released in 2006 – indicate that M. genitalium is the second most common cause of nongonococcal urethritis (NGU), with a prevalence about half that of Chlamydia trachomatis, Dr. Anagrius said at the congress.

The first-line treatment options recommended by the CDC for NGU and presumptive treatment of cervicitis (doxycycline and azithromycin) both have problems, said Dr. Anagrius of Falu Hospital in Falun, Sweden. Doxycycline at 100 mg twice daily for 7 days has an unacceptable eradication rate for M. genitalium, and azithromycin in a single 1-g dose promotes emergence of macrolide-resistant organisms.

For this reason, she said, a revision of the guidelines is in order. The best solution would be to elevate azithromycin given over 5 days to preferred first-line therapy status. This regimen consists of 500 mg of azithromycin on day 1 followed by 250 mg on days 2-5. Studies found it has a 95% M. genitalium eradication rate and a substantially lower risk of inducing azithromycin resistance than with a single 1-g dose, she said.

An observational study by Dr. Anagrius and coworkers showed that eradication rates in symptomatic M. genitalium NGU in Scandinavia were about 85% for azithromycin 1 g and less than 30% for doxycycline (Sex. Transm. Infect. 2008;84:72-6). Similar rates have been confirmed by other investigators, she noted.

For example, University of Mississippi investigators randomized men with known M. genitalium urethritis at a New Orleans STD clinic to doxycycline (100 mg twice a day for 7 days) or azithromycin (1 g as a single dose). The cure rates at the first follow-up visit were 87% with azithromycin, compared with 45% with doxycycline; 47% of those who were initially cured experienced clinical relapse in the next 2-6 weeks (Clin. Infect. Dis. 2009;48:1649-54).

The latest data from large population studies suggest M. genitalium causes about 15% of all NGU, noted Dr. Anagrius. Since there is as no commercially available diagnostic assay for M. genitalium infections, for every 1,000 patients with NGU who are treated with doxycycline, roughly 84 will return with persistent symptomatic M. genitalium urethritis. However, if the 1,000 patients were treated with single-dose azithromycin at 1 g, only 18 would return with persistent symptomatic M. genitalium urethritis.

Dr. Anagrius's studies indicate roughly 70% of these unsuccessfully treated patients would as a consequence of this unsuccessful treatment develop resistance to azithromycin in the form of a single base mutation in domain V of the 23S rRNA gene. Extended azithromycin as second-line therapy is unlikely to be successful in these patients. For them the only effective second-line antimicrobials are moxifloxacin and gatifloxacin. And there is as yet no third-line therapy.

If, on the other hand, 1,000 NGU patients were treated with 1.5 g of azithromycin over a 5-day period, only 6 would return because of persistent M. genitalium urethritis, she said. Thus, the number of individuals with azithromycin-resistant M. genitalium infections would be reduced by two-thirds, compared with the count if azithromycin 1 g were used.

The impact of using azithromycin 1 g as first-line therapy for NGU is illustrated by the markedly contrasting prevalence of macrolide-resistant M. genitalium in Sweden and neighboring Denmark. In Sweden, where using 1 g of azithromycin to treat NGU is uncommon, Dr. Anagrius and coworkers found the prevalence of azithromycin resistance to be only 1.6% among 181 patients presenting with new confirmed M. genitalium.

In Denmark, where azithromycin 1 g is widely prescribed as first-line therapy, Dr. Anagrius's Danish collaborators found a 40% prevalence of macrolide resistance in 415 patients presenting with new confirmed M. genitalium urethritis.

Dr. Anagrius noted that discussion about screening for M. genitalium infection in asymptomatic individuals in high-prevalence settings is starting to occur among venereologists and public health officials. The problem is the lack of a commercial polymerase chain reaction assay, which must be a high developmental priority. In the meantime, Dr. Anagrius urged physicians to “think M. genitalium” in patients with repeated urinary tract infections, abnormal bleeding, lower abdominal pain, persistent discharge, epididymitis, prostatitis, and what is often labeled treatment-resistant candidiasis.

And since M. genitalium NGU and cervicitis are sexually transmitted infections, optimal care includes treatment of the patient's partner or partners, she stressed.

Dr. Anagrius said she had no financial conflicts of interest.

The best solution would be to elevate azithromycin given over 5 days to preferred first-line therapy status.

Source DR. ANAGRIUS

GOTHENBURG, SWEDEN – The treatment regimens currently recommended for nongonococcal urethritis and cervicitis by the Centers for Disease Control and Prevention have significant drawbacks for infections caused by Mycoplasma genitalium, according to Dr. Carin Anagrius.

Multiple studies – reported since the Centers for Disease Control and Prevention's guidelines were released in 2006 – indicate that M. genitalium is the second most common cause of nongonococcal urethritis (NGU), with a prevalence about half that of Chlamydia trachomatis, Dr. Anagrius said at the congress.

The first-line treatment options recommended by the CDC for NGU and presumptive treatment of cervicitis (doxycycline and azithromycin) both have problems, said Dr. Anagrius of Falu Hospital in Falun, Sweden. Doxycycline at 100 mg twice daily for 7 days has an unacceptable eradication rate for M. genitalium, and azithromycin in a single 1-g dose promotes emergence of macrolide-resistant organisms.

For this reason, she said, a revision of the guidelines is in order. The best solution would be to elevate azithromycin given over 5 days to preferred first-line therapy status. This regimen consists of 500 mg of azithromycin on day 1 followed by 250 mg on days 2-5. Studies found it has a 95% M. genitalium eradication rate and a substantially lower risk of inducing azithromycin resistance than with a single 1-g dose, she said.

An observational study by Dr. Anagrius and coworkers showed that eradication rates in symptomatic M. genitalium NGU in Scandinavia were about 85% for azithromycin 1 g and less than 30% for doxycycline (Sex. Transm. Infect. 2008;84:72-6). Similar rates have been confirmed by other investigators, she noted.

For example, University of Mississippi investigators randomized men with known M. genitalium urethritis at a New Orleans STD clinic to doxycycline (100 mg twice a day for 7 days) or azithromycin (1 g as a single dose). The cure rates at the first follow-up visit were 87% with azithromycin, compared with 45% with doxycycline; 47% of those who were initially cured experienced clinical relapse in the next 2-6 weeks (Clin. Infect. Dis. 2009;48:1649-54).

The latest data from large population studies suggest M. genitalium causes about 15% of all NGU, noted Dr. Anagrius. Since there is as no commercially available diagnostic assay for M. genitalium infections, for every 1,000 patients with NGU who are treated with doxycycline, roughly 84 will return with persistent symptomatic M. genitalium urethritis. However, if the 1,000 patients were treated with single-dose azithromycin at 1 g, only 18 would return with persistent symptomatic M. genitalium urethritis.

Dr. Anagrius's studies indicate roughly 70% of these unsuccessfully treated patients would as a consequence of this unsuccessful treatment develop resistance to azithromycin in the form of a single base mutation in domain V of the 23S rRNA gene. Extended azithromycin as second-line therapy is unlikely to be successful in these patients. For them the only effective second-line antimicrobials are moxifloxacin and gatifloxacin. And there is as yet no third-line therapy.

If, on the other hand, 1,000 NGU patients were treated with 1.5 g of azithromycin over a 5-day period, only 6 would return because of persistent M. genitalium urethritis, she said. Thus, the number of individuals with azithromycin-resistant M. genitalium infections would be reduced by two-thirds, compared with the count if azithromycin 1 g were used.

The impact of using azithromycin 1 g as first-line therapy for NGU is illustrated by the markedly contrasting prevalence of macrolide-resistant M. genitalium in Sweden and neighboring Denmark. In Sweden, where using 1 g of azithromycin to treat NGU is uncommon, Dr. Anagrius and coworkers found the prevalence of azithromycin resistance to be only 1.6% among 181 patients presenting with new confirmed M. genitalium.

In Denmark, where azithromycin 1 g is widely prescribed as first-line therapy, Dr. Anagrius's Danish collaborators found a 40% prevalence of macrolide resistance in 415 patients presenting with new confirmed M. genitalium urethritis.

Dr. Anagrius noted that discussion about screening for M. genitalium infection in asymptomatic individuals in high-prevalence settings is starting to occur among venereologists and public health officials. The problem is the lack of a commercial polymerase chain reaction assay, which must be a high developmental priority. In the meantime, Dr. Anagrius urged physicians to “think M. genitalium” in patients with repeated urinary tract infections, abnormal bleeding, lower abdominal pain, persistent discharge, epididymitis, prostatitis, and what is often labeled treatment-resistant candidiasis.

And since M. genitalium NGU and cervicitis are sexually transmitted infections, optimal care includes treatment of the patient's partner or partners, she stressed.

Dr. Anagrius said she had no financial conflicts of interest.

The best solution would be to elevate azithromycin given over 5 days to preferred first-line therapy status.

Source DR. ANAGRIUS

DENVER – A novel oral formulation of tranexamic acid provided immediate and enduring improvement in two quality of life measures among women with menorrhagia in a large open-label study.

The improvements were noted during the first menstrual cycle after initiation of treatment. The benefits were maintained throughout the 15-cycle study, Dr. Ken Muse reported at the meeting.

Tranexamic acid is a lysine analogue that acts as a competitive plasmin inhibitor and an antifibrinolytic agent. The oral formulation was approved by the Food and Drug Administration late last year for the treatment of cyclic heavy menstrual bleeding and is marketed under the trade name Lysteda. It's a valuable alternative to surgical or hormonal treatments for this disorder, which affects up to 22 million Americans, said Dr. Muse of the University of Kentucky, Lexington.

Oral tranexamic acid won marketing approval on the strength of studies showing it reduced menstrual flow by nearly 40%.

The quality of life study involved 723 women who took oral tranexamic acid at 1.3 g three times per day for a maximum of 5 days per menstrual cycle, starting with the onset of heavy menstrual bleeding. General quality of life was assessed using the 36-Item Short Form Health Survey. The Aberdeen Menorrhagia Clinical Outcome Questionnaire (AMCused as a disease-specific measure of the impact of treatment. Signif

Significant improvements were noted in six of eight SF-36 categories and domains at cycle 15 compared with baseline. The greatest improvements were in vitality, with a 13.5% gain, and social functioning, with an 8.3% gain. Patients also showed significant long-term improvements in bodily pain, mental health, role-physical, and role-emotional items. Only physical functioning and general health weren't significantly different at cycle 15 compared with baseline.

Women on oral tranexamic acid had a mean 5.4% long-term improvement in the mental health component of the SF-36, and a less robust but nonetheless significant 1.7% gain in the physical functioning component, Dr. Muse said.

Treatment-related adverse eventsdoccurred in 7.3% of subjects, the researchers noted.; Tthese were mild to moderate in nature and usually consisted of headache, menstrual discomfort, or back pain. There were few gastrointestinal side effects, and no thrombotic or thromboembolic events.

Scores on the AMCOQ indicated patients had a consistent improvement in daily activities that are affected by cyclic heavy menstrual bleeding.

The study was funded by Xanodyne Pharmaceuticals Inc. and Ferring Pharmaceuticals, which acquired global marketing rights to Lysteda last May. Dr. Muse disclosed that he has received research grants from, and served as an adviser to, Xanodyne.

DENVER – A novel oral formulation of tranexamic acid provided immediate and enduring improvement in two quality of life measures among women with menorrhagia in a large open-label study.

The improvements were noted during the first menstrual cycle after initiation of treatment. The benefits were maintained throughout the 15-cycle study, Dr. Ken Muse reported at the meeting.

Tranexamic acid is a lysine analogue that acts as a competitive plasmin inhibitor and an antifibrinolytic agent. The oral formulation was approved by the Food and Drug Administration late last year for the treatment of cyclic heavy menstrual bleeding and is marketed under the trade name Lysteda. It's a valuable alternative to surgical or hormonal treatments for this disorder, which affects up to 22 million Americans, said Dr. Muse of the University of Kentucky, Lexington.

Oral tranexamic acid won marketing approval on the strength of studies showing it reduced menstrual flow by nearly 40%.

The quality of life study involved 723 women who took oral tranexamic acid at 1.3 g three times per day for a maximum of 5 days per menstrual cycle, starting with the onset of heavy menstrual bleeding. General quality of life was assessed using the 36-Item Short Form Health Survey. The Aberdeen Menorrhagia Clinical Outcome Questionnaire (AMCused as a disease-specific measure of the impact of treatment. Signif

Significant improvements were noted in six of eight SF-36 categories and domains at cycle 15 compared with baseline. The greatest improvements were in vitality, with a 13.5% gain, and social functioning, with an 8.3% gain. Patients also showed significant long-term improvements in bodily pain, mental health, role-physical, and role-emotional items. Only physical functioning and general health weren't significantly different at cycle 15 compared with baseline.

Women on oral tranexamic acid had a mean 5.4% long-term improvement in the mental health component of the SF-36, and a less robust but nonetheless significant 1.7% gain in the physical functioning component, Dr. Muse said.

Treatment-related adverse eventsdoccurred in 7.3% of subjects, the researchers noted.; Tthese were mild to moderate in nature and usually consisted of headache, menstrual discomfort, or back pain. There were few gastrointestinal side effects, and no thrombotic or thromboembolic events.

Scores on the AMCOQ indicated patients had a consistent improvement in daily activities that are affected by cyclic heavy menstrual bleeding.

The study was funded by Xanodyne Pharmaceuticals Inc. and Ferring Pharmaceuticals, which acquired global marketing rights to Lysteda last May. Dr. Muse disclosed that he has received research grants from, and served as an adviser to, Xanodyne.

DENVER – A novel oral formulation of tranexamic acid provided immediate and enduring improvement in two quality of life measures among women with menorrhagia in a large open-label study.

The improvements were noted during the first menstrual cycle after initiation of treatment. The benefits were maintained throughout the 15-cycle study, Dr. Ken Muse reported at the meeting.

Tranexamic acid is a lysine analogue that acts as a competitive plasmin inhibitor and an antifibrinolytic agent. The oral formulation was approved by the Food and Drug Administration late last year for the treatment of cyclic heavy menstrual bleeding and is marketed under the trade name Lysteda. It's a valuable alternative to surgical or hormonal treatments for this disorder, which affects up to 22 million Americans, said Dr. Muse of the University of Kentucky, Lexington.

Oral tranexamic acid won marketing approval on the strength of studies showing it reduced menstrual flow by nearly 40%.

The quality of life study involved 723 women who took oral tranexamic acid at 1.3 g three times per day for a maximum of 5 days per menstrual cycle, starting with the onset of heavy menstrual bleeding. General quality of life was assessed using the 36-Item Short Form Health Survey. The Aberdeen Menorrhagia Clinical Outcome Questionnaire (AMCused as a disease-specific measure of the impact of treatment. Signif

Significant improvements were noted in six of eight SF-36 categories and domains at cycle 15 compared with baseline. The greatest improvements were in vitality, with a 13.5% gain, and social functioning, with an 8.3% gain. Patients also showed significant long-term improvements in bodily pain, mental health, role-physical, and role-emotional items. Only physical functioning and general health weren't significantly different at cycle 15 compared with baseline.

Women on oral tranexamic acid had a mean 5.4% long-term improvement in the mental health component of the SF-36, and a less robust but nonetheless significant 1.7% gain in the physical functioning component, Dr. Muse said.

Treatment-related adverse eventsdoccurred in 7.3% of subjects, the researchers noted.; Tthese were mild to moderate in nature and usually consisted of headache, menstrual discomfort, or back pain. There were few gastrointestinal side effects, and no thrombotic or thromboembolic events.

Scores on the AMCOQ indicated patients had a consistent improvement in daily activities that are affected by cyclic heavy menstrual bleeding.

The study was funded by Xanodyne Pharmaceuticals Inc. and Ferring Pharmaceuticals, which acquired global marketing rights to Lysteda last May. Dr. Muse disclosed that he has received research grants from, and served as an adviser to, Xanodyne.

STOCKHOLM – A cardiac rehabilitation program built around supervised high-intensity treadmill aerobic interval workouts improves peak oxygen uptake to a greater degree than does standard moderate-intensity cardiac rehab, according to a randomized trial.

Moreover, the advantage favoring aerobic interval training remained significant at follow-up 30 months after patients completed their formal 12-week cardiac rehab program, Dr. Trine T. Moholdt reported at the congress.

“One of the biggest challenges in cardiac rehabilitation is how to make patients continue with a healthier lifestyle after ending the rehab program. There are no long-term effects of exercise training; that is, you have to keep on doing it to get the benefit from it,” observed Dr. Moholdt of the Norwegian University of Science and Technology, Trondheim.

The group assigned to the aerobic interval cardiac rehab program reported exercising more regularly and at considerably higher intensity than did the standard rehab group during the 30 months after their structured program ended. That's the likely explanation for why their peak oxygen uptake (VO₂max) at 30 months remained significantly higher than in the control group, although VO₂max declined over time in both groups, she said.

Her study comprised 107 MI patients undergoing 12 weeks of cardiac rehab at three Norwegian hospitals. They were randomized to aerobic interval training or conventional cardiac rehab entailing two physical therapist-led group sessions per week, each lasting about 60 minutes and performed at 70%-80% of an individual's maximum heart rate.

The aerobic interval regimen consisted of a 10-minute warm-up followed by 40 minutes of uphill treadmill walking or jogging intervals. The workout consisted of four 4-minute-long high-intensity intervals at 85%-95% of a patient's individually determined maximum heart rate, followed by a 3-minute recovery, then a cool down. The high-intensity intervals were designed to be just challenging enough so that patients could say only a few words while doing them but would not experience pain in the chest or legs.

Subjects in both study arms were encouraged to do one additional workout per week at home.

Eighteen patients dropped out of the 12-week cardiac rehab program. Among completers, the aerobic interval group showed a mean improvement in VO₂max from 31.6 mL/kg per minute at baseline to 36.2 at 12 weeks. This was a significantly greater gain than that seen in the moderate-intensity rehab group, which improved from 32.2 to 34.7 mL/kg per minute.

Follow-up assessments were conducted at 6 and 30 months after completion of the rehab program. VO₂max declined over time in both groups. By 30 months VO₂max in the aerobic interval training group was back to baseline; however, VO₂max in the standard cardiac rehab group had declined to significantly below baseline. Thus, the aerobic interval training group retained a significant relative advantage, although it seems clear that some sort of refresher intervention needs to be developed.

In terms of secondary study end points, flow-mediated dilatation of the brachial artery increased significantly in both groups after the rehab program, with no between-group difference. So did quality of life scores and increases in plasma adiponectin, a hormone with multiple beneficial metabolic effects. Only the aerobic interval program graduates experienced a significant increase in HDL levels, which rose from 49.9 mg/dL at baseline to 51.5 mg/dL after 12 weeks.

In the 69 subjects who presented at 30 months post rehab, self-reported physical activity varied markedly between the two study groups. Fully 20% of the standard-rehab patients reported being physically inactive, compared with 4% in the aerobic interval group. Fifteen percent in the standard-rehab group indicated they engaged in high-intensity exercise, compared with 46% of graduates of the aerobic interval-based program – and therein lies the explanation for the significant long-term difference between the two groups in VO₂max, according to Dr. Moholdt.

She noted that these results are consistent with an earlier randomized study she and her coworkers conducted in coronary artery bypass graft surgery patients followed for 6 months after completing cardiac rehab emphasizing either aerobic interval training or continuous moderate exercise (Am. Heart J. 2009;158:1031-7).

Attendees at the session devoted to research in cardiac rehab were generally enthusiastic about the Trondheim study findings and found the data convincing. One attendee said that the aerobic interval training program was as much a psychological as a physiological intervention.

“You've proved that a different self-reported behavior pattern was created. You've shown the patients that they could dare to perform high-level exercise,” he said.

“I do agree,” Dr. Moholdt replied. “Many patients quickly realized, often after the very first session, that it's not dangerous to become exhausted.”

Dr. Josef Niebauer, session cochair, was the sole vocal skeptic.

“I'm just not buying it. I think these data should not be overinterpreted in the face of quite a high number of dropouts and mainly self-reported data,” said Dr. Niebauer of the University of Salzburg (Austria).

He added that although he believes aerobic interval training has a useful place in cardiac rehab, he believes it is currently in an “overhyped” phase within the field.

Dr. Moholdt's study was funded by the Norwegian Foundation for Health and Rehabilitation. She declared having no financial conflicts.

STOCKHOLM – A cardiac rehabilitation program built around supervised high-intensity treadmill aerobic interval workouts improves peak oxygen uptake to a greater degree than does standard moderate-intensity cardiac rehab, according to a randomized trial.

Moreover, the advantage favoring aerobic interval training remained significant at follow-up 30 months after patients completed their formal 12-week cardiac rehab program, Dr. Trine T. Moholdt reported at the congress.

“One of the biggest challenges in cardiac rehabilitation is how to make patients continue with a healthier lifestyle after ending the rehab program. There are no long-term effects of exercise training; that is, you have to keep on doing it to get the benefit from it,” observed Dr. Moholdt of the Norwegian University of Science and Technology, Trondheim.

The group assigned to the aerobic interval cardiac rehab program reported exercising more regularly and at considerably higher intensity than did the standard rehab group during the 30 months after their structured program ended. That's the likely explanation for why their peak oxygen uptake (VO₂max) at 30 months remained significantly higher than in the control group, although VO₂max declined over time in both groups, she said.

Her study comprised 107 MI patients undergoing 12 weeks of cardiac rehab at three Norwegian hospitals. They were randomized to aerobic interval training or conventional cardiac rehab entailing two physical therapist-led group sessions per week, each lasting about 60 minutes and performed at 70%-80% of an individual's maximum heart rate.

The aerobic interval regimen consisted of a 10-minute warm-up followed by 40 minutes of uphill treadmill walking or jogging intervals. The workout consisted of four 4-minute-long high-intensity intervals at 85%-95% of a patient's individually determined maximum heart rate, followed by a 3-minute recovery, then a cool down. The high-intensity intervals were designed to be just challenging enough so that patients could say only a few words while doing them but would not experience pain in the chest or legs.

Subjects in both study arms were encouraged to do one additional workout per week at home.

Eighteen patients dropped out of the 12-week cardiac rehab program. Among completers, the aerobic interval group showed a mean improvement in VO₂max from 31.6 mL/kg per minute at baseline to 36.2 at 12 weeks. This was a significantly greater gain than that seen in the moderate-intensity rehab group, which improved from 32.2 to 34.7 mL/kg per minute.

Follow-up assessments were conducted at 6 and 30 months after completion of the rehab program. VO₂max declined over time in both groups. By 30 months VO₂max in the aerobic interval training group was back to baseline; however, VO₂max in the standard cardiac rehab group had declined to significantly below baseline. Thus, the aerobic interval training group retained a significant relative advantage, although it seems clear that some sort of refresher intervention needs to be developed.

In terms of secondary study end points, flow-mediated dilatation of the brachial artery increased significantly in both groups after the rehab program, with no between-group difference. So did quality of life scores and increases in plasma adiponectin, a hormone with multiple beneficial metabolic effects. Only the aerobic interval program graduates experienced a significant increase in HDL levels, which rose from 49.9 mg/dL at baseline to 51.5 mg/dL after 12 weeks.

In the 69 subjects who presented at 30 months post rehab, self-reported physical activity varied markedly between the two study groups. Fully 20% of the standard-rehab patients reported being physically inactive, compared with 4% in the aerobic interval group. Fifteen percent in the standard-rehab group indicated they engaged in high-intensity exercise, compared with 46% of graduates of the aerobic interval-based program – and therein lies the explanation for the significant long-term difference between the two groups in VO₂max, according to Dr. Moholdt.

She noted that these results are consistent with an earlier randomized study she and her coworkers conducted in coronary artery bypass graft surgery patients followed for 6 months after completing cardiac rehab emphasizing either aerobic interval training or continuous moderate exercise (Am. Heart J. 2009;158:1031-7).

Attendees at the session devoted to research in cardiac rehab were generally enthusiastic about the Trondheim study findings and found the data convincing. One attendee said that the aerobic interval training program was as much a psychological as a physiological intervention.

“You've proved that a different self-reported behavior pattern was created. You've shown the patients that they could dare to perform high-level exercise,” he said.

“I do agree,” Dr. Moholdt replied. “Many patients quickly realized, often after the very first session, that it's not dangerous to become exhausted.”

Dr. Josef Niebauer, session cochair, was the sole vocal skeptic.

“I'm just not buying it. I think these data should not be overinterpreted in the face of quite a high number of dropouts and mainly self-reported data,” said Dr. Niebauer of the University of Salzburg (Austria).

He added that although he believes aerobic interval training has a useful place in cardiac rehab, he believes it is currently in an “overhyped” phase within the field.

Dr. Moholdt's study was funded by the Norwegian Foundation for Health and Rehabilitation. She declared having no financial conflicts.

STOCKHOLM – A cardiac rehabilitation program built around supervised high-intensity treadmill aerobic interval workouts improves peak oxygen uptake to a greater degree than does standard moderate-intensity cardiac rehab, according to a randomized trial.

Moreover, the advantage favoring aerobic interval training remained significant at follow-up 30 months after patients completed their formal 12-week cardiac rehab program, Dr. Trine T. Moholdt reported at the congress.

“One of the biggest challenges in cardiac rehabilitation is how to make patients continue with a healthier lifestyle after ending the rehab program. There are no long-term effects of exercise training; that is, you have to keep on doing it to get the benefit from it,” observed Dr. Moholdt of the Norwegian University of Science and Technology, Trondheim.

The group assigned to the aerobic interval cardiac rehab program reported exercising more regularly and at considerably higher intensity than did the standard rehab group during the 30 months after their structured program ended. That's the likely explanation for why their peak oxygen uptake (VO₂max) at 30 months remained significantly higher than in the control group, although VO₂max declined over time in both groups, she said.

Her study comprised 107 MI patients undergoing 12 weeks of cardiac rehab at three Norwegian hospitals. They were randomized to aerobic interval training or conventional cardiac rehab entailing two physical therapist-led group sessions per week, each lasting about 60 minutes and performed at 70%-80% of an individual's maximum heart rate.

The aerobic interval regimen consisted of a 10-minute warm-up followed by 40 minutes of uphill treadmill walking or jogging intervals. The workout consisted of four 4-minute-long high-intensity intervals at 85%-95% of a patient's individually determined maximum heart rate, followed by a 3-minute recovery, then a cool down. The high-intensity intervals were designed to be just challenging enough so that patients could say only a few words while doing them but would not experience pain in the chest or legs.

Subjects in both study arms were encouraged to do one additional workout per week at home.

Eighteen patients dropped out of the 12-week cardiac rehab program. Among completers, the aerobic interval group showed a mean improvement in VO₂max from 31.6 mL/kg per minute at baseline to 36.2 at 12 weeks. This was a significantly greater gain than that seen in the moderate-intensity rehab group, which improved from 32.2 to 34.7 mL/kg per minute.

Follow-up assessments were conducted at 6 and 30 months after completion of the rehab program. VO₂max declined over time in both groups. By 30 months VO₂max in the aerobic interval training group was back to baseline; however, VO₂max in the standard cardiac rehab group had declined to significantly below baseline. Thus, the aerobic interval training group retained a significant relative advantage, although it seems clear that some sort of refresher intervention needs to be developed.

In terms of secondary study end points, flow-mediated dilatation of the brachial artery increased significantly in both groups after the rehab program, with no between-group difference. So did quality of life scores and increases in plasma adiponectin, a hormone with multiple beneficial metabolic effects. Only the aerobic interval program graduates experienced a significant increase in HDL levels, which rose from 49.9 mg/dL at baseline to 51.5 mg/dL after 12 weeks.

In the 69 subjects who presented at 30 months post rehab, self-reported physical activity varied markedly between the two study groups. Fully 20% of the standard-rehab patients reported being physically inactive, compared with 4% in the aerobic interval group. Fifteen percent in the standard-rehab group indicated they engaged in high-intensity exercise, compared with 46% of graduates of the aerobic interval-based program – and therein lies the explanation for the significant long-term difference between the two groups in VO₂max, according to Dr. Moholdt.

She noted that these results are consistent with an earlier randomized study she and her coworkers conducted in coronary artery bypass graft surgery patients followed for 6 months after completing cardiac rehab emphasizing either aerobic interval training or continuous moderate exercise (Am. Heart J. 2009;158:1031-7).

Attendees at the session devoted to research in cardiac rehab were generally enthusiastic about the Trondheim study findings and found the data convincing. One attendee said that the aerobic interval training program was as much a psychological as a physiological intervention.

“You've proved that a different self-reported behavior pattern was created. You've shown the patients that they could dare to perform high-level exercise,” he said.

“I do agree,” Dr. Moholdt replied. “Many patients quickly realized, often after the very first session, that it's not dangerous to become exhausted.”

Dr. Josef Niebauer, session cochair, was the sole vocal skeptic.

“I'm just not buying it. I think these data should not be overinterpreted in the face of quite a high number of dropouts and mainly self-reported data,” said Dr. Niebauer of the University of Salzburg (Austria).

He added that although he believes aerobic interval training has a useful place in cardiac rehab, he believes it is currently in an “overhyped” phase within the field.

Dr. Moholdt's study was funded by the Norwegian Foundation for Health and Rehabilitation. She declared having no financial conflicts.

DENVER – A novel oral, once-daily, tissue-selective estrogen complex designed to treat postmenopausal symptoms more safely than traditional estrogen/progestin hormone therapy achieved an overall favorable effect on metabolic parameters in a large phase III clinical trial.

The combination of the selective estrogen receptor modulator (SERM) bazedoxifene and conjugated estrogens produced “very favorable” changes in lipid profiles and no clinically meaningful effects on coagulation parameters, fibrinolytic activity, or carbohydrate metabolism in the phase III SMART-1 trial, Dr. Hugh S. Taylor reported at the meeting.

The concept underlying the tissue-selective estrogen complex (TSEC) is that the SERM will serve as an antagonist to estrogen's adverse effects on the uterus and breast without interfering with its favorable CNS effects on vasomotor symptoms, explained Dr. Taylor of Yale University, New Haven, Conn.

The Selective Estrogens, Menopause, and Response to Therapy (SMART-1) trial was a 2-year, double-blind, multicenter, placebo- and active comparator-controlled study involving 7,492 postmenopausal women aged 40-72 years with an intact uterus and acceptable baseline endometrial biopsy results. They were randomized to one of eight treatment arms: bazedoxifene at 10, 20, or 40 mg, each combined with conjugated estrogens at 0.45 or 0.625 mg; raloxifene at 60 mg/day; or placebo.

There are three large randomized SMART trials in the bazedoxifene/conjugated estrogens development program. Prior reports from SMART-1 showed that the TSEC significantly increased bone mineral density while reducing hot flashes and vulvar/vaginal symptoms compared with placebo (Fertil. Steril. 2009;92:1045-52 and 1025-38). TSEC also was associated with low rates of endometrial hyperplasia and cumulative amenorrhea rates comparable to those with placebo (Fertil. Steril. 2009;92:1018-24 and 1039-44).hIn the overall SMART series, the thrombotic event rate in TSEC-treated patients was similar to that of estrogen alone. In other words, there was no synergistic effect on clotting events with the combined therapy. The TSEC had no effect on blood pressure, Dr. Taylor continued.

At the meeting, he presented for the first time the results of the SMART-1 metabolic substudy. Metabolic end points take on particular importance because menopause is often associated with unfavorable effects on the metabolic profile. Dr. Taylor focused on the subset of women treated with bazedoxifene 20 mg/conjugated estrogens 0.45 mg because that's the regimen going forward in development under the trade name Aprela.

The metabolic substudy included 111 women randomized to Aprela and 108 on placebo. All were 1-5 years postmenopausal, with an average of 3 years since their last menstrual period.

Patients who took Aprela had a mean 11% reduction in LDL cholesterol over a 2-year period compared with baseline, a significantly greater change than with placebo.

Other significant lipid changes in the Aprela group included a 4% decrease in total cholesterol, an 11% increase in HDL cholesterol level, a 28% rise in the cardioprotective HDL₂ subfraction, an 11% increase in apolipoprotein A-I, and a 19% drop in lipoprotein (a). Most of these favorable changes were significantly greater than with placebo at all time points in the study, with testing done at 6, 12, 18, and 24 months.

The fly in the lipid ointment was the 23% increase in triglyceride levels in the Aprela group, which was significantly greater than the 6% increase in the placebo arm. Most hormonal therapies have this unwelcome effect of boosting triglycerides, Dr. Taylor observed.

In terms of coagulation parameters, the Aprela group showed favorable changes in fibrinogen, antithrombin III activity, and plasminogen activator inhibitor–1 activity that were statistically significantly greater than with placebo, but small in size and not clinically meaningful. Fasting insulin, fasting glucose, plasma homocysteine, C-reactive protein, and thyroid-stimulating hormone levels were unaffected by Aprela, he said.

The SMART-1 trial was funded by Wyeth, which has been acquired by Pfizer. Dr. Taylor declared that he has received research grants from and has been on the speakers bureau for the companies.

DENVER – A novel oral, once-daily, tissue-selective estrogen complex designed to treat postmenopausal symptoms more safely than traditional estrogen/progestin hormone therapy achieved an overall favorable effect on metabolic parameters in a large phase III clinical trial.

The combination of the selective estrogen receptor modulator (SERM) bazedoxifene and conjugated estrogens produced “very favorable” changes in lipid profiles and no clinically meaningful effects on coagulation parameters, fibrinolytic activity, or carbohydrate metabolism in the phase III SMART-1 trial, Dr. Hugh S. Taylor reported at the meeting.

The concept underlying the tissue-selective estrogen complex (TSEC) is that the SERM will serve as an antagonist to estrogen's adverse effects on the uterus and breast without interfering with its favorable CNS effects on vasomotor symptoms, explained Dr. Taylor of Yale University, New Haven, Conn.

The Selective Estrogens, Menopause, and Response to Therapy (SMART-1) trial was a 2-year, double-blind, multicenter, placebo- and active comparator-controlled study involving 7,492 postmenopausal women aged 40-72 years with an intact uterus and acceptable baseline endometrial biopsy results. They were randomized to one of eight treatment arms: bazedoxifene at 10, 20, or 40 mg, each combined with conjugated estrogens at 0.45 or 0.625 mg; raloxifene at 60 mg/day; or placebo.

There are three large randomized SMART trials in the bazedoxifene/conjugated estrogens development program. Prior reports from SMART-1 showed that the TSEC significantly increased bone mineral density while reducing hot flashes and vulvar/vaginal symptoms compared with placebo (Fertil. Steril. 2009;92:1045-52 and 1025-38). TSEC also was associated with low rates of endometrial hyperplasia and cumulative amenorrhea rates comparable to those with placebo (Fertil. Steril. 2009;92:1018-24 and 1039-44).hIn the overall SMART series, the thrombotic event rate in TSEC-treated patients was similar to that of estrogen alone. In other words, there was no synergistic effect on clotting events with the combined therapy. The TSEC had no effect on blood pressure, Dr. Taylor continued.

At the meeting, he presented for the first time the results of the SMART-1 metabolic substudy. Metabolic end points take on particular importance because menopause is often associated with unfavorable effects on the metabolic profile. Dr. Taylor focused on the subset of women treated with bazedoxifene 20 mg/conjugated estrogens 0.45 mg because that's the regimen going forward in development under the trade name Aprela.

The metabolic substudy included 111 women randomized to Aprela and 108 on placebo. All were 1-5 years postmenopausal, with an average of 3 years since their last menstrual period.

Patients who took Aprela had a mean 11% reduction in LDL cholesterol over a 2-year period compared with baseline, a significantly greater change than with placebo.

Other significant lipid changes in the Aprela group included a 4% decrease in total cholesterol, an 11% increase in HDL cholesterol level, a 28% rise in the cardioprotective HDL₂ subfraction, an 11% increase in apolipoprotein A-I, and a 19% drop in lipoprotein (a). Most of these favorable changes were significantly greater than with placebo at all time points in the study, with testing done at 6, 12, 18, and 24 months.

The fly in the lipid ointment was the 23% increase in triglyceride levels in the Aprela group, which was significantly greater than the 6% increase in the placebo arm. Most hormonal therapies have this unwelcome effect of boosting triglycerides, Dr. Taylor observed.

In terms of coagulation parameters, the Aprela group showed favorable changes in fibrinogen, antithrombin III activity, and plasminogen activator inhibitor–1 activity that were statistically significantly greater than with placebo, but small in size and not clinically meaningful. Fasting insulin, fasting glucose, plasma homocysteine, C-reactive protein, and thyroid-stimulating hormone levels were unaffected by Aprela, he said.

The SMART-1 trial was funded by Wyeth, which has been acquired by Pfizer. Dr. Taylor declared that he has received research grants from and has been on the speakers bureau for the companies.

DENVER – A novel oral, once-daily, tissue-selective estrogen complex designed to treat postmenopausal symptoms more safely than traditional estrogen/progestin hormone therapy achieved an overall favorable effect on metabolic parameters in a large phase III clinical trial.

The combination of the selective estrogen receptor modulator (SERM) bazedoxifene and conjugated estrogens produced “very favorable” changes in lipid profiles and no clinically meaningful effects on coagulation parameters, fibrinolytic activity, or carbohydrate metabolism in the phase III SMART-1 trial, Dr. Hugh S. Taylor reported at the meeting.

The concept underlying the tissue-selective estrogen complex (TSEC) is that the SERM will serve as an antagonist to estrogen's adverse effects on the uterus and breast without interfering with its favorable CNS effects on vasomotor symptoms, explained Dr. Taylor of Yale University, New Haven, Conn.

The Selective Estrogens, Menopause, and Response to Therapy (SMART-1) trial was a 2-year, double-blind, multicenter, placebo- and active comparator-controlled study involving 7,492 postmenopausal women aged 40-72 years with an intact uterus and acceptable baseline endometrial biopsy results. They were randomized to one of eight treatment arms: bazedoxifene at 10, 20, or 40 mg, each combined with conjugated estrogens at 0.45 or 0.625 mg; raloxifene at 60 mg/day; or placebo.

There are three large randomized SMART trials in the bazedoxifene/conjugated estrogens development program. Prior reports from SMART-1 showed that the TSEC significantly increased bone mineral density while reducing hot flashes and vulvar/vaginal symptoms compared with placebo (Fertil. Steril. 2009;92:1045-52 and 1025-38). TSEC also was associated with low rates of endometrial hyperplasia and cumulative amenorrhea rates comparable to those with placebo (Fertil. Steril. 2009;92:1018-24 and 1039-44).hIn the overall SMART series, the thrombotic event rate in TSEC-treated patients was similar to that of estrogen alone. In other words, there was no synergistic effect on clotting events with the combined therapy. The TSEC had no effect on blood pressure, Dr. Taylor continued.

At the meeting, he presented for the first time the results of the SMART-1 metabolic substudy. Metabolic end points take on particular importance because menopause is often associated with unfavorable effects on the metabolic profile. Dr. Taylor focused on the subset of women treated with bazedoxifene 20 mg/conjugated estrogens 0.45 mg because that's the regimen going forward in development under the trade name Aprela.

The metabolic substudy included 111 women randomized to Aprela and 108 on placebo. All were 1-5 years postmenopausal, with an average of 3 years since their last menstrual period.

Patients who took Aprela had a mean 11% reduction in LDL cholesterol over a 2-year period compared with baseline, a significantly greater change than with placebo.

Other significant lipid changes in the Aprela group included a 4% decrease in total cholesterol, an 11% increase in HDL cholesterol level, a 28% rise in the cardioprotective HDL₂ subfraction, an 11% increase in apolipoprotein A-I, and a 19% drop in lipoprotein (a). Most of these favorable changes were significantly greater than with placebo at all time points in the study, with testing done at 6, 12, 18, and 24 months.

The fly in the lipid ointment was the 23% increase in triglyceride levels in the Aprela group, which was significantly greater than the 6% increase in the placebo arm. Most hormonal therapies have this unwelcome effect of boosting triglycerides, Dr. Taylor observed.

In terms of coagulation parameters, the Aprela group showed favorable changes in fibrinogen, antithrombin III activity, and plasminogen activator inhibitor–1 activity that were statistically significantly greater than with placebo, but small in size and not clinically meaningful. Fasting insulin, fasting glucose, plasma homocysteine, C-reactive protein, and thyroid-stimulating hormone levels were unaffected by Aprela, he said.

The SMART-1 trial was funded by Wyeth, which has been acquired by Pfizer. Dr. Taylor declared that he has received research grants from and has been on the speakers bureau for the companies.

DENVER – Acupuncture performed on the day of embryo transfer may boost pregnancy rates in women undergoing in vitro fertilization.

In a prospective randomized trial involving 168 consecutive women undergoing IVF, the clinical pregnancy rate documented by ultrasound 6 weeks post procedure was 45% in the 44 women assigned to acupuncture, compared with 28% in 124 controls, Dr. Umberto Omodei reported at the annual meeting of the American Society for Reproductive Medicine.

Although this must be considered a pilot study because of its limited size, the traditional Chinese medical practice shows promise in the treatment of infertility, and it was entirely free of side effects, noted Dr. Omodei of the University of Brescia (Italy).

The acupuncture-treated women reported a sense of well being regarding the embryo transfer experience, while the controls generally reported feeling emotionally stressed and fatigued.

Steel acupuncture needles were inserted at five points 25 minutes before and at four points after embryo transfer. The traditional acupuncture points were located on the ear, foot, hand, and calf. The control group did not undergo sham acupuncture.

Acupuncture has been used in China for many centuries to regulate the female reproductive system. The mechanism of benefit in women undergoing IVF is unknown. There is some evidence that the treatment mediates release of neurotransmitters and stimulates secretion of gonadotrophin-releasing hormone. The traditional Chinese medical view is that the needling stimulates blood flow and positive energy to the uterus, while also providing a calming effect, perhaps by stimulating production of endogenous opioids, Dr. Omodei explained.

He said he had no relevant financial conflicts of interest.

DENVER – Acupuncture performed on the day of embryo transfer may boost pregnancy rates in women undergoing in vitro fertilization.

In a prospective randomized trial involving 168 consecutive women undergoing IVF, the clinical pregnancy rate documented by ultrasound 6 weeks post procedure was 45% in the 44 women assigned to acupuncture, compared with 28% in 124 controls, Dr. Umberto Omodei reported at the annual meeting of the American Society for Reproductive Medicine.

Although this must be considered a pilot study because of its limited size, the traditional Chinese medical practice shows promise in the treatment of infertility, and it was entirely free of side effects, noted Dr. Omodei of the University of Brescia (Italy).

The acupuncture-treated women reported a sense of well being regarding the embryo transfer experience, while the controls generally reported feeling emotionally stressed and fatigued.

Steel acupuncture needles were inserted at five points 25 minutes before and at four points after embryo transfer. The traditional acupuncture points were located on the ear, foot, hand, and calf. The control group did not undergo sham acupuncture.

Acupuncture has been used in China for many centuries to regulate the female reproductive system. The mechanism of benefit in women undergoing IVF is unknown. There is some evidence that the treatment mediates release of neurotransmitters and stimulates secretion of gonadotrophin-releasing hormone. The traditional Chinese medical view is that the needling stimulates blood flow and positive energy to the uterus, while also providing a calming effect, perhaps by stimulating production of endogenous opioids, Dr. Omodei explained.

He said he had no relevant financial conflicts of interest.

DENVER – Acupuncture performed on the day of embryo transfer may boost pregnancy rates in women undergoing in vitro fertilization.

In a prospective randomized trial involving 168 consecutive women undergoing IVF, the clinical pregnancy rate documented by ultrasound 6 weeks post procedure was 45% in the 44 women assigned to acupuncture, compared with 28% in 124 controls, Dr. Umberto Omodei reported at the annual meeting of the American Society for Reproductive Medicine.

Although this must be considered a pilot study because of its limited size, the traditional Chinese medical practice shows promise in the treatment of infertility, and it was entirely free of side effects, noted Dr. Omodei of the University of Brescia (Italy).

The acupuncture-treated women reported a sense of well being regarding the embryo transfer experience, while the controls generally reported feeling emotionally stressed and fatigued.

Steel acupuncture needles were inserted at five points 25 minutes before and at four points after embryo transfer. The traditional acupuncture points were located on the ear, foot, hand, and calf. The control group did not undergo sham acupuncture.

Acupuncture has been used in China for many centuries to regulate the female reproductive system. The mechanism of benefit in women undergoing IVF is unknown. There is some evidence that the treatment mediates release of neurotransmitters and stimulates secretion of gonadotrophin-releasing hormone. The traditional Chinese medical view is that the needling stimulates blood flow and positive energy to the uterus, while also providing a calming effect, perhaps by stimulating production of endogenous opioids, Dr. Omodei explained.

He said he had no relevant financial conflicts of interest.

GOTHENBURG, SWEDEN – Long-term risks of malignancies, serious infections, and cardiovascular events in ustekinumab-treated psoriasis patients was found to be what is expected in the general U.S. population, according to a 3-year safety analysis of the major randomized clinical trials of the biologic agent.

Placebo-treated control groups were utilized during the first 12 weeks of the phase III PHOENIX I and II trials and not at all in the phase III Active Comparator Psoriasis Trial (ACCEPT). For the safety analysis based on 3 years of follow-up – for purposes of comparison – risk estimates for the general U.S. population were derived from the National Institute of Health’s Surveillance, Epidemiology and End Results (SEER) database and MarketScan Research Data, Dr. Kenneth B. Gordon explained at the annual congress of the European Academy of Dermatology and Venereology.

The 3-year safety analysis included 3,117 psoriasis patients treated with ustekinumab (Stelara) at 45 mg or 90 mg per dose based on body weight, in accordance with the product labeling. Among this group were 1,247 patients who received the interleukin-12 and -23 inhibitor for at least 2 years, noted Dr. Gordon, a dermatologist at the University of Chicago.

The cumulative incidence of nonmelanoma skin cancer through year 3 in the 3,117 psoriasis patients was 0.64 cases per 100 patient-years in patients on ustekinumab 45 mg and 0.77 per 100 patient-years in those on ustekinumab 90 mg. During the 12-week controlled period of the studies, the incidence in placebo-treated patients was 1.13 cases per 100 patient-years.

Rates of other malignancies, including melanoma and lymphoma, through 3 years were 0.69 and 0.46 cases per 100 patient-years in patients on ustekinumab 45 and 90 mg, respectively. These rates were consistent with those expected in the U.S. general population based upon SEER data. Rates of malignancies other than nonmelanoma skin cancer were also comparable to those reported in a large population of psoriasis patients treated with systemic agents in the U.K. General Practice Research Database, where the incidence was 0.58 cases per 100 patient-years (J. Invest. Dermatol. 2009;129:2604-12).

The rate of serious infections through 3 years was 0.82 per 100 patient-years in psoriasis patients on ustekinumab 45 mg and 1.5 per 100 patient-years in those on the higher dose, for a combined event rate of 1.19 per 100 patient-years. This compared favorably to the expected rate of 1.51 per 100 patient-years in psoriasis patients with nonbiologic systemic agents derived from the MarketScan database, Dr. Gordon said.

The combined rate of cardiovascular death, MI, or stroke through 3 years in ustekinumab-treated psoriasis patients was 0.41 per 100 patient-years in those on the lower dose and 0.35 per 100 patient-years in those receiving 90 mg. These rates were lower, albeit not significantly so, than rates expected in the general population using data from the Framingham Heart Study and in psoriasis patients using the U.K. General Practice Research Database.

Rates of malignancies, serious infections, and cardiovascular events in ustekinumab-treated patients remained stable over time without any indication of cumulative toxicity. Another safety analysis is planned when participants in the phase III trials reach the 5-year follow-up mark.

The study was funded by Centocor. Dr. Gordon disclosed that he serves as a consultant to the company.

GOTHENBURG, SWEDEN – Long-term risks of malignancies, serious infections, and cardiovascular events in ustekinumab-treated psoriasis patients was found to be what is expected in the general U.S. population, according to a 3-year safety analysis of the major randomized clinical trials of the biologic agent.

Placebo-treated control groups were utilized during the first 12 weeks of the phase III PHOENIX I and II trials and not at all in the phase III Active Comparator Psoriasis Trial (ACCEPT). For the safety analysis based on 3 years of follow-up – for purposes of comparison – risk estimates for the general U.S. population were derived from the National Institute of Health’s Surveillance, Epidemiology and End Results (SEER) database and MarketScan Research Data, Dr. Kenneth B. Gordon explained at the annual congress of the European Academy of Dermatology and Venereology.

The 3-year safety analysis included 3,117 psoriasis patients treated with ustekinumab (Stelara) at 45 mg or 90 mg per dose based on body weight, in accordance with the product labeling. Among this group were 1,247 patients who received the interleukin-12 and -23 inhibitor for at least 2 years, noted Dr. Gordon, a dermatologist at the University of Chicago.

The cumulative incidence of nonmelanoma skin cancer through year 3 in the 3,117 psoriasis patients was 0.64 cases per 100 patient-years in patients on ustekinumab 45 mg and 0.77 per 100 patient-years in those on ustekinumab 90 mg. During the 12-week controlled period of the studies, the incidence in placebo-treated patients was 1.13 cases per 100 patient-years.

Rates of other malignancies, including melanoma and lymphoma, through 3 years were 0.69 and 0.46 cases per 100 patient-years in patients on ustekinumab 45 and 90 mg, respectively. These rates were consistent with those expected in the U.S. general population based upon SEER data. Rates of malignancies other than nonmelanoma skin cancer were also comparable to those reported in a large population of psoriasis patients treated with systemic agents in the U.K. General Practice Research Database, where the incidence was 0.58 cases per 100 patient-years (J. Invest. Dermatol. 2009;129:2604-12).

The rate of serious infections through 3 years was 0.82 per 100 patient-years in psoriasis patients on ustekinumab 45 mg and 1.5 per 100 patient-years in those on the higher dose, for a combined event rate of 1.19 per 100 patient-years. This compared favorably to the expected rate of 1.51 per 100 patient-years in psoriasis patients with nonbiologic systemic agents derived from the MarketScan database, Dr. Gordon said.

The combined rate of cardiovascular death, MI, or stroke through 3 years in ustekinumab-treated psoriasis patients was 0.41 per 100 patient-years in those on the lower dose and 0.35 per 100 patient-years in those receiving 90 mg. These rates were lower, albeit not significantly so, than rates expected in the general population using data from the Framingham Heart Study and in psoriasis patients using the U.K. General Practice Research Database.

Rates of malignancies, serious infections, and cardiovascular events in ustekinumab-treated patients remained stable over time without any indication of cumulative toxicity. Another safety analysis is planned when participants in the phase III trials reach the 5-year follow-up mark.

The study was funded by Centocor. Dr. Gordon disclosed that he serves as a consultant to the company.

GOTHENBURG, SWEDEN – Long-term risks of malignancies, serious infections, and cardiovascular events in ustekinumab-treated psoriasis patients was found to be what is expected in the general U.S. population, according to a 3-year safety analysis of the major randomized clinical trials of the biologic agent.

Placebo-treated control groups were utilized during the first 12 weeks of the phase III PHOENIX I and II trials and not at all in the phase III Active Comparator Psoriasis Trial (ACCEPT). For the safety analysis based on 3 years of follow-up – for purposes of comparison – risk estimates for the general U.S. population were derived from the National Institute of Health’s Surveillance, Epidemiology and End Results (SEER) database and MarketScan Research Data, Dr. Kenneth B. Gordon explained at the annual congress of the European Academy of Dermatology and Venereology.

The 3-year safety analysis included 3,117 psoriasis patients treated with ustekinumab (Stelara) at 45 mg or 90 mg per dose based on body weight, in accordance with the product labeling. Among this group were 1,247 patients who received the interleukin-12 and -23 inhibitor for at least 2 years, noted Dr. Gordon, a dermatologist at the University of Chicago.

The cumulative incidence of nonmelanoma skin cancer through year 3 in the 3,117 psoriasis patients was 0.64 cases per 100 patient-years in patients on ustekinumab 45 mg and 0.77 per 100 patient-years in those on ustekinumab 90 mg. During the 12-week controlled period of the studies, the incidence in placebo-treated patients was 1.13 cases per 100 patient-years.

Rates of other malignancies, including melanoma and lymphoma, through 3 years were 0.69 and 0.46 cases per 100 patient-years in patients on ustekinumab 45 and 90 mg, respectively. These rates were consistent with those expected in the U.S. general population based upon SEER data. Rates of malignancies other than nonmelanoma skin cancer were also comparable to those reported in a large population of psoriasis patients treated with systemic agents in the U.K. General Practice Research Database, where the incidence was 0.58 cases per 100 patient-years (J. Invest. Dermatol. 2009;129:2604-12).

The rate of serious infections through 3 years was 0.82 per 100 patient-years in psoriasis patients on ustekinumab 45 mg and 1.5 per 100 patient-years in those on the higher dose, for a combined event rate of 1.19 per 100 patient-years. This compared favorably to the expected rate of 1.51 per 100 patient-years in psoriasis patients with nonbiologic systemic agents derived from the MarketScan database, Dr. Gordon said.

The combined rate of cardiovascular death, MI, or stroke through 3 years in ustekinumab-treated psoriasis patients was 0.41 per 100 patient-years in those on the lower dose and 0.35 per 100 patient-years in those receiving 90 mg. These rates were lower, albeit not significantly so, than rates expected in the general population using data from the Framingham Heart Study and in psoriasis patients using the U.K. General Practice Research Database.

Rates of malignancies, serious infections, and cardiovascular events in ustekinumab-treated patients remained stable over time without any indication of cumulative toxicity. Another safety analysis is planned when participants in the phase III trials reach the 5-year follow-up mark.

The study was funded by Centocor. Dr. Gordon disclosed that he serves as a consultant to the company.

GOTHENBURG, SWEDEN – Long-term risks of malignancies, serious infections, and cardiovascular events in ustekinumab-treated psoriasis patients was found to be what is expected in the general U.S. population, according to a 3-year safety analysis of the major randomized clinical trials of the biologic agent.

Placebo-treated control groups were utilized during the first 12 weeks of the phase III PHOENIX I and II trials and not at all in the phase III Active Comparator Psoriasis Trial (ACCEPT). For the safety analysis based on 3 years of follow-up – for purposes of comparison – risk estimates for the general U.S. population were derived from the National Institute of Health’s Surveillance, Epidemiology and End Results (SEER) database and MarketScan Research Data, Dr. Kenneth B. Gordon explained at the annual congress of the European Academy of Dermatology and Venereology.

The 3-year safety analysis included 3,117 psoriasis patients treated with ustekinumab (Stelara) at 45 mg or 90 mg per dose based on body weight, in accordance with the product labeling. Among this group were 1,247 patients who received the interleukin-12 and -23 inhibitor for at least 2 years, noted Dr. Gordon, a dermatologist at the University of Chicago.

The cumulative incidence of nonmelanoma skin cancer through year 3 in the 3,117 psoriasis patients was 0.64 cases per 100 patient-years in patients on ustekinumab 45 mg and 0.77 per 100 patient-years in those on ustekinumab 90 mg. During the 12-week controlled period of the studies, the incidence in placebo-treated patients was 1.13 cases per 100 patient-years.

Rates of other malignancies, including melanoma and lymphoma, through 3 years were 0.69 and 0.46 cases per 100 patient-years in patients on ustekinumab 45 and 90 mg, respectively. These rates were consistent with those expected in the U.S. general population based upon SEER data. Rates of malignancies other than nonmelanoma skin cancer were also comparable to those reported in a large population of psoriasis patients treated with systemic agents in the U.K. General Practice Research Database, where the incidence was 0.58 cases per 100 patient-years (J. Invest. Dermatol. 2009;129:2604-12).

The rate of serious infections through 3 years was 0.82 per 100 patient-years in psoriasis patients on ustekinumab 45 mg and 1.5 per 100 patient-years in those on the higher dose, for a combined event rate of 1.19 per 100 patient-years. This compared favorably to the expected rate of 1.51 per 100 patient-years in psoriasis patients with nonbiologic systemic agents derived from the MarketScan database, Dr. Gordon said.

The combined rate of cardiovascular death, MI, or stroke through 3 years in ustekinumab-treated psoriasis patients was 0.41 per 100 patient-years in those on the lower dose and 0.35 per 100 patient-years in those receiving 90 mg. These rates were lower, albeit not significantly so, than rates expected in the general population using data from the Framingham Heart Study and in psoriasis patients using the U.K. General Practice Research Database.

Rates of malignancies, serious infections, and cardiovascular events in ustekinumab-treated patients remained stable over time without any indication of cumulative toxicity. Another safety analysis is planned when participants in the phase III trials reach the 5-year follow-up mark.

The study was funded by Centocor. Dr. Gordon disclosed that he serves as a consultant to the company.☐

GOTHENBURG, SWEDEN – Long-term risks of malignancies, serious infections, and cardiovascular events in ustekinumab-treated psoriasis patients was found to be what is expected in the general U.S. population, according to a 3-year safety analysis of the major randomized clinical trials of the biologic agent.

Placebo-treated control groups were utilized during the first 12 weeks of the phase III PHOENIX I and II trials and not at all in the phase III Active Comparator Psoriasis Trial (ACCEPT). For the safety analysis based on 3 years of follow-up – for purposes of comparison – risk estimates for the general U.S. population were derived from the National Institute of Health’s Surveillance, Epidemiology and End Results (SEER) database and MarketScan Research Data, Dr. Kenneth B. Gordon explained at the annual congress of the European Academy of Dermatology and Venereology.

The 3-year safety analysis included 3,117 psoriasis patients treated with ustekinumab (Stelara) at 45 mg or 90 mg per dose based on body weight, in accordance with the product labeling. Among this group were 1,247 patients who received the interleukin-12 and -23 inhibitor for at least 2 years, noted Dr. Gordon, a dermatologist at the University of Chicago.

The cumulative incidence of nonmelanoma skin cancer through year 3 in the 3,117 psoriasis patients was 0.64 cases per 100 patient-years in patients on ustekinumab 45 mg and 0.77 per 100 patient-years in those on ustekinumab 90 mg. During the 12-week controlled period of the studies, the incidence in placebo-treated patients was 1.13 cases per 100 patient-years.

Rates of other malignancies, including melanoma and lymphoma, through 3 years were 0.69 and 0.46 cases per 100 patient-years in patients on ustekinumab 45 and 90 mg, respectively. These rates were consistent with those expected in the U.S. general population based upon SEER data. Rates of malignancies other than nonmelanoma skin cancer were also comparable to those reported in a large population of psoriasis patients treated with systemic agents in the U.K. General Practice Research Database, where the incidence was 0.58 cases per 100 patient-years (J. Invest. Dermatol. 2009;129:2604-12).

The rate of serious infections through 3 years was 0.82 per 100 patient-years in psoriasis patients on ustekinumab 45 mg and 1.5 per 100 patient-years in those on the higher dose, for a combined event rate of 1.19 per 100 patient-years. This compared favorably to the expected rate of 1.51 per 100 patient-years in psoriasis patients with nonbiologic systemic agents derived from the MarketScan database, Dr. Gordon said.

The combined rate of cardiovascular death, MI, or stroke through 3 years in ustekinumab-treated psoriasis patients was 0.41 per 100 patient-years in those on the lower dose and 0.35 per 100 patient-years in those receiving 90 mg. These rates were lower, albeit not significantly so, than rates expected in the general population using data from the Framingham Heart Study and in psoriasis patients using the U.K. General Practice Research Database.

Rates of malignancies, serious infections, and cardiovascular events in ustekinumab-treated patients remained stable over time without any indication of cumulative toxicity. Another safety analysis is planned when participants in the phase III trials reach the 5-year follow-up mark.

The study was funded by Centocor. Dr. Gordon disclosed that he serves as a consultant to the company.☐

GOTHENBURG, SWEDEN – Long-term risks of malignancies, serious infections, and cardiovascular events in ustekinumab-treated psoriasis patients was found to be what is expected in the general U.S. population, according to a 3-year safety analysis of the major randomized clinical trials of the biologic agent.

Placebo-treated control groups were utilized during the first 12 weeks of the phase III PHOENIX I and II trials and not at all in the phase III Active Comparator Psoriasis Trial (ACCEPT). For the safety analysis based on 3 years of follow-up – for purposes of comparison – risk estimates for the general U.S. population were derived from the National Institute of Health’s Surveillance, Epidemiology and End Results (SEER) database and MarketScan Research Data, Dr. Kenneth B. Gordon explained at the annual congress of the European Academy of Dermatology and Venereology.

The 3-year safety analysis included 3,117 psoriasis patients treated with ustekinumab (Stelara) at 45 mg or 90 mg per dose based on body weight, in accordance with the product labeling. Among this group were 1,247 patients who received the interleukin-12 and -23 inhibitor for at least 2 years, noted Dr. Gordon, a dermatologist at the University of Chicago.

The cumulative incidence of nonmelanoma skin cancer through year 3 in the 3,117 psoriasis patients was 0.64 cases per 100 patient-years in patients on ustekinumab 45 mg and 0.77 per 100 patient-years in those on ustekinumab 90 mg. During the 12-week controlled period of the studies, the incidence in placebo-treated patients was 1.13 cases per 100 patient-years.

Rates of other malignancies, including melanoma and lymphoma, through 3 years were 0.69 and 0.46 cases per 100 patient-years in patients on ustekinumab 45 and 90 mg, respectively. These rates were consistent with those expected in the U.S. general population based upon SEER data. Rates of malignancies other than nonmelanoma skin cancer were also comparable to those reported in a large population of psoriasis patients treated with systemic agents in the U.K. General Practice Research Database, where the incidence was 0.58 cases per 100 patient-years (J. Invest. Dermatol. 2009;129:2604-12).

The rate of serious infections through 3 years was 0.82 per 100 patient-years in psoriasis patients on ustekinumab 45 mg and 1.5 per 100 patient-years in those on the higher dose, for a combined event rate of 1.19 per 100 patient-years. This compared favorably to the expected rate of 1.51 per 100 patient-years in psoriasis patients with nonbiologic systemic agents derived from the MarketScan database, Dr. Gordon said.

The combined rate of cardiovascular death, MI, or stroke through 3 years in ustekinumab-treated psoriasis patients was 0.41 per 100 patient-years in those on the lower dose and 0.35 per 100 patient-years in those receiving 90 mg. These rates were lower, albeit not significantly so, than rates expected in the general population using data from the Framingham Heart Study and in psoriasis patients using the U.K. General Practice Research Database.

Rates of malignancies, serious infections, and cardiovascular events in ustekinumab-treated patients remained stable over time without any indication of cumulative toxicity. Another safety analysis is planned when participants in the phase III trials reach the 5-year follow-up mark.

The study was funded by Centocor. Dr. Gordon disclosed that he serves as a consultant to the company.☐

GOTHENBURG, SWEDEN – Patients with longstanding chronic pruritus refractory to the full array of conventional therapies had a high response rate to a neurokinin-1 receptor antagonist in a proof-of-concept study.

"To the best of our knowledge, this is the first clinical report demonstrating that targeting the neuropeptide substance P via applying the NK-1 receptor antagonist aprepitant is an effective approach for the treatment of chronic pruritus," Dr. Sonja Ständer said at the annual congress of the European Academy of Dermatology and Venereology.

She reported on 20 patients, mean age 67 years, with an average 61-month duration of pruritus refractory to antihistamines, topical and systemic steroids, cyclosporine, and/or UV phototherapy.

Participants were placed on oral aprepitant at 80 mg once daily for 1 week, with no other anti-pruritic therapy allowed. Sixteen of the 20 patients responded with a significant reduction in itching. Mean values on a daily self-rated pruritus visual analog scale improved from 8.4 points on the 0-10 scale at baseline to 4.9 points after a week on aprepitant (Emend).

Four patients reported complete or nearly complete relief, eight others had a 40%-60% reduction in pruritus, and four patients had a modest 10%-30% improvement. Four others were nonresponders, according to Dr. Ständer of the University Hospital, Münster, Germany.

Responses varied considerably depending upon the presumed pathophysiology of a patient’s pruritus. The best results were seen in the 10 patients with an atopic predisposition and in the 13 with prurigo nodularis and scratch lesions. The seven patients whose pruritus was thought to be caused by underlying systemic disease, such as diabetes or chronic kidney disease, had a far more modest mean 24% reduction in pruritus. However, those who had uremic pruritus, caused by chronic kidney disease as well as an atopic predisposition, fared much better on aprepitant, with a mean 50% reduction in pruritus.

Side effects were limited to mild nausea, drowsiness, and vertigo in three patients.

Aprepitant is approved for the prevention of chemotherapy-induced nausea and vomiting, as well as postoperative nausea and vomiting. The rationale for studying this antiemetic as a potential therapy for chronic pruritus lies in the fact that as an NK-1 receptor antagonist, aprepitant inhibits substance P. And studies in both animals and humans indicate substance P is an important mediator of itch.

Substance P binds to the NK-1 receptor, which is expressed in the skin and the central nervous system. When substance P binds to NK-1 receptors on mast cells, it triggers mast cell degranulation, with release of pruritus-inducing tumor necrosis factor–alpha, histamine, leukotriene B4, and prostaglandin D2. And when substance P binds to NK-1 receptors on keratinocytes, it stimulates production of interleukin-1–alpha and –beta, interleukin-8, and other proinflammatory cytokines, Dr. Ständer explained.

Previous studies indicate chronic pruritus patients with prurigo nodularis or an atopic predisposition are characterized by particularly high levels of substance P in the skin – and these were just the patients with the greatest response to aprepitant in this initial study, she added. Based upon the encouraging results of this pilot study, a randomized, controlled study is planned.

Dr. Ständer declared having no relevant financial interests.

GOTHENBURG, SWEDEN – Patients with longstanding chronic pruritus refractory to the full array of conventional therapies had a high response rate to a neurokinin-1 receptor antagonist in a proof-of-concept study.

"To the best of our knowledge, this is the first clinical report demonstrating that targeting the neuropeptide substance P via applying the NK-1 receptor antagonist aprepitant is an effective approach for the treatment of chronic pruritus," Dr. Sonja Ständer said at the annual congress of the European Academy of Dermatology and Venereology.

She reported on 20 patients, mean age 67 years, with an average 61-month duration of pruritus refractory to antihistamines, topical and systemic steroids, cyclosporine, and/or UV phototherapy.

Participants were placed on oral aprepitant at 80 mg once daily for 1 week, with no other anti-pruritic therapy allowed. Sixteen of the 20 patients responded with a significant reduction in itching. Mean values on a daily self-rated pruritus visual analog scale improved from 8.4 points on the 0-10 scale at baseline to 4.9 points after a week on aprepitant (Emend).

Four patients reported complete or nearly complete relief, eight others had a 40%-60% reduction in pruritus, and four patients had a modest 10%-30% improvement. Four others were nonresponders, according to Dr. Ständer of the University Hospital, Münster, Germany.

Responses varied considerably depending upon the presumed pathophysiology of a patient’s pruritus. The best results were seen in the 10 patients with an atopic predisposition and in the 13 with prurigo nodularis and scratch lesions. The seven patients whose pruritus was thought to be caused by underlying systemic disease, such as diabetes or chronic kidney disease, had a far more modest mean 24% reduction in pruritus. However, those who had uremic pruritus, caused by chronic kidney disease as well as an atopic predisposition, fared much better on aprepitant, with a mean 50% reduction in pruritus.

Side effects were limited to mild nausea, drowsiness, and vertigo in three patients.

Aprepitant is approved for the prevention of chemotherapy-induced nausea and vomiting, as well as postoperative nausea and vomiting. The rationale for studying this antiemetic as a potential therapy for chronic pruritus lies in the fact that as an NK-1 receptor antagonist, aprepitant inhibits substance P. And studies in both animals and humans indicate substance P is an important mediator of itch.

Substance P binds to the NK-1 receptor, which is expressed in the skin and the central nervous system. When substance P binds to NK-1 receptors on mast cells, it triggers mast cell degranulation, with release of pruritus-inducing tumor necrosis factor–alpha, histamine, leukotriene B4, and prostaglandin D2. And when substance P binds to NK-1 receptors on keratinocytes, it stimulates production of interleukin-1–alpha and –beta, interleukin-8, and other proinflammatory cytokines, Dr. Ständer explained.

Previous studies indicate chronic pruritus patients with prurigo nodularis or an atopic predisposition are characterized by particularly high levels of substance P in the skin – and these were just the patients with the greatest response to aprepitant in this initial study, she added. Based upon the encouraging results of this pilot study, a randomized, controlled study is planned.

Dr. Ständer declared having no relevant financial interests.

GOTHENBURG, SWEDEN – Patients with longstanding chronic pruritus refractory to the full array of conventional therapies had a high response rate to a neurokinin-1 receptor antagonist in a proof-of-concept study.

"To the best of our knowledge, this is the first clinical report demonstrating that targeting the neuropeptide substance P via applying the NK-1 receptor antagonist aprepitant is an effective approach for the treatment of chronic pruritus," Dr. Sonja Ständer said at the annual congress of the European Academy of Dermatology and Venereology.

She reported on 20 patients, mean age 67 years, with an average 61-month duration of pruritus refractory to antihistamines, topical and systemic steroids, cyclosporine, and/or UV phototherapy.

Participants were placed on oral aprepitant at 80 mg once daily for 1 week, with no other anti-pruritic therapy allowed. Sixteen of the 20 patients responded with a significant reduction in itching. Mean values on a daily self-rated pruritus visual analog scale improved from 8.4 points on the 0-10 scale at baseline to 4.9 points after a week on aprepitant (Emend).

Four patients reported complete or nearly complete relief, eight others had a 40%-60% reduction in pruritus, and four patients had a modest 10%-30% improvement. Four others were nonresponders, according to Dr. Ständer of the University Hospital, Münster, Germany.

Responses varied considerably depending upon the presumed pathophysiology of a patient’s pruritus. The best results were seen in the 10 patients with an atopic predisposition and in the 13 with prurigo nodularis and scratch lesions. The seven patients whose pruritus was thought to be caused by underlying systemic disease, such as diabetes or chronic kidney disease, had a far more modest mean 24% reduction in pruritus. However, those who had uremic pruritus, caused by chronic kidney disease as well as an atopic predisposition, fared much better on aprepitant, with a mean 50% reduction in pruritus.

Side effects were limited to mild nausea, drowsiness, and vertigo in three patients.

Aprepitant is approved for the prevention of chemotherapy-induced nausea and vomiting, as well as postoperative nausea and vomiting. The rationale for studying this antiemetic as a potential therapy for chronic pruritus lies in the fact that as an NK-1 receptor antagonist, aprepitant inhibits substance P. And studies in both animals and humans indicate substance P is an important mediator of itch.

Substance P binds to the NK-1 receptor, which is expressed in the skin and the central nervous system. When substance P binds to NK-1 receptors on mast cells, it triggers mast cell degranulation, with release of pruritus-inducing tumor necrosis factor–alpha, histamine, leukotriene B4, and prostaglandin D2. And when substance P binds to NK-1 receptors on keratinocytes, it stimulates production of interleukin-1–alpha and –beta, interleukin-8, and other proinflammatory cytokines, Dr. Ständer explained.

Previous studies indicate chronic pruritus patients with prurigo nodularis or an atopic predisposition are characterized by particularly high levels of substance P in the skin – and these were just the patients with the greatest response to aprepitant in this initial study, she added. Based upon the encouraging results of this pilot study, a randomized, controlled study is planned.

Dr. Ständer declared having no relevant financial interests.

GOTHENBURG, SWEDEN – Patients with longstanding chronic pruritus refractory to the full array of conventional therapies had a high response rate to a neurokinin-1 receptor antagonist in a proof-of-concept study.

"To the best of our knowledge, this is the first clinical report demonstrating that targeting the neuropeptide substance P via applying the NK-1 receptor antagonist aprepitant is an effective approach for the treatment of chronic pruritus," Dr. Sonja Ständer said at the annual congress of the European Academy of Dermatology and Venereology.

She reported on 20 patients, mean age 67 years, with an average 61-month duration of pruritus refractory to antihistamines, topical and systemic steroids, cyclosporine, and/or UV phototherapy.

Participants were placed on oral aprepitant at 80 mg once daily for 1 week, with no other anti-pruritic therapy allowed. Sixteen of the 20 patients responded with a significant reduction in itching. Mean values on a daily self-rated pruritus visual analog scale improved from 8.4 points on the 0-10 scale at baseline to 4.9 points after a week on aprepitant (Emend).

Four patients reported complete or nearly complete relief, eight others had a 40%-60% reduction in pruritus, and four patients had a modest 10%-30% improvement. Four others were nonresponders, according to Dr. Ständer of the University Hospital, Münster, Germany.

Responses varied considerably depending upon the presumed pathophysiology of a patient’s pruritus. The best results were seen in the 10 patients with an atopic predisposition and in the 13 with prurigo nodularis and scratch lesions. The seven patients whose pruritus was thought to be caused by underlying systemic disease, such as diabetes or chronic kidney disease, had a far more modest mean 24% reduction in pruritus. However, those who had uremic pruritus, caused by chronic kidney disease as well as an atopic predisposition, fared much better on aprepitant, with a mean 50% reduction in pruritus.

Side effects were limited to mild nausea, drowsiness, and vertigo in three patients.

Aprepitant is approved for the prevention of chemotherapy-induced nausea and vomiting, as well as postoperative nausea and vomiting. The rationale for studying this antiemetic as a potential therapy for chronic pruritus lies in the fact that as an NK-1 receptor antagonist, aprepitant inhibits substance P. And studies in both animals and humans indicate substance P is an important mediator of itch.

Substance P binds to the NK-1 receptor, which is expressed in the skin and the central nervous system. When substance P binds to NK-1 receptors on mast cells, it triggers mast cell degranulation, with release of pruritus-inducing tumor necrosis factor–alpha, histamine, leukotriene B4, and prostaglandin D2. And when substance P binds to NK-1 receptors on keratinocytes, it stimulates production of interleukin-1–alpha and –beta, interleukin-8, and other proinflammatory cytokines, Dr. Ständer explained.

Previous studies indicate chronic pruritus patients with prurigo nodularis or an atopic predisposition are characterized by particularly high levels of substance P in the skin – and these were just the patients with the greatest response to aprepitant in this initial study, she added. Based upon the encouraging results of this pilot study, a randomized, controlled study is planned.

Dr. Ständer declared having no relevant financial interests.

GOTHENBURG, SWEDEN – Patients with longstanding chronic pruritus refractory to the full array of conventional therapies had a high response rate to a neurokinin-1 receptor antagonist in a proof-of-concept study.

"To the best of our knowledge, this is the first clinical report demonstrating that targeting the neuropeptide substance P via applying the NK-1 receptor antagonist aprepitant is an effective approach for the treatment of chronic pruritus," Dr. Sonja Ständer said at the annual congress of the European Academy of Dermatology and Venereology.

She reported on 20 patients, mean age 67 years, with an average 61-month duration of pruritus refractory to antihistamines, topical and systemic steroids, cyclosporine, and/or UV phototherapy.

Participants were placed on oral aprepitant at 80 mg once daily for 1 week, with no other anti-pruritic therapy allowed. Sixteen of the 20 patients responded with a significant reduction in itching. Mean values on a daily self-rated pruritus visual analog scale improved from 8.4 points on the 0-10 scale at baseline to 4.9 points after a week on aprepitant (Emend).

Four patients reported complete or nearly complete relief, eight others had a 40%-60% reduction in pruritus, and four patients had a modest 10%-30% improvement. Four others were nonresponders, according to Dr. Ständer of the University Hospital, Münster, Germany.

Responses varied considerably depending upon the presumed pathophysiology of a patient’s pruritus. The best results were seen in the 10 patients with an atopic predisposition and in the 13 with prurigo nodularis and scratch lesions. The seven patients whose pruritus was thought to be caused by underlying systemic disease, such as diabetes or chronic kidney disease, had a far more modest mean 24% reduction in pruritus. However, those who had uremic pruritus, caused by chronic kidney disease as well as an atopic predisposition, fared much better on aprepitant, with a mean 50% reduction in pruritus.

Side effects were limited to mild nausea, drowsiness, and vertigo in three patients.

Aprepitant is approved for the prevention of chemotherapy-induced nausea and vomiting, as well as postoperative nausea and vomiting. The rationale for studying this antiemetic as a potential therapy for chronic pruritus lies in the fact that as an NK-1 receptor antagonist, aprepitant inhibits substance P. And studies in both animals and humans indicate substance P is an important mediator of itch.

Substance P binds to the NK-1 receptor, which is expressed in the skin and the central nervous system. When substance P binds to NK-1 receptors on mast cells, it triggers mast cell degranulation, with release of pruritus-inducing tumor necrosis factor–alpha, histamine, leukotriene B4, and prostaglandin D2. And when substance P binds to NK-1 receptors on keratinocytes, it stimulates production of interleukin-1–alpha and –beta, interleukin-8, and other proinflammatory cytokines, Dr. Ständer explained.

Previous studies indicate chronic pruritus patients with prurigo nodularis or an atopic predisposition are characterized by particularly high levels of substance P in the skin – and these were just the patients with the greatest response to aprepitant in this initial study, she added. Based upon the encouraging results of this pilot study, a randomized, controlled study is planned.

Dr. Ständer declared having no relevant financial interests.

GOTHENBURG, SWEDEN – Patients with longstanding chronic pruritus refractory to the full array of conventional therapies had a high response rate to a neurokinin-1 receptor antagonist in a proof-of-concept study.

"To the best of our knowledge, this is the first clinical report demonstrating that targeting the neuropeptide substance P via applying the NK-1 receptor antagonist aprepitant is an effective approach for the treatment of chronic pruritus," Dr. Sonja Ständer said at the annual congress of the European Academy of Dermatology and Venereology.

She reported on 20 patients, mean age 67 years, with an average 61-month duration of pruritus refractory to antihistamines, topical and systemic steroids, cyclosporine, and/or UV phototherapy.

Participants were placed on oral aprepitant at 80 mg once daily for 1 week, with no other anti-pruritic therapy allowed. Sixteen of the 20 patients responded with a significant reduction in itching. Mean values on a daily self-rated pruritus visual analog scale improved from 8.4 points on the 0-10 scale at baseline to 4.9 points after a week on aprepitant (Emend).

Four patients reported complete or nearly complete relief, eight others had a 40%-60% reduction in pruritus, and four patients had a modest 10%-30% improvement. Four others were nonresponders, according to Dr. Ständer of the University Hospital, Münster, Germany.

Responses varied considerably depending upon the presumed pathophysiology of a patient’s pruritus. The best results were seen in the 10 patients with an atopic predisposition and in the 13 with prurigo nodularis and scratch lesions. The seven patients whose pruritus was thought to be caused by underlying systemic disease, such as diabetes or chronic kidney disease, had a far more modest mean 24% reduction in pruritus. However, those who had uremic pruritus, caused by chronic kidney disease as well as an atopic predisposition, fared much better on aprepitant, with a mean 50% reduction in pruritus.

Side effects were limited to mild nausea, drowsiness, and vertigo in three patients.

Aprepitant is approved for the prevention of chemotherapy-induced nausea and vomiting, as well as postoperative nausea and vomiting. The rationale for studying this antiemetic as a potential therapy for chronic pruritus lies in the fact that as an NK-1 receptor antagonist, aprepitant inhibits substance P. And studies in both animals and humans indicate substance P is an important mediator of itch.

Substance P binds to the NK-1 receptor, which is expressed in the skin and the central nervous system. When substance P binds to NK-1 receptors on mast cells, it triggers mast cell degranulation, with release of pruritus-inducing tumor necrosis factor–alpha, histamine, leukotriene B4, and prostaglandin D2. And when substance P binds to NK-1 receptors on keratinocytes, it stimulates production of interleukin-1–alpha and –beta, interleukin-8, and other proinflammatory cytokines, Dr. Ständer explained.

Previous studies indicate chronic pruritus patients with prurigo nodularis or an atopic predisposition are characterized by particularly high levels of substance P in the skin – and these were just the patients with the greatest response to aprepitant in this initial study, she added. Based upon the encouraging results of this pilot study, a randomized, controlled study is planned.

Dr. Ständer declared having no relevant financial interests.