Nancy Walsh

TORONTO — A substantial proportion of patients with severe, refractory asthma are unable to become well controlled despite the availability of updated guidelines, even in subspecialty care, according to Dr. Amandeep S. Gill of the Medical College of Wisconsin, Milwaukee.

The National Asthma Education and Prevention Program's Guidelines for the Diagnosis and Management of Asthma have been updated periodically since they were first published in 1991, reflecting changes in evidence-based data since that time, with the latest revision being released in 2007.

However, little is known about the effect of the guidelines on the prevalence of severe refractory asthma. To assess the impact, a study was undertaken of 172 patients referred to subspecialty management programs in two Midwestern cities, comparing disease status at presentation and after 1 year of guideline-based care that included education and minimized barriers to care.

A total of 103 patients were seen in an asthma clinic at Case Western Reserve University, Cleveland, and 69 patients in a disease management program at the Medical College of Wisconsin, Milwaukee. Asthma morbidity was assessed retrospectively for the previous year, while patients were being managed in primary care, and prospectively for the subsequent year while they were receiving subspecialty care.

Controlled asthma was defined as:

▸ Symptoms no more than twice per week.

▸ Nocturnal symptoms fewer than two times per month.

▸ Short-acting bronchodilator use no more than twice per week.

▸ No interference with normal activities.

▸ Forced expiratory volume in 1 second (FEV₁) at least 80% of predicted.

▸ No more than one exacerbation per year requiring oral corticosteroids.

In contrast, severe refractory asthma was classified as the requirement for high-dose inhaled corticosteroids and a long-acting β-agonist with or without oral steroids and/or omalizumab (step 5 or 6 pharmacotherapy in the guidelines).

The mean age at entry among patients from both cities was 48 years, and the mean duration of asthma was 17 years. More than three-quarters were female, and more than half were African American or Latino.

At presentation, 20% of patients from Cleveland and slightly more than 30% of patients from Milwaukee had severe refractory asthma, yet only 34% and 46%, respectively, were on appropriate medications for their level of disease severity. Only 54% and 62%, respectively, were able to demonstrate the proper use of a metered-dose inhaler.

After 1 year of subspecialty treatment, the numbers of urgent care and emergency department visits fell significantly in both groups, but many other disease characteristics did not improve significantly.

Overall, the percentage of patients whose asthma was well controlled improved from less than 10% to 20% after 1 year. However, 32% of patients still had severe persistent disease at 1 year, and half of those whose disease was not well controlled were receiving high-dose inhaled corticosteroids and a long-acting β-agonist.

Furthermore, at 1 year, 40% of patients from both cohorts were using the maximum available level of pharmacotherapy but could not achieve well-controlled status.

“Even when asthmatics are well educated in self-management techniques and have access to continuity of care and appropriate medications, more than three-fourths are unable to become well controlled,” Dr. Gill wrote.

ELSEVIER GLOBAL MEDICAL NEWS

TORONTO — A substantial proportion of patients with severe, refractory asthma are unable to become well controlled despite the availability of updated guidelines, even in subspecialty care, according to Dr. Amandeep S. Gill of the Medical College of Wisconsin, Milwaukee.

The National Asthma Education and Prevention Program's Guidelines for the Diagnosis and Management of Asthma have been updated periodically since they were first published in 1991, reflecting changes in evidence-based data since that time, with the latest revision being released in 2007.

However, little is known about the effect of the guidelines on the prevalence of severe refractory asthma. To assess the impact, a study was undertaken of 172 patients referred to subspecialty management programs in two Midwestern cities, comparing disease status at presentation and after 1 year of guideline-based care that included education and minimized barriers to care.

A total of 103 patients were seen in an asthma clinic at Case Western Reserve University, Cleveland, and 69 patients in a disease management program at the Medical College of Wisconsin, Milwaukee. Asthma morbidity was assessed retrospectively for the previous year, while patients were being managed in primary care, and prospectively for the subsequent year while they were receiving subspecialty care.

Controlled asthma was defined as:

▸ Symptoms no more than twice per week.

▸ Nocturnal symptoms fewer than two times per month.

▸ Short-acting bronchodilator use no more than twice per week.

▸ No interference with normal activities.

▸ Forced expiratory volume in 1 second (FEV₁) at least 80% of predicted.

▸ No more than one exacerbation per year requiring oral corticosteroids.

In contrast, severe refractory asthma was classified as the requirement for high-dose inhaled corticosteroids and a long-acting β-agonist with or without oral steroids and/or omalizumab (step 5 or 6 pharmacotherapy in the guidelines).

The mean age at entry among patients from both cities was 48 years, and the mean duration of asthma was 17 years. More than three-quarters were female, and more than half were African American or Latino.

At presentation, 20% of patients from Cleveland and slightly more than 30% of patients from Milwaukee had severe refractory asthma, yet only 34% and 46%, respectively, were on appropriate medications for their level of disease severity. Only 54% and 62%, respectively, were able to demonstrate the proper use of a metered-dose inhaler.

After 1 year of subspecialty treatment, the numbers of urgent care and emergency department visits fell significantly in both groups, but many other disease characteristics did not improve significantly.

Overall, the percentage of patients whose asthma was well controlled improved from less than 10% to 20% after 1 year. However, 32% of patients still had severe persistent disease at 1 year, and half of those whose disease was not well controlled were receiving high-dose inhaled corticosteroids and a long-acting β-agonist.

Furthermore, at 1 year, 40% of patients from both cohorts were using the maximum available level of pharmacotherapy but could not achieve well-controlled status.

“Even when asthmatics are well educated in self-management techniques and have access to continuity of care and appropriate medications, more than three-fourths are unable to become well controlled,” Dr. Gill wrote.

ELSEVIER GLOBAL MEDICAL NEWS

TORONTO — A substantial proportion of patients with severe, refractory asthma are unable to become well controlled despite the availability of updated guidelines, even in subspecialty care, according to Dr. Amandeep S. Gill of the Medical College of Wisconsin, Milwaukee.

The National Asthma Education and Prevention Program's Guidelines for the Diagnosis and Management of Asthma have been updated periodically since they were first published in 1991, reflecting changes in evidence-based data since that time, with the latest revision being released in 2007.

However, little is known about the effect of the guidelines on the prevalence of severe refractory asthma. To assess the impact, a study was undertaken of 172 patients referred to subspecialty management programs in two Midwestern cities, comparing disease status at presentation and after 1 year of guideline-based care that included education and minimized barriers to care.

A total of 103 patients were seen in an asthma clinic at Case Western Reserve University, Cleveland, and 69 patients in a disease management program at the Medical College of Wisconsin, Milwaukee. Asthma morbidity was assessed retrospectively for the previous year, while patients were being managed in primary care, and prospectively for the subsequent year while they were receiving subspecialty care.

Controlled asthma was defined as:

▸ Symptoms no more than twice per week.

▸ Nocturnal symptoms fewer than two times per month.

▸ Short-acting bronchodilator use no more than twice per week.

▸ No interference with normal activities.

▸ Forced expiratory volume in 1 second (FEV₁) at least 80% of predicted.

▸ No more than one exacerbation per year requiring oral corticosteroids.

In contrast, severe refractory asthma was classified as the requirement for high-dose inhaled corticosteroids and a long-acting β-agonist with or without oral steroids and/or omalizumab (step 5 or 6 pharmacotherapy in the guidelines).

The mean age at entry among patients from both cities was 48 years, and the mean duration of asthma was 17 years. More than three-quarters were female, and more than half were African American or Latino.

At presentation, 20% of patients from Cleveland and slightly more than 30% of patients from Milwaukee had severe refractory asthma, yet only 34% and 46%, respectively, were on appropriate medications for their level of disease severity. Only 54% and 62%, respectively, were able to demonstrate the proper use of a metered-dose inhaler.

After 1 year of subspecialty treatment, the numbers of urgent care and emergency department visits fell significantly in both groups, but many other disease characteristics did not improve significantly.

Overall, the percentage of patients whose asthma was well controlled improved from less than 10% to 20% after 1 year. However, 32% of patients still had severe persistent disease at 1 year, and half of those whose disease was not well controlled were receiving high-dose inhaled corticosteroids and a long-acting β-agonist.

Furthermore, at 1 year, 40% of patients from both cohorts were using the maximum available level of pharmacotherapy but could not achieve well-controlled status.

“Even when asthmatics are well educated in self-management techniques and have access to continuity of care and appropriate medications, more than three-fourths are unable to become well controlled,” Dr. Gill wrote.

ELSEVIER GLOBAL MEDICAL NEWS

TORONTO — Gene expression profiling of peripheral blood lymphocytes successfully identified lung cancer patients with an overall accuracy of 87% in a cross-sectional study of 230 subjects.

The test, which is in the early development stage, had a sensitivity of 85% and a specificity of 87%, Dr. Anil Vachani said at an international conference of the American Thoracic Society. Of the 230 subjects, 140 had lung cancer and 90 did not.

Lung cancer is difficult to diagnose. Many patients have lung nodules detected incidentally on chest x-ray or CT scan. The next step is problematic, as needle biopsy of the chest is difficult and bronchoscopy requires anesthesia and is risky. Often, the nodule is surgically removed and found to be benign, Dr. Vachani of the University of Pennsylvania, Philadelphia, said in a press conference.

A blood test for a patient who has a lung nodule would be useful. Other researchers have worked on this, but most have focused on finding a signature protein secreted by tumor cells into the bloodstream. But lung cancer is a more heterogeneous cancer, and no single protein has been found to identify all types of the disease, said Dr. Vachani.

He and his colleagues profiled “gene expression in peripheral blood mononuclear cells that are involved in tumor immunity” by isolating lymphocytes from peripheral blood and performing global gene expression profiling. “We measured the 20,000 genes found in these cells, and using advanced statistical algorithms, identified genes that are differentially expressed between patients and controls. We then see if we can validate whether genes that are differentially expressed can actually predict which patients have cancer and which do not.” The study was funded by the Pennsylvania Department of Health.

TORONTO — Gene expression profiling of peripheral blood lymphocytes successfully identified lung cancer patients with an overall accuracy of 87% in a cross-sectional study of 230 subjects.

The test, which is in the early development stage, had a sensitivity of 85% and a specificity of 87%, Dr. Anil Vachani said at an international conference of the American Thoracic Society. Of the 230 subjects, 140 had lung cancer and 90 did not.

Lung cancer is difficult to diagnose. Many patients have lung nodules detected incidentally on chest x-ray or CT scan. The next step is problematic, as needle biopsy of the chest is difficult and bronchoscopy requires anesthesia and is risky. Often, the nodule is surgically removed and found to be benign, Dr. Vachani of the University of Pennsylvania, Philadelphia, said in a press conference.

A blood test for a patient who has a lung nodule would be useful. Other researchers have worked on this, but most have focused on finding a signature protein secreted by tumor cells into the bloodstream. But lung cancer is a more heterogeneous cancer, and no single protein has been found to identify all types of the disease, said Dr. Vachani.

He and his colleagues profiled “gene expression in peripheral blood mononuclear cells that are involved in tumor immunity” by isolating lymphocytes from peripheral blood and performing global gene expression profiling. “We measured the 20,000 genes found in these cells, and using advanced statistical algorithms, identified genes that are differentially expressed between patients and controls. We then see if we can validate whether genes that are differentially expressed can actually predict which patients have cancer and which do not.” The study was funded by the Pennsylvania Department of Health.

TORONTO — Gene expression profiling of peripheral blood lymphocytes successfully identified lung cancer patients with an overall accuracy of 87% in a cross-sectional study of 230 subjects.

The test, which is in the early development stage, had a sensitivity of 85% and a specificity of 87%, Dr. Anil Vachani said at an international conference of the American Thoracic Society. Of the 230 subjects, 140 had lung cancer and 90 did not.

Lung cancer is difficult to diagnose. Many patients have lung nodules detected incidentally on chest x-ray or CT scan. The next step is problematic, as needle biopsy of the chest is difficult and bronchoscopy requires anesthesia and is risky. Often, the nodule is surgically removed and found to be benign, Dr. Vachani of the University of Pennsylvania, Philadelphia, said in a press conference.

A blood test for a patient who has a lung nodule would be useful. Other researchers have worked on this, but most have focused on finding a signature protein secreted by tumor cells into the bloodstream. But lung cancer is a more heterogeneous cancer, and no single protein has been found to identify all types of the disease, said Dr. Vachani.

He and his colleagues profiled “gene expression in peripheral blood mononuclear cells that are involved in tumor immunity” by isolating lymphocytes from peripheral blood and performing global gene expression profiling. “We measured the 20,000 genes found in these cells, and using advanced statistical algorithms, identified genes that are differentially expressed between patients and controls. We then see if we can validate whether genes that are differentially expressed can actually predict which patients have cancer and which do not.” The study was funded by the Pennsylvania Department of Health.

TORONTO — Patients with chronic obstructive pulmonary disease treated with a combination of formoterol and tiotropium required less rescue medication than did those treated with tiotropium alone.

In a 12-week double-blind trial sponsored by Schering-Plough, Dr. Donald P. Tashkin of the University of California, Los Angeles, and colleagues, tested a combination of the long-acting anticholinergic tiotropium plus the long-acting β₂-agonist formoterol to improve symptom control and lessen the need for rescue albuterol to a greater degree than the anticholinergic alone.

The 255 participating patients were aged 40 years or older and had at least a 10 pack-year history of smoking. Postbronchodilator forced expiratory volume in 1 second (FEV1) was 30%–70% of predicted normal, or 0.75 L, and the ratio of FEV1 to forced vital capacity was less than 70%.

Spirometric measurements were performed weekly, and the number of puffs of rescue medication was recorded in patient diaries. The majority of patients were white men, and the average age was 64 years.

Overall daily rescue medication use was reduced by 0.81 puffs/day in the combination group, which was significantly greater than the reduction in the monotherapy group of 0.53 puffs/day, Dr. Tashkin reported in a poster session at an international conference of the American Thoracic Society.

Daytime albuterol puffs were reduced by 1.16/day in the combination group, which also was significantly greater than the reduction of 0.76 in the monotherapy group.

Overall nighttime albuterol use was reduced by 0.44 puffs/day and 0.28 puffs/day in the combination and monotherapy groups, respectively.

Both treatments were generally well tolerated. Four patients in the monotherapy group experienced serious adverse events that were considered to be treatment related, whereas no patients in the combination group experienced serious adverse events.

The rationale for combining an anticholinergic with a β-agonist to relieve the impaired lung function in COPD derives from the drugs' different mechanisms of bronchodilation, Dr. Tashkin wrote in a recent review (Chest 2004;125:249–59).

TORONTO — Patients with chronic obstructive pulmonary disease treated with a combination of formoterol and tiotropium required less rescue medication than did those treated with tiotropium alone.

In a 12-week double-blind trial sponsored by Schering-Plough, Dr. Donald P. Tashkin of the University of California, Los Angeles, and colleagues, tested a combination of the long-acting anticholinergic tiotropium plus the long-acting β₂-agonist formoterol to improve symptom control and lessen the need for rescue albuterol to a greater degree than the anticholinergic alone.

The 255 participating patients were aged 40 years or older and had at least a 10 pack-year history of smoking. Postbronchodilator forced expiratory volume in 1 second (FEV1) was 30%–70% of predicted normal, or 0.75 L, and the ratio of FEV1 to forced vital capacity was less than 70%.

Spirometric measurements were performed weekly, and the number of puffs of rescue medication was recorded in patient diaries. The majority of patients were white men, and the average age was 64 years.

Overall daily rescue medication use was reduced by 0.81 puffs/day in the combination group, which was significantly greater than the reduction in the monotherapy group of 0.53 puffs/day, Dr. Tashkin reported in a poster session at an international conference of the American Thoracic Society.

Daytime albuterol puffs were reduced by 1.16/day in the combination group, which also was significantly greater than the reduction of 0.76 in the monotherapy group.

Overall nighttime albuterol use was reduced by 0.44 puffs/day and 0.28 puffs/day in the combination and monotherapy groups, respectively.

Both treatments were generally well tolerated. Four patients in the monotherapy group experienced serious adverse events that were considered to be treatment related, whereas no patients in the combination group experienced serious adverse events.

The rationale for combining an anticholinergic with a β-agonist to relieve the impaired lung function in COPD derives from the drugs' different mechanisms of bronchodilation, Dr. Tashkin wrote in a recent review (Chest 2004;125:249–59).

TORONTO — Patients with chronic obstructive pulmonary disease treated with a combination of formoterol and tiotropium required less rescue medication than did those treated with tiotropium alone.

In a 12-week double-blind trial sponsored by Schering-Plough, Dr. Donald P. Tashkin of the University of California, Los Angeles, and colleagues, tested a combination of the long-acting anticholinergic tiotropium plus the long-acting β₂-agonist formoterol to improve symptom control and lessen the need for rescue albuterol to a greater degree than the anticholinergic alone.

The 255 participating patients were aged 40 years or older and had at least a 10 pack-year history of smoking. Postbronchodilator forced expiratory volume in 1 second (FEV1) was 30%–70% of predicted normal, or 0.75 L, and the ratio of FEV1 to forced vital capacity was less than 70%.

Spirometric measurements were performed weekly, and the number of puffs of rescue medication was recorded in patient diaries. The majority of patients were white men, and the average age was 64 years.

Overall daily rescue medication use was reduced by 0.81 puffs/day in the combination group, which was significantly greater than the reduction in the monotherapy group of 0.53 puffs/day, Dr. Tashkin reported in a poster session at an international conference of the American Thoracic Society.

Daytime albuterol puffs were reduced by 1.16/day in the combination group, which also was significantly greater than the reduction of 0.76 in the monotherapy group.

Overall nighttime albuterol use was reduced by 0.44 puffs/day and 0.28 puffs/day in the combination and monotherapy groups, respectively.

Both treatments were generally well tolerated. Four patients in the monotherapy group experienced serious adverse events that were considered to be treatment related, whereas no patients in the combination group experienced serious adverse events.

The rationale for combining an anticholinergic with a β-agonist to relieve the impaired lung function in COPD derives from the drugs' different mechanisms of bronchodilation, Dr. Tashkin wrote in a recent review (Chest 2004;125:249–59).

TORONTO – Long-term treatment with extended-release naltrexone selectively inhibited the hedonic response associated with drinking alcohol while sparing the experience of pleasure associated with other activities such as reading and listening to music, a study has found.

A total of 74 patients who participated in a 4-year trial comparing two doses of injectable extended-release naltrexone (Vivitrol) with placebo or a 3-year trial comparing the injectable drug with the oral formulation agreed to participate in an extension phase involving high- or low-dose naltrexone and a questionnaire, according to Dr. Charles O'Brien, Kenneth Appel Professor of Psychiatry, University of Pennsylvania, Philadelphia.

The activities ranged from drinking alcohol to eating good food, and for each activity, respondents rated how pleasurable the activity was, Dr. O'Brien reported in a poster at the annual conference of the American Society of Addiction Medicine.

Those who had consumed alcohol within the previous 90 days showed relatively low ratings of pleasure from drinking.

Dr. O'Brien reported no financial conflicts of interest.

TORONTO – Long-term treatment with extended-release naltrexone selectively inhibited the hedonic response associated with drinking alcohol while sparing the experience of pleasure associated with other activities such as reading and listening to music, a study has found.

A total of 74 patients who participated in a 4-year trial comparing two doses of injectable extended-release naltrexone (Vivitrol) with placebo or a 3-year trial comparing the injectable drug with the oral formulation agreed to participate in an extension phase involving high- or low-dose naltrexone and a questionnaire, according to Dr. Charles O'Brien, Kenneth Appel Professor of Psychiatry, University of Pennsylvania, Philadelphia.

The activities ranged from drinking alcohol to eating good food, and for each activity, respondents rated how pleasurable the activity was, Dr. O'Brien reported in a poster at the annual conference of the American Society of Addiction Medicine.

Those who had consumed alcohol within the previous 90 days showed relatively low ratings of pleasure from drinking.

Dr. O'Brien reported no financial conflicts of interest.

TORONTO – Long-term treatment with extended-release naltrexone selectively inhibited the hedonic response associated with drinking alcohol while sparing the experience of pleasure associated with other activities such as reading and listening to music, a study has found.

A total of 74 patients who participated in a 4-year trial comparing two doses of injectable extended-release naltrexone (Vivitrol) with placebo or a 3-year trial comparing the injectable drug with the oral formulation agreed to participate in an extension phase involving high- or low-dose naltrexone and a questionnaire, according to Dr. Charles O'Brien, Kenneth Appel Professor of Psychiatry, University of Pennsylvania, Philadelphia.

The activities ranged from drinking alcohol to eating good food, and for each activity, respondents rated how pleasurable the activity was, Dr. O'Brien reported in a poster at the annual conference of the American Society of Addiction Medicine.

Those who had consumed alcohol within the previous 90 days showed relatively low ratings of pleasure from drinking.

Dr. O'Brien reported no financial conflicts of interest.

BOSTON — The diagnosis of syphilis is often delayed in HIV-positive patients, as it is characterized by a wide range of symptoms that may not be recognized as infection with Treponema pallidum, according to Dr. Lawrence A. Siegel of the division of international medicine and infectious diseases, Cornell University, New York.

After declining to an all-time low in 2000, the rate of syphilis in the United States rose from 3 per 100,000 population in 2001 to 5.7 per 100,000 in 2006. Syphilis has increased particularly dramatically among men who have sex with men (MSM), who made up 4% of cases in 2000 but who represented 64% of cases in 2006, Dr. Siegel reported in a poster session at the 15th Conference on Retroviruses and Opportunistic Infections.

Nationwide, approximately 60% of cases of syphilis now are seen in HIV-positive, urban MSM, but in New York City, 97% of syphilis cases are in MSM. To more fully characterize this coinfected population in New York City, Dr. Siegel and his colleagues undertook a retrospective chart review of all HIV-positive MSM diagnosed with incident syphilis at the Cornell HIV clinic between January 2001 and December 2007.

A total of 118 cases of syphilis were identified. Stage at diagnosis was primary in 8 patients, secondary in 80, early latent in 17, and late latent in 13, Dr. Siegel reported. Three patients had neurosyphilis.

Median age of the patients was 38 years. A total of 33% were white, 30% were black, 34% were Hispanic, and the rest were classified as “other.”

The HIV RNA level was less than 400 copies/mL in 56%, and median CD4 count was 399 cells/mm

A multivariate analysis showed that higher baseline RPR titer and diagnosis of latent syphilis were associated with a longer time until the RPR titer became negative, Dr. Siegel reported at the meeting, which was sponsored by the Foundation for Retrovirology and Human Health and the Centers for Disease Control and Prevention.

Different treatment regimens—one or three doses of 2.4 million U benzathine penicillin, or doxycycline 100 mg twice daily for 30 days—were not associated with a longer time until RPR negativity, the researchers found.

Cases of early syphilis in this population are often not identified, so a higher index of suspicion is needed among clinicians. More frequent serologic testing also is warranted, Dr. Siegel and his colleagues concluded.

ELSEVIER GLOBAL MEDICAL NEWS

BOSTON — The diagnosis of syphilis is often delayed in HIV-positive patients, as it is characterized by a wide range of symptoms that may not be recognized as infection with Treponema pallidum, according to Dr. Lawrence A. Siegel of the division of international medicine and infectious diseases, Cornell University, New York.

After declining to an all-time low in 2000, the rate of syphilis in the United States rose from 3 per 100,000 population in 2001 to 5.7 per 100,000 in 2006. Syphilis has increased particularly dramatically among men who have sex with men (MSM), who made up 4% of cases in 2000 but who represented 64% of cases in 2006, Dr. Siegel reported in a poster session at the 15th Conference on Retroviruses and Opportunistic Infections.

Nationwide, approximately 60% of cases of syphilis now are seen in HIV-positive, urban MSM, but in New York City, 97% of syphilis cases are in MSM. To more fully characterize this coinfected population in New York City, Dr. Siegel and his colleagues undertook a retrospective chart review of all HIV-positive MSM diagnosed with incident syphilis at the Cornell HIV clinic between January 2001 and December 2007.

A total of 118 cases of syphilis were identified. Stage at diagnosis was primary in 8 patients, secondary in 80, early latent in 17, and late latent in 13, Dr. Siegel reported. Three patients had neurosyphilis.

Median age of the patients was 38 years. A total of 33% were white, 30% were black, 34% were Hispanic, and the rest were classified as “other.”

The HIV RNA level was less than 400 copies/mL in 56%, and median CD4 count was 399 cells/mm

A multivariate analysis showed that higher baseline RPR titer and diagnosis of latent syphilis were associated with a longer time until the RPR titer became negative, Dr. Siegel reported at the meeting, which was sponsored by the Foundation for Retrovirology and Human Health and the Centers for Disease Control and Prevention.

Different treatment regimens—one or three doses of 2.4 million U benzathine penicillin, or doxycycline 100 mg twice daily for 30 days—were not associated with a longer time until RPR negativity, the researchers found.

Cases of early syphilis in this population are often not identified, so a higher index of suspicion is needed among clinicians. More frequent serologic testing also is warranted, Dr. Siegel and his colleagues concluded.

ELSEVIER GLOBAL MEDICAL NEWS

BOSTON — The diagnosis of syphilis is often delayed in HIV-positive patients, as it is characterized by a wide range of symptoms that may not be recognized as infection with Treponema pallidum, according to Dr. Lawrence A. Siegel of the division of international medicine and infectious diseases, Cornell University, New York.

After declining to an all-time low in 2000, the rate of syphilis in the United States rose from 3 per 100,000 population in 2001 to 5.7 per 100,000 in 2006. Syphilis has increased particularly dramatically among men who have sex with men (MSM), who made up 4% of cases in 2000 but who represented 64% of cases in 2006, Dr. Siegel reported in a poster session at the 15th Conference on Retroviruses and Opportunistic Infections.

Nationwide, approximately 60% of cases of syphilis now are seen in HIV-positive, urban MSM, but in New York City, 97% of syphilis cases are in MSM. To more fully characterize this coinfected population in New York City, Dr. Siegel and his colleagues undertook a retrospective chart review of all HIV-positive MSM diagnosed with incident syphilis at the Cornell HIV clinic between January 2001 and December 2007.

A total of 118 cases of syphilis were identified. Stage at diagnosis was primary in 8 patients, secondary in 80, early latent in 17, and late latent in 13, Dr. Siegel reported. Three patients had neurosyphilis.

Median age of the patients was 38 years. A total of 33% were white, 30% were black, 34% were Hispanic, and the rest were classified as “other.”

The HIV RNA level was less than 400 copies/mL in 56%, and median CD4 count was 399 cells/mm

A multivariate analysis showed that higher baseline RPR titer and diagnosis of latent syphilis were associated with a longer time until the RPR titer became negative, Dr. Siegel reported at the meeting, which was sponsored by the Foundation for Retrovirology and Human Health and the Centers for Disease Control and Prevention.

Different treatment regimens—one or three doses of 2.4 million U benzathine penicillin, or doxycycline 100 mg twice daily for 30 days—were not associated with a longer time until RPR negativity, the researchers found.

Cases of early syphilis in this population are often not identified, so a higher index of suspicion is needed among clinicians. More frequent serologic testing also is warranted, Dr. Siegel and his colleagues concluded.

ELSEVIER GLOBAL MEDICAL NEWS

Low-dose methotrexate combined with topical betamethasone dipropionate was a safe and effective treatment for bullous pemphigoid in a retrospective study conducted by Dr. Petra Kjellman and colleagues.

For the past 50 years, glucocorticoids have been the mainstay of treatment for bullous pemphigoid (BP), but the high doses of these drugs that are typically needed to control inflammation are poorly tolerated, particularly among the elderly, who are most commonly affected, according to the researchers.

To minimize the adverse effects of glucocorticoids, which include sepsis, pneumonia, gastrointestinal tract bleeding, diabetes, and osteoporosis, other immunosuppressants also have been tried as steroid-sparing agents in BP, but few controlled trials have been done, they noted.

For the past decade, Dr. Kjellman and colleagues from the department of dermatology and venereology, Karolinska University Hospital, Stockholm, have preferentially used methotrexate for BP patients, with prednisone if needed or if methotrexate could not be given or tolerated.

The usual regimen involved an initial dosage of 5 mg/week of methotrexate, with topical betamethasone dipropionate applied twice daily until the disease was controlled. If necessary, methotrexate dosage was increased by 2.5 mg/week.

If symptoms persisted despite methotrexate treatment, prednisone was added in doses of 10-20 mg/day, and if methotrexate could not be given because of anemia, liver disease, or renal failure, prednisone was given alone.

Between 1999 and 2003, 138 patients whose mean age was 81 years were diagnosed with BP. Of these, 57% were women, 51% had mild disease, 38% had moderate disease, and 11% had severe disease.

Methotrexate treatment was initiated in 98 (71%), with a median weekly dosage of 5 mg. Among these patients, 61 continued on methotrexate monotherapy (group 1) and had a mean cumulative dose of 280 mg.

Among patients who received methotrexate, 37 also were treated with prednisone (group 2). The median weekly dosage of methotrexate in this group was 6 mg, and the median cumulative dose was 440 mg.

Forty patients did not receive methotrexate, with 15 receiving high-dose prednisone alone at a median daily dosage of 12 mg and with a median cumulative dose of 4,000 mg (group 3). The other 25 patients who did not receive methotrexate (group 4) had mild disease and were managed with topical betamethasone gel alone.

Median follow-up was 26 months. At 24 months, the remission rates were 43% in group 1, 35% in group 2, 0% in group 3, and 83% in group 4 (Arch. Dermatol. 2008;144:612-16).

Mortality in BP is considerable, with previous reports finding 1-year mortality ranging from 10% to 41%, according to the researchers. In this series, 2-year survival was 65%, 67%, 47%, and 52% in the four groups, respectively, and there was a tendency toward better survival for the methotrexate-treated patients, with median survival times of 38 and 24 months in groups 1 and 2, respectively.

Only one patient in this series developed anemia, and although elevated liver enzymes were seen on occasion during the first weeks of therapy, normalization usually followed within 4-6 weeks. They did not perform pretreatment liver biopsies.

They researchers noted that they are also developing a BP quality register and biobank to enable further follow-up of these patients, and they plan a prospective study to provide further information. They had no conflicts of interest to disclose.

Low-dose methotrexate combined with topical betamethasone dipropionate was a safe and effective treatment for bullous pemphigoid in a retrospective study conducted by Dr. Petra Kjellman and colleagues.

For the past 50 years, glucocorticoids have been the mainstay of treatment for bullous pemphigoid (BP), but the high doses of these drugs that are typically needed to control inflammation are poorly tolerated, particularly among the elderly, who are most commonly affected, according to the researchers.

To minimize the adverse effects of glucocorticoids, which include sepsis, pneumonia, gastrointestinal tract bleeding, diabetes, and osteoporosis, other immunosuppressants also have been tried as steroid-sparing agents in BP, but few controlled trials have been done, they noted.

For the past decade, Dr. Kjellman and colleagues from the department of dermatology and venereology, Karolinska University Hospital, Stockholm, have preferentially used methotrexate for BP patients, with prednisone if needed or if methotrexate could not be given or tolerated.

The usual regimen involved an initial dosage of 5 mg/week of methotrexate, with topical betamethasone dipropionate applied twice daily until the disease was controlled. If necessary, methotrexate dosage was increased by 2.5 mg/week.

If symptoms persisted despite methotrexate treatment, prednisone was added in doses of 10-20 mg/day, and if methotrexate could not be given because of anemia, liver disease, or renal failure, prednisone was given alone.

Between 1999 and 2003, 138 patients whose mean age was 81 years were diagnosed with BP. Of these, 57% were women, 51% had mild disease, 38% had moderate disease, and 11% had severe disease.

Methotrexate treatment was initiated in 98 (71%), with a median weekly dosage of 5 mg. Among these patients, 61 continued on methotrexate monotherapy (group 1) and had a mean cumulative dose of 280 mg.

Among patients who received methotrexate, 37 also were treated with prednisone (group 2). The median weekly dosage of methotrexate in this group was 6 mg, and the median cumulative dose was 440 mg.

Forty patients did not receive methotrexate, with 15 receiving high-dose prednisone alone at a median daily dosage of 12 mg and with a median cumulative dose of 4,000 mg (group 3). The other 25 patients who did not receive methotrexate (group 4) had mild disease and were managed with topical betamethasone gel alone.

Median follow-up was 26 months. At 24 months, the remission rates were 43% in group 1, 35% in group 2, 0% in group 3, and 83% in group 4 (Arch. Dermatol. 2008;144:612-16).

Mortality in BP is considerable, with previous reports finding 1-year mortality ranging from 10% to 41%, according to the researchers. In this series, 2-year survival was 65%, 67%, 47%, and 52% in the four groups, respectively, and there was a tendency toward better survival for the methotrexate-treated patients, with median survival times of 38 and 24 months in groups 1 and 2, respectively.

Only one patient in this series developed anemia, and although elevated liver enzymes were seen on occasion during the first weeks of therapy, normalization usually followed within 4-6 weeks. They did not perform pretreatment liver biopsies.

They researchers noted that they are also developing a BP quality register and biobank to enable further follow-up of these patients, and they plan a prospective study to provide further information. They had no conflicts of interest to disclose.

Low-dose methotrexate combined with topical betamethasone dipropionate was a safe and effective treatment for bullous pemphigoid in a retrospective study conducted by Dr. Petra Kjellman and colleagues.

For the past 50 years, glucocorticoids have been the mainstay of treatment for bullous pemphigoid (BP), but the high doses of these drugs that are typically needed to control inflammation are poorly tolerated, particularly among the elderly, who are most commonly affected, according to the researchers.

To minimize the adverse effects of glucocorticoids, which include sepsis, pneumonia, gastrointestinal tract bleeding, diabetes, and osteoporosis, other immunosuppressants also have been tried as steroid-sparing agents in BP, but few controlled trials have been done, they noted.

For the past decade, Dr. Kjellman and colleagues from the department of dermatology and venereology, Karolinska University Hospital, Stockholm, have preferentially used methotrexate for BP patients, with prednisone if needed or if methotrexate could not be given or tolerated.

The usual regimen involved an initial dosage of 5 mg/week of methotrexate, with topical betamethasone dipropionate applied twice daily until the disease was controlled. If necessary, methotrexate dosage was increased by 2.5 mg/week.

If symptoms persisted despite methotrexate treatment, prednisone was added in doses of 10-20 mg/day, and if methotrexate could not be given because of anemia, liver disease, or renal failure, prednisone was given alone.

Between 1999 and 2003, 138 patients whose mean age was 81 years were diagnosed with BP. Of these, 57% were women, 51% had mild disease, 38% had moderate disease, and 11% had severe disease.

Methotrexate treatment was initiated in 98 (71%), with a median weekly dosage of 5 mg. Among these patients, 61 continued on methotrexate monotherapy (group 1) and had a mean cumulative dose of 280 mg.

Among patients who received methotrexate, 37 also were treated with prednisone (group 2). The median weekly dosage of methotrexate in this group was 6 mg, and the median cumulative dose was 440 mg.

Forty patients did not receive methotrexate, with 15 receiving high-dose prednisone alone at a median daily dosage of 12 mg and with a median cumulative dose of 4,000 mg (group 3). The other 25 patients who did not receive methotrexate (group 4) had mild disease and were managed with topical betamethasone gel alone.

Median follow-up was 26 months. At 24 months, the remission rates were 43% in group 1, 35% in group 2, 0% in group 3, and 83% in group 4 (Arch. Dermatol. 2008;144:612-16).

Mortality in BP is considerable, with previous reports finding 1-year mortality ranging from 10% to 41%, according to the researchers. In this series, 2-year survival was 65%, 67%, 47%, and 52% in the four groups, respectively, and there was a tendency toward better survival for the methotrexate-treated patients, with median survival times of 38 and 24 months in groups 1 and 2, respectively.

Only one patient in this series developed anemia, and although elevated liver enzymes were seen on occasion during the first weeks of therapy, normalization usually followed within 4-6 weeks. They did not perform pretreatment liver biopsies.

They researchers noted that they are also developing a BP quality register and biobank to enable further follow-up of these patients, and they plan a prospective study to provide further information. They had no conflicts of interest to disclose.

NEW YORK — The contemporary use of minocycline for acne and hydralazine for heart failure is expanding the spectrum of drug-induced lupus, and physicians need to be aware of this, as well as other types of drug-induced lupus.

Minocycline-induced lupus was first reported in the early 1990s, and more than 250 cases have now been reported to the World Health Organization. There is a 5:1 female-to-male predominance, and the clinical features include fever, morning stiffness, myalgias, polyarthralgias, and symmetric arthritis.

It is also characterized by large vessel vasculitis, and in more than 60% of patients, antineutrophil cytoplasmic antibodies are present and antihistone antibodies are not. This is in contrast to "classic" drug-induced lupus, in which antihistone antibodies are prominent.

Other autoantibodies also can be seen in minocycline-induced lupus, including antinuclear antibody (ANA) and anti-double-stranded DNA, according to Dr. Andrew G. Franks Jr.

"The likelihood of developing a lupuslike syndrome is elevated 8.5-fold with minocycline, so many clinicians are now moving away from using minocycline for acne and rosacea and switching to doxycycline, which really doesn't have this effect. I haven't used minocycline for 5 years," said Dr. Franks of the department of dermatology at New York University Medical Center, New York.

Hydralazine, which had fallen out of favor as an antihypertensive, has regained popularity as part of combination therapy for heart failure in African Americans following the benefits seen in the African-American Heart Failure Trial (N. Engl. J. Med. 2004;351:2049-57).

Younger physicians in particular might not be familiar with hydralazine's link to drug-induced lupus, Dr. Franks said.

Hydralazine is one of the five causes of classic drug-induced lupus, along with procainamide, isoniazid, quinidine, and phenytoin, but more than 100 drugs have been implicated, he said.

Classic drug-induced lupus is characterized by flulike symptoms and significant musculoskeletal involvement, with most patients being ANA and antihistone antibody positive. "In my opinion, patients starting hydralazine—or any drug in the big five, for that matter—should have a baseline test for ANA, although that is somewhat controversial," Dr. Franks said.

The third main type of drug-induced lupus is subacute cutaneous lupus erythematosus (SCLE), which also is associated with an ever-widening variety of agents, including the thiazide diuretics, antifungals, calcium channel blockers, and ACE inhibitors. There also have been reports involving statins, leflunomide, and tumor necrosis factor inhibitors.

Clinically, SCLE can be very difficult to sort out, according to Dr. Franks, with targetoid lesions mixed with papulosquamous or annular lesions. The presentation can also resemble erythema multiforme or toxic epidermal necrolysis, with disadhesion of the epidermal layer and sloughing of the skin, he said.

An audience member asked what happens when the offending drug is withdrawn. Dr. Franks explained that the situation is different than an allergic reaction. "It can sometimes take months for this to remit, and some patients require additional therapy, but 95% of patients ultimately do remit," he said at a rheumatology meeting sponsored by New York University.

No single unifying mechanism has been identified that can explain the variety of drugs associated with drug-induced lupus or the varied clinical and laboratory manifestations. Hypotheses include the possibility that the drugs can act as haptens or antigens that drive an immune response, or as immune system modulators that permit the development of self-directed responses (Semin. Arthritis Rheum. 2007 Dec. 31 [doi:10.1016/j.semarthrit.2007.10.001]).

Dr. Franks reported having no financial relationships to disclose. n

The likelihood of developing a lupus-like syndrome is elevated 8.5-fold with minocycline. DR. FRANKS

NEW YORK — The contemporary use of minocycline for acne and hydralazine for heart failure is expanding the spectrum of drug-induced lupus, and physicians need to be aware of this, as well as other types of drug-induced lupus.

Minocycline-induced lupus was first reported in the early 1990s, and more than 250 cases have now been reported to the World Health Organization. There is a 5:1 female-to-male predominance, and the clinical features include fever, morning stiffness, myalgias, polyarthralgias, and symmetric arthritis.

It is also characterized by large vessel vasculitis, and in more than 60% of patients, antineutrophil cytoplasmic antibodies are present and antihistone antibodies are not. This is in contrast to "classic" drug-induced lupus, in which antihistone antibodies are prominent.

Other autoantibodies also can be seen in minocycline-induced lupus, including antinuclear antibody (ANA) and anti-double-stranded DNA, according to Dr. Andrew G. Franks Jr.

"The likelihood of developing a lupuslike syndrome is elevated 8.5-fold with minocycline, so many clinicians are now moving away from using minocycline for acne and rosacea and switching to doxycycline, which really doesn't have this effect. I haven't used minocycline for 5 years," said Dr. Franks of the department of dermatology at New York University Medical Center, New York.

Hydralazine, which had fallen out of favor as an antihypertensive, has regained popularity as part of combination therapy for heart failure in African Americans following the benefits seen in the African-American Heart Failure Trial (N. Engl. J. Med. 2004;351:2049-57).

Younger physicians in particular might not be familiar with hydralazine's link to drug-induced lupus, Dr. Franks said.

Hydralazine is one of the five causes of classic drug-induced lupus, along with procainamide, isoniazid, quinidine, and phenytoin, but more than 100 drugs have been implicated, he said.

Classic drug-induced lupus is characterized by flulike symptoms and significant musculoskeletal involvement, with most patients being ANA and antihistone antibody positive. "In my opinion, patients starting hydralazine—or any drug in the big five, for that matter—should have a baseline test for ANA, although that is somewhat controversial," Dr. Franks said.

The third main type of drug-induced lupus is subacute cutaneous lupus erythematosus (SCLE), which also is associated with an ever-widening variety of agents, including the thiazide diuretics, antifungals, calcium channel blockers, and ACE inhibitors. There also have been reports involving statins, leflunomide, and tumor necrosis factor inhibitors.

Clinically, SCLE can be very difficult to sort out, according to Dr. Franks, with targetoid lesions mixed with papulosquamous or annular lesions. The presentation can also resemble erythema multiforme or toxic epidermal necrolysis, with disadhesion of the epidermal layer and sloughing of the skin, he said.

An audience member asked what happens when the offending drug is withdrawn. Dr. Franks explained that the situation is different than an allergic reaction. "It can sometimes take months for this to remit, and some patients require additional therapy, but 95% of patients ultimately do remit," he said at a rheumatology meeting sponsored by New York University.

No single unifying mechanism has been identified that can explain the variety of drugs associated with drug-induced lupus or the varied clinical and laboratory manifestations. Hypotheses include the possibility that the drugs can act as haptens or antigens that drive an immune response, or as immune system modulators that permit the development of self-directed responses (Semin. Arthritis Rheum. 2007 Dec. 31 [doi:10.1016/j.semarthrit.2007.10.001]).

Dr. Franks reported having no financial relationships to disclose. n

The likelihood of developing a lupus-like syndrome is elevated 8.5-fold with minocycline. DR. FRANKS

NEW YORK — The contemporary use of minocycline for acne and hydralazine for heart failure is expanding the spectrum of drug-induced lupus, and physicians need to be aware of this, as well as other types of drug-induced lupus.

Minocycline-induced lupus was first reported in the early 1990s, and more than 250 cases have now been reported to the World Health Organization. There is a 5:1 female-to-male predominance, and the clinical features include fever, morning stiffness, myalgias, polyarthralgias, and symmetric arthritis.

It is also characterized by large vessel vasculitis, and in more than 60% of patients, antineutrophil cytoplasmic antibodies are present and antihistone antibodies are not. This is in contrast to "classic" drug-induced lupus, in which antihistone antibodies are prominent.

Other autoantibodies also can be seen in minocycline-induced lupus, including antinuclear antibody (ANA) and anti-double-stranded DNA, according to Dr. Andrew G. Franks Jr.

"The likelihood of developing a lupuslike syndrome is elevated 8.5-fold with minocycline, so many clinicians are now moving away from using minocycline for acne and rosacea and switching to doxycycline, which really doesn't have this effect. I haven't used minocycline for 5 years," said Dr. Franks of the department of dermatology at New York University Medical Center, New York.

Hydralazine, which had fallen out of favor as an antihypertensive, has regained popularity as part of combination therapy for heart failure in African Americans following the benefits seen in the African-American Heart Failure Trial (N. Engl. J. Med. 2004;351:2049-57).

Younger physicians in particular might not be familiar with hydralazine's link to drug-induced lupus, Dr. Franks said.

Hydralazine is one of the five causes of classic drug-induced lupus, along with procainamide, isoniazid, quinidine, and phenytoin, but more than 100 drugs have been implicated, he said.

Classic drug-induced lupus is characterized by flulike symptoms and significant musculoskeletal involvement, with most patients being ANA and antihistone antibody positive. "In my opinion, patients starting hydralazine—or any drug in the big five, for that matter—should have a baseline test for ANA, although that is somewhat controversial," Dr. Franks said.

The third main type of drug-induced lupus is subacute cutaneous lupus erythematosus (SCLE), which also is associated with an ever-widening variety of agents, including the thiazide diuretics, antifungals, calcium channel blockers, and ACE inhibitors. There also have been reports involving statins, leflunomide, and tumor necrosis factor inhibitors.

Clinically, SCLE can be very difficult to sort out, according to Dr. Franks, with targetoid lesions mixed with papulosquamous or annular lesions. The presentation can also resemble erythema multiforme or toxic epidermal necrolysis, with disadhesion of the epidermal layer and sloughing of the skin, he said.

An audience member asked what happens when the offending drug is withdrawn. Dr. Franks explained that the situation is different than an allergic reaction. "It can sometimes take months for this to remit, and some patients require additional therapy, but 95% of patients ultimately do remit," he said at a rheumatology meeting sponsored by New York University.

No single unifying mechanism has been identified that can explain the variety of drugs associated with drug-induced lupus or the varied clinical and laboratory manifestations. Hypotheses include the possibility that the drugs can act as haptens or antigens that drive an immune response, or as immune system modulators that permit the development of self-directed responses (Semin. Arthritis Rheum. 2007 Dec. 31 [doi:10.1016/j.semarthrit.2007.10.001]).

Dr. Franks reported having no financial relationships to disclose. n

The likelihood of developing a lupus-like syndrome is elevated 8.5-fold with minocycline. DR. FRANKS

TORONTO — Steroid resistance is increasingly being recognized as a factor contributing to uncontrolled asthma and progression of lung disease, according to a pediatric allergy/immunology expert.

Resistance to inhaled corticosteroids is more common than was previously recognized, and can be found in 25%–35% of patients with asthma.

“In general, steroids are extremely effective in asthma, and really are the most effective anti-inflammatory drugs we have; but in any study of inhaled steroids in asthma, there is remarkable variability in response,” said Dr. Donald Y.M. Leung, head of pediatric allergy and immunology at the National Jewish Medical and Research Center, Denver.

Multiple factors can contribute to steroid resistance, including genetics and ethnicity, with blacks being affected more commonly than whites, he said at an international conference of the American Thoracic Society. Allergen exposure, smoking, and obesity also have been implicated.

Steroid sensitivity is defined as a greater-than-20% improvement in FEV1 (forced expiratory volume in 1 second) from baseline after a week of treatment with oral prednisone in doses of 20 mg twice a day, whereas steroid resistance is a less-than-15% improvement, Dr. Leung said.

Investigations of patients who are steroid resistant found that they have persistent airway activation, with elevations in interleukin-2, -4, -5, -8, and -13, as well as tumor necrosis factor, despite the use of prednisone. Those cytokines target different cell types, with IL-2 and IL-4 being capable of inducing steroid resistance in T cells, IL-8 inducing resistance in neutrophils, and IL-13 inducing resistance in monocytes and macrophages, he said.

Recent studies have shown that steroid-resistant patients also have increased levels of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) in their bronchoalveolar lavage samples. Those molecules control collagen deposition, and a correct ratio of them is needed to prevent airway remodeling. Patients who are steroid resistant have an imbalance between MMPs and TIMPs, and more ongoing protease activity. Steroids' inability to enhance TIMP-1 production contributes to the abnormal MMP/TIMP ratio in steroid resistant patients. The result of those abnormalities is modification of airway wall matrix deposition, remodeling, and irreversible lung disease (J. Allergy Clin. Immunol. 2007;120:1065-72).

“We have also investigated the mechanisms by which resistance develops [and] have found that a key element in corticosteroid action is the ability to induce nuclear translocation of the glucocorticoid receptor from the cytoplasm into the nucleus,” Dr. Leung said. The anti-inflammatory effects of those drugs are mediated through the a (rather than the b) isoform of the glucocorticoid receptor, he explained.

Bronchoalveolar lavage samples from patients who have steroid-resistant asthma have been shown to have reduced a-receptor translocation in response to the drugs, as well as overexpression of its endogenous inhibitor, the b receptor. “The inflammatory milieu in the airways of these patients is driving up the expression of the b receptor.” Microbial superantigens also can induce T-cell resistance to steroids, suggesting a possible role for infection in the development of resistance, he said.

That superantigen-induced resistance can occur via a specific T-cell receptor signaling pathway involving the mitogen-activated protein kinase and the extracellular signal-regulated kinase, leading to phosphorylation of the a receptor of the glucocorticoid receptor and inhibition of nuclear translocation (J. Allergy Clin. Immunol. 2004; 114:1059-69). Those studies suggest that the glucocorticoid receptor itself might be a potential therapeutic target in resistant asthma, he noted. Dr. Leung said he has no financial relationship with a commercial entity involved in this work.

TORONTO — Steroid resistance is increasingly being recognized as a factor contributing to uncontrolled asthma and progression of lung disease, according to a pediatric allergy/immunology expert.

Resistance to inhaled corticosteroids is more common than was previously recognized, and can be found in 25%–35% of patients with asthma.

“In general, steroids are extremely effective in asthma, and really are the most effective anti-inflammatory drugs we have; but in any study of inhaled steroids in asthma, there is remarkable variability in response,” said Dr. Donald Y.M. Leung, head of pediatric allergy and immunology at the National Jewish Medical and Research Center, Denver.

Multiple factors can contribute to steroid resistance, including genetics and ethnicity, with blacks being affected more commonly than whites, he said at an international conference of the American Thoracic Society. Allergen exposure, smoking, and obesity also have been implicated.

Steroid sensitivity is defined as a greater-than-20% improvement in FEV1 (forced expiratory volume in 1 second) from baseline after a week of treatment with oral prednisone in doses of 20 mg twice a day, whereas steroid resistance is a less-than-15% improvement, Dr. Leung said.

Investigations of patients who are steroid resistant found that they have persistent airway activation, with elevations in interleukin-2, -4, -5, -8, and -13, as well as tumor necrosis factor, despite the use of prednisone. Those cytokines target different cell types, with IL-2 and IL-4 being capable of inducing steroid resistance in T cells, IL-8 inducing resistance in neutrophils, and IL-13 inducing resistance in monocytes and macrophages, he said.

Recent studies have shown that steroid-resistant patients also have increased levels of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) in their bronchoalveolar lavage samples. Those molecules control collagen deposition, and a correct ratio of them is needed to prevent airway remodeling. Patients who are steroid resistant have an imbalance between MMPs and TIMPs, and more ongoing protease activity. Steroids' inability to enhance TIMP-1 production contributes to the abnormal MMP/TIMP ratio in steroid resistant patients. The result of those abnormalities is modification of airway wall matrix deposition, remodeling, and irreversible lung disease (J. Allergy Clin. Immunol. 2007;120:1065-72).

“We have also investigated the mechanisms by which resistance develops [and] have found that a key element in corticosteroid action is the ability to induce nuclear translocation of the glucocorticoid receptor from the cytoplasm into the nucleus,” Dr. Leung said. The anti-inflammatory effects of those drugs are mediated through the a (rather than the b) isoform of the glucocorticoid receptor, he explained.

Bronchoalveolar lavage samples from patients who have steroid-resistant asthma have been shown to have reduced a-receptor translocation in response to the drugs, as well as overexpression of its endogenous inhibitor, the b receptor. “The inflammatory milieu in the airways of these patients is driving up the expression of the b receptor.” Microbial superantigens also can induce T-cell resistance to steroids, suggesting a possible role for infection in the development of resistance, he said.

That superantigen-induced resistance can occur via a specific T-cell receptor signaling pathway involving the mitogen-activated protein kinase and the extracellular signal-regulated kinase, leading to phosphorylation of the a receptor of the glucocorticoid receptor and inhibition of nuclear translocation (J. Allergy Clin. Immunol. 2004; 114:1059-69). Those studies suggest that the glucocorticoid receptor itself might be a potential therapeutic target in resistant asthma, he noted. Dr. Leung said he has no financial relationship with a commercial entity involved in this work.

TORONTO — Steroid resistance is increasingly being recognized as a factor contributing to uncontrolled asthma and progression of lung disease, according to a pediatric allergy/immunology expert.

Resistance to inhaled corticosteroids is more common than was previously recognized, and can be found in 25%–35% of patients with asthma.

“In general, steroids are extremely effective in asthma, and really are the most effective anti-inflammatory drugs we have; but in any study of inhaled steroids in asthma, there is remarkable variability in response,” said Dr. Donald Y.M. Leung, head of pediatric allergy and immunology at the National Jewish Medical and Research Center, Denver.

Multiple factors can contribute to steroid resistance, including genetics and ethnicity, with blacks being affected more commonly than whites, he said at an international conference of the American Thoracic Society. Allergen exposure, smoking, and obesity also have been implicated.

Steroid sensitivity is defined as a greater-than-20% improvement in FEV1 (forced expiratory volume in 1 second) from baseline after a week of treatment with oral prednisone in doses of 20 mg twice a day, whereas steroid resistance is a less-than-15% improvement, Dr. Leung said.

Investigations of patients who are steroid resistant found that they have persistent airway activation, with elevations in interleukin-2, -4, -5, -8, and -13, as well as tumor necrosis factor, despite the use of prednisone. Those cytokines target different cell types, with IL-2 and IL-4 being capable of inducing steroid resistance in T cells, IL-8 inducing resistance in neutrophils, and IL-13 inducing resistance in monocytes and macrophages, he said.

Recent studies have shown that steroid-resistant patients also have increased levels of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) in their bronchoalveolar lavage samples. Those molecules control collagen deposition, and a correct ratio of them is needed to prevent airway remodeling. Patients who are steroid resistant have an imbalance between MMPs and TIMPs, and more ongoing protease activity. Steroids' inability to enhance TIMP-1 production contributes to the abnormal MMP/TIMP ratio in steroid resistant patients. The result of those abnormalities is modification of airway wall matrix deposition, remodeling, and irreversible lung disease (J. Allergy Clin. Immunol. 2007;120:1065-72).

“We have also investigated the mechanisms by which resistance develops [and] have found that a key element in corticosteroid action is the ability to induce nuclear translocation of the glucocorticoid receptor from the cytoplasm into the nucleus,” Dr. Leung said. The anti-inflammatory effects of those drugs are mediated through the a (rather than the b) isoform of the glucocorticoid receptor, he explained.

Bronchoalveolar lavage samples from patients who have steroid-resistant asthma have been shown to have reduced a-receptor translocation in response to the drugs, as well as overexpression of its endogenous inhibitor, the b receptor. “The inflammatory milieu in the airways of these patients is driving up the expression of the b receptor.” Microbial superantigens also can induce T-cell resistance to steroids, suggesting a possible role for infection in the development of resistance, he said.

That superantigen-induced resistance can occur via a specific T-cell receptor signaling pathway involving the mitogen-activated protein kinase and the extracellular signal-regulated kinase, leading to phosphorylation of the a receptor of the glucocorticoid receptor and inhibition of nuclear translocation (J. Allergy Clin. Immunol. 2004; 114:1059-69). Those studies suggest that the glucocorticoid receptor itself might be a potential therapeutic target in resistant asthma, he noted. Dr. Leung said he has no financial relationship with a commercial entity involved in this work.

People aged 60 years and older should receive the herpes zoster vaccine to prevent the development of shingles, the Centers for Disease Control and Prevention's Advisory Committee on Immunization Practices recommends.

A single dose of the vaccine can be given to adults 60 years and older even if they have already had an episode of shingles, which is characterized by the development of blisters and severe pain that can persist for months or even years. The vaccine—made by Merck & Co.—is not indicated to treat acute zoster, to prevent patients with zoster from developing postherpetic neuralgia, or to treat ongoing postherpetic neuralgia. It does not compromise the immunogenicity of trivalent inactivated influenza vaccine when given simultaneously.

The new recommendation, published in an early-release electronic edition of Morbidity and Mortality Weekly Report, replaces a provisional recommendation made by the CDC's Advisory Committee on Immunization Practices after licensure of the vaccine in 2006 by the Food and Drug Administration. The MMWR report also addresses other aspects of treating herpes zoster, such as oral antiviral agents acyclovir, valacyclovir, and famciclovir, which reduce the severity and duration of acute pain from zoster.

The zoster vaccine is not licensed for persons under age 60 years or for persons of any age who have received varicella vaccine.

Zoster vaccine is contraindicated for persons with a history of anaphylactic reaction to any component of the vaccine, including gelatin and neomycin; persons with primary or acquired immunodeficiency; and pregnant women, although that is not very likely in this age group.

In a phase III, double-blind, placebo-controlled study of 38,546 healthy adults aged 60 years and older with a history of varicella or residency in the United States of 30 years of more, the vaccine reduced the risk of developing zoster by 51% and was 67% effective in preventing postherpetic neuralgia. The mean severity-by-duration of zoster was reduced by 57% in vaccine recipients who developed postherpetic neuralgia. The vaccine's efficacy declined with age: Efficacy against zoster was 18% for persons aged 80 years and older, but efficacy against postherpetic neuralgia was 39%.

The most common side effects associated with the vaccine are redness, pain, and swelling at the injection site, as well as pruritus and headache.

The risk of developing shingles increases with age, and approximately half of people who live to age 85 will develop the condition.

People aged 60 years and older should receive the herpes zoster vaccine to prevent the development of shingles, the Centers for Disease Control and Prevention's Advisory Committee on Immunization Practices recommends.

A single dose of the vaccine can be given to adults 60 years and older even if they have already had an episode of shingles, which is characterized by the development of blisters and severe pain that can persist for months or even years. The vaccine—made by Merck & Co.—is not indicated to treat acute zoster, to prevent patients with zoster from developing postherpetic neuralgia, or to treat ongoing postherpetic neuralgia. It does not compromise the immunogenicity of trivalent inactivated influenza vaccine when given simultaneously.

The new recommendation, published in an early-release electronic edition of Morbidity and Mortality Weekly Report, replaces a provisional recommendation made by the CDC's Advisory Committee on Immunization Practices after licensure of the vaccine in 2006 by the Food and Drug Administration. The MMWR report also addresses other aspects of treating herpes zoster, such as oral antiviral agents acyclovir, valacyclovir, and famciclovir, which reduce the severity and duration of acute pain from zoster.

The zoster vaccine is not licensed for persons under age 60 years or for persons of any age who have received varicella vaccine.

Zoster vaccine is contraindicated for persons with a history of anaphylactic reaction to any component of the vaccine, including gelatin and neomycin; persons with primary or acquired immunodeficiency; and pregnant women, although that is not very likely in this age group.

In a phase III, double-blind, placebo-controlled study of 38,546 healthy adults aged 60 years and older with a history of varicella or residency in the United States of 30 years of more, the vaccine reduced the risk of developing zoster by 51% and was 67% effective in preventing postherpetic neuralgia. The mean severity-by-duration of zoster was reduced by 57% in vaccine recipients who developed postherpetic neuralgia. The vaccine's efficacy declined with age: Efficacy against zoster was 18% for persons aged 80 years and older, but efficacy against postherpetic neuralgia was 39%.

The most common side effects associated with the vaccine are redness, pain, and swelling at the injection site, as well as pruritus and headache.

The risk of developing shingles increases with age, and approximately half of people who live to age 85 will develop the condition.

People aged 60 years and older should receive the herpes zoster vaccine to prevent the development of shingles, the Centers for Disease Control and Prevention's Advisory Committee on Immunization Practices recommends.

A single dose of the vaccine can be given to adults 60 years and older even if they have already had an episode of shingles, which is characterized by the development of blisters and severe pain that can persist for months or even years. The vaccine—made by Merck & Co.—is not indicated to treat acute zoster, to prevent patients with zoster from developing postherpetic neuralgia, or to treat ongoing postherpetic neuralgia. It does not compromise the immunogenicity of trivalent inactivated influenza vaccine when given simultaneously.

The new recommendation, published in an early-release electronic edition of Morbidity and Mortality Weekly Report, replaces a provisional recommendation made by the CDC's Advisory Committee on Immunization Practices after licensure of the vaccine in 2006 by the Food and Drug Administration. The MMWR report also addresses other aspects of treating herpes zoster, such as oral antiviral agents acyclovir, valacyclovir, and famciclovir, which reduce the severity and duration of acute pain from zoster.

The zoster vaccine is not licensed for persons under age 60 years or for persons of any age who have received varicella vaccine.

Zoster vaccine is contraindicated for persons with a history of anaphylactic reaction to any component of the vaccine, including gelatin and neomycin; persons with primary or acquired immunodeficiency; and pregnant women, although that is not very likely in this age group.

In a phase III, double-blind, placebo-controlled study of 38,546 healthy adults aged 60 years and older with a history of varicella or residency in the United States of 30 years of more, the vaccine reduced the risk of developing zoster by 51% and was 67% effective in preventing postherpetic neuralgia. The mean severity-by-duration of zoster was reduced by 57% in vaccine recipients who developed postherpetic neuralgia. The vaccine's efficacy declined with age: Efficacy against zoster was 18% for persons aged 80 years and older, but efficacy against postherpetic neuralgia was 39%.

The most common side effects associated with the vaccine are redness, pain, and swelling at the injection site, as well as pruritus and headache.

The risk of developing shingles increases with age, and approximately half of people who live to age 85 will develop the condition.

LIVERPOOL, ENGLAND — Maternal exposure to sunlight in late pregnancy can apparently exert a beneficial influence on the offspring's bone mineral density in later life, according to analysis of data from a longitudinal study of more than 17,000 Korean patients.

Peak bone mass contributes to bone strength in later life, and although the peak is reached in early adulthood it is influenced by factors in early life, Dr. Nicola J. Goodson said at the annual meeting of the British Society for Rheumatology. For example, it has been shown that vitamin D supplementation during the first year of life is associated with higher bone mineral content in prepubertal children, she reported.

Antenatal factors such as maternal and fetal vitamin D exposure also appear to contribute. Most fetal skeletal calcium accumulation occurs in the third trimester of pregnancy, and placental calcium transport is influenced by maternal vitamin D, said Dr. Goodson of University Hospital Aintree, University of Liverpool (England).

It has not yet been determined, however, whether birth month—either influenced by antenatal or postnatal exposure to ultraviolet B (UVB) sunlight—affects the offspring's later life risk for low bone mineral density (BMD), she commented.

One study found that Korean babies born in winter had lower bone mineral concentration than did those born in summer (J. Pediatr. 1998;132:421–5), she noted.

“In the United Kingdom the main dietary sources of vitamin D are fish and fortified margarine, but more than 90% of the vitamin is obtained by casual exposure to the sun, and because of the latitude the majority of the population is vitamin D deficient for much of the year,” said Dr. Goodson.

This is in contrast to Canada and the United States, where milk is fortified with the vitamin, she noted.

To determine if variations in vitamin D levels resulting from either maternal exposure to sunlight during late pregnancy or neonatal exposure during the first 3 months of life could be associated with BMD in later life, birth records and dual energy x-ray absorptiometry (DXA) scan results for a large cohort of patients were examined.

All patients from the Morecambe Bay catchment district who had DXA scans between 1992 and 2004 were included in the study. The cohort included 15,042 women and 2,160 men whose mean age was 62 years.

At the latitude of this Korean district, 54 degrees north, the months with adequate sunlight are May through September. Patients therefore were categorized as having infant sunlight exposure if their birth months were between March and September and they could be expected to have at least 1 month of exposure to ultraviolet B light in the first 3 months of life.

They were classified as having antenatal exposure if their birth months were between May and November and they had at least 1 neonatal month of exposure to sunlight, explained Dr. Goodson.

Overall, 51% of patients had BMD in the normal range, and, as expected, women had lower mean T scores, at −1.7, than did men, at -0.91, she said.

Analysis of sunlight exposure in the first 3 months of life and normal BMD, after adjustment for age at the time of the DXA scan, found no significant association, with an odds ratio (OR) of 1.

In contrast, for those categorized as antenatal exposure, there was a modest association with normal bone mineral density in adulthood, with an OR of 1.16, Dr. Goodson said.

Those patients who had antenatal sunlight exposure also were less likely to have osteopenia or osteoporosis: Those who were osteopenic had a 12% reduced odds of antenatal exposure and those who were osteoporotic had a 19% reduced odds of antenatal exposure, she said.

These associations were only seen among women.

In a separate analysis for those whose DXA scans were done before age 50, again there was no association of early life sunlight exposure in either men or women. However, in these younger patients there was a very strong association of early life, rather than antenatal, exposure with osteoporosis. “Those patients in the osteoporotic range had a 49% reduced odds of having a birth month that enabled antenatal exposure to UVB,” she said.

In summary, she said, adult BMD was associated with birth month in this unselected DXA cohort.

“These findings suggest that maternal vitamin D levels should be optimized, particularly during the third trimester, either by diet or by safe UV exposure, and this may be particularly important in the U.K., where vitamin D deficiency is very common,” Dr. Goodson said.

LIVERPOOL, ENGLAND — Maternal exposure to sunlight in late pregnancy can apparently exert a beneficial influence on the offspring's bone mineral density in later life, according to analysis of data from a longitudinal study of more than 17,000 Korean patients.

Peak bone mass contributes to bone strength in later life, and although the peak is reached in early adulthood it is influenced by factors in early life, Dr. Nicola J. Goodson said at the annual meeting of the British Society for Rheumatology. For example, it has been shown that vitamin D supplementation during the first year of life is associated with higher bone mineral content in prepubertal children, she reported.

Antenatal factors such as maternal and fetal vitamin D exposure also appear to contribute. Most fetal skeletal calcium accumulation occurs in the third trimester of pregnancy, and placental calcium transport is influenced by maternal vitamin D, said Dr. Goodson of University Hospital Aintree, University of Liverpool (England).

It has not yet been determined, however, whether birth month—either influenced by antenatal or postnatal exposure to ultraviolet B (UVB) sunlight—affects the offspring's later life risk for low bone mineral density (BMD), she commented.

One study found that Korean babies born in winter had lower bone mineral concentration than did those born in summer (J. Pediatr. 1998;132:421–5), she noted.

“In the United Kingdom the main dietary sources of vitamin D are fish and fortified margarine, but more than 90% of the vitamin is obtained by casual exposure to the sun, and because of the latitude the majority of the population is vitamin D deficient for much of the year,” said Dr. Goodson.

This is in contrast to Canada and the United States, where milk is fortified with the vitamin, she noted.

To determine if variations in vitamin D levels resulting from either maternal exposure to sunlight during late pregnancy or neonatal exposure during the first 3 months of life could be associated with BMD in later life, birth records and dual energy x-ray absorptiometry (DXA) scan results for a large cohort of patients were examined.

All patients from the Morecambe Bay catchment district who had DXA scans between 1992 and 2004 were included in the study. The cohort included 15,042 women and 2,160 men whose mean age was 62 years.

At the latitude of this Korean district, 54 degrees north, the months with adequate sunlight are May through September. Patients therefore were categorized as having infant sunlight exposure if their birth months were between March and September and they could be expected to have at least 1 month of exposure to ultraviolet B light in the first 3 months of life.

They were classified as having antenatal exposure if their birth months were between May and November and they had at least 1 neonatal month of exposure to sunlight, explained Dr. Goodson.

Overall, 51% of patients had BMD in the normal range, and, as expected, women had lower mean T scores, at −1.7, than did men, at -0.91, she said.

Analysis of sunlight exposure in the first 3 months of life and normal BMD, after adjustment for age at the time of the DXA scan, found no significant association, with an odds ratio (OR) of 1.

In contrast, for those categorized as antenatal exposure, there was a modest association with normal bone mineral density in adulthood, with an OR of 1.16, Dr. Goodson said.

Those patients who had antenatal sunlight exposure also were less likely to have osteopenia or osteoporosis: Those who were osteopenic had a 12% reduced odds of antenatal exposure and those who were osteoporotic had a 19% reduced odds of antenatal exposure, she said.

These associations were only seen among women.

In a separate analysis for those whose DXA scans were done before age 50, again there was no association of early life sunlight exposure in either men or women. However, in these younger patients there was a very strong association of early life, rather than antenatal, exposure with osteoporosis. “Those patients in the osteoporotic range had a 49% reduced odds of having a birth month that enabled antenatal exposure to UVB,” she said.

In summary, she said, adult BMD was associated with birth month in this unselected DXA cohort.

“These findings suggest that maternal vitamin D levels should be optimized, particularly during the third trimester, either by diet or by safe UV exposure, and this may be particularly important in the U.K., where vitamin D deficiency is very common,” Dr. Goodson said.

LIVERPOOL, ENGLAND — Maternal exposure to sunlight in late pregnancy can apparently exert a beneficial influence on the offspring's bone mineral density in later life, according to analysis of data from a longitudinal study of more than 17,000 Korean patients.

Peak bone mass contributes to bone strength in later life, and although the peak is reached in early adulthood it is influenced by factors in early life, Dr. Nicola J. Goodson said at the annual meeting of the British Society for Rheumatology. For example, it has been shown that vitamin D supplementation during the first year of life is associated with higher bone mineral content in prepubertal children, she reported.

Antenatal factors such as maternal and fetal vitamin D exposure also appear to contribute. Most fetal skeletal calcium accumulation occurs in the third trimester of pregnancy, and placental calcium transport is influenced by maternal vitamin D, said Dr. Goodson of University Hospital Aintree, University of Liverpool (England).

It has not yet been determined, however, whether birth month—either influenced by antenatal or postnatal exposure to ultraviolet B (UVB) sunlight—affects the offspring's later life risk for low bone mineral density (BMD), she commented.

One study found that Korean babies born in winter had lower bone mineral concentration than did those born in summer (J. Pediatr. 1998;132:421–5), she noted.

“In the United Kingdom the main dietary sources of vitamin D are fish and fortified margarine, but more than 90% of the vitamin is obtained by casual exposure to the sun, and because of the latitude the majority of the population is vitamin D deficient for much of the year,” said Dr. Goodson.

This is in contrast to Canada and the United States, where milk is fortified with the vitamin, she noted.

To determine if variations in vitamin D levels resulting from either maternal exposure to sunlight during late pregnancy or neonatal exposure during the first 3 months of life could be associated with BMD in later life, birth records and dual energy x-ray absorptiometry (DXA) scan results for a large cohort of patients were examined.

All patients from the Morecambe Bay catchment district who had DXA scans between 1992 and 2004 were included in the study. The cohort included 15,042 women and 2,160 men whose mean age was 62 years.

At the latitude of this Korean district, 54 degrees north, the months with adequate sunlight are May through September. Patients therefore were categorized as having infant sunlight exposure if their birth months were between March and September and they could be expected to have at least 1 month of exposure to ultraviolet B light in the first 3 months of life.

They were classified as having antenatal exposure if their birth months were between May and November and they had at least 1 neonatal month of exposure to sunlight, explained Dr. Goodson.

Overall, 51% of patients had BMD in the normal range, and, as expected, women had lower mean T scores, at −1.7, than did men, at -0.91, she said.

Analysis of sunlight exposure in the first 3 months of life and normal BMD, after adjustment for age at the time of the DXA scan, found no significant association, with an odds ratio (OR) of 1.

In contrast, for those categorized as antenatal exposure, there was a modest association with normal bone mineral density in adulthood, with an OR of 1.16, Dr. Goodson said.

Those patients who had antenatal sunlight exposure also were less likely to have osteopenia or osteoporosis: Those who were osteopenic had a 12% reduced odds of antenatal exposure and those who were osteoporotic had a 19% reduced odds of antenatal exposure, she said.

These associations were only seen among women.

In a separate analysis for those whose DXA scans were done before age 50, again there was no association of early life sunlight exposure in either men or women. However, in these younger patients there was a very strong association of early life, rather than antenatal, exposure with osteoporosis. “Those patients in the osteoporotic range had a 49% reduced odds of having a birth month that enabled antenatal exposure to UVB,” she said.

In summary, she said, adult BMD was associated with birth month in this unselected DXA cohort.

“These findings suggest that maternal vitamin D levels should be optimized, particularly during the third trimester, either by diet or by safe UV exposure, and this may be particularly important in the U.K., where vitamin D deficiency is very common,” Dr. Goodson said.