Betsy Bates

SAN FRANCISCO — The erstwhile antimalarial drug hydroxychloroquine is gaining new respect, as study results point to its ability to prevent long-term lupus-induced renal damage in patients living longer lives.

The multicenter, multiethnic cohort included 582 patients with systemic lupus erythematatosus (SLE) who were followed for a mean of 5.5 years, according to data presented during the annual meeting of the American College of Rheumatology.

Treatment with hydroxychloroquine, long used as a disease-modifying antirheumatic drug (DMARD), was far less common among the 73 patients who had developed new-onset renal damage (defined as glomerular filtration rate of less than 50%, 24-hour protein of at least 3.5 g, and end-stage renal disease) than among those who did not, reported Dr. Graciela S. Alarcón of the University of Alabama at Birmingham.

Because hydroxychloroquine is often prescribed only to patients with mild, early-stage disease, statistical modeling was used to ensure that demographic and disease severity differences were accounted for between the two patient groups, she explained.

“After making adjustment for all of the [potentially confounding] variables, the protection is on the order of 70%,” said Dr. Alarcón.

“Our data strongly suggest that if renal damage is to be prevented, hydroxychloroquine should be prescribed to all lupus patients early in the course of the disease,” concluded the report from Dr. Alarcón and associates at the University of Puerto Rico, San Juan, and the University of Texas, Houston.

Hydroxychloroquine, marketed as Plaquenil, has long been known as a relatively safe, inexpensive, disease-modifying drug for rheumatic diseases, having originally proven its muster against malaria during World War II.

In recent years, however, it has taken a back seat to more powerful disease-modifying medications, especially methotrexate and the biologics.

In treatment algorithms, hydroxychloroquine hovers in the “mild disease” column, generally used only for early-stage patients with nonerosive RA.

Over half of lupus patients develop renal involvement, with 10%–30% eventually experiencing renal damage and, often, end-stage renal disease, she said.

A safe, inexpensive drug that could prevent a “very serious complication” in a substantial majority of patients would represent a highly significant improvement in their long-term care, she said.

Dr. Alarcón reported no financial conflicts of interest.

Use of hydroxy-chloroquine by lupus patients reduced their risk for early renal damage by about 70%. DR. ALARCÓN

SAN FRANCISCO — The erstwhile antimalarial drug hydroxychloroquine is gaining new respect, as study results point to its ability to prevent long-term lupus-induced renal damage in patients living longer lives.

The multicenter, multiethnic cohort included 582 patients with systemic lupus erythematatosus (SLE) who were followed for a mean of 5.5 years, according to data presented during the annual meeting of the American College of Rheumatology.

Treatment with hydroxychloroquine, long used as a disease-modifying antirheumatic drug (DMARD), was far less common among the 73 patients who had developed new-onset renal damage (defined as glomerular filtration rate of less than 50%, 24-hour protein of at least 3.5 g, and end-stage renal disease) than among those who did not, reported Dr. Graciela S. Alarcón of the University of Alabama at Birmingham.

Because hydroxychloroquine is often prescribed only to patients with mild, early-stage disease, statistical modeling was used to ensure that demographic and disease severity differences were accounted for between the two patient groups, she explained.

“After making adjustment for all of the [potentially confounding] variables, the protection is on the order of 70%,” said Dr. Alarcón.

“Our data strongly suggest that if renal damage is to be prevented, hydroxychloroquine should be prescribed to all lupus patients early in the course of the disease,” concluded the report from Dr. Alarcón and associates at the University of Puerto Rico, San Juan, and the University of Texas, Houston.

Hydroxychloroquine, marketed as Plaquenil, has long been known as a relatively safe, inexpensive, disease-modifying drug for rheumatic diseases, having originally proven its muster against malaria during World War II.

In recent years, however, it has taken a back seat to more powerful disease-modifying medications, especially methotrexate and the biologics.

In treatment algorithms, hydroxychloroquine hovers in the “mild disease” column, generally used only for early-stage patients with nonerosive RA.

Over half of lupus patients develop renal involvement, with 10%–30% eventually experiencing renal damage and, often, end-stage renal disease, she said.

A safe, inexpensive drug that could prevent a “very serious complication” in a substantial majority of patients would represent a highly significant improvement in their long-term care, she said.

Dr. Alarcón reported no financial conflicts of interest.

Use of hydroxy-chloroquine by lupus patients reduced their risk for early renal damage by about 70%. DR. ALARCÓN

SAN FRANCISCO — The erstwhile antimalarial drug hydroxychloroquine is gaining new respect, as study results point to its ability to prevent long-term lupus-induced renal damage in patients living longer lives.

The multicenter, multiethnic cohort included 582 patients with systemic lupus erythematatosus (SLE) who were followed for a mean of 5.5 years, according to data presented during the annual meeting of the American College of Rheumatology.

Treatment with hydroxychloroquine, long used as a disease-modifying antirheumatic drug (DMARD), was far less common among the 73 patients who had developed new-onset renal damage (defined as glomerular filtration rate of less than 50%, 24-hour protein of at least 3.5 g, and end-stage renal disease) than among those who did not, reported Dr. Graciela S. Alarcón of the University of Alabama at Birmingham.

Because hydroxychloroquine is often prescribed only to patients with mild, early-stage disease, statistical modeling was used to ensure that demographic and disease severity differences were accounted for between the two patient groups, she explained.

“After making adjustment for all of the [potentially confounding] variables, the protection is on the order of 70%,” said Dr. Alarcón.

“Our data strongly suggest that if renal damage is to be prevented, hydroxychloroquine should be prescribed to all lupus patients early in the course of the disease,” concluded the report from Dr. Alarcón and associates at the University of Puerto Rico, San Juan, and the University of Texas, Houston.

Hydroxychloroquine, marketed as Plaquenil, has long been known as a relatively safe, inexpensive, disease-modifying drug for rheumatic diseases, having originally proven its muster against malaria during World War II.

In recent years, however, it has taken a back seat to more powerful disease-modifying medications, especially methotrexate and the biologics.

In treatment algorithms, hydroxychloroquine hovers in the “mild disease” column, generally used only for early-stage patients with nonerosive RA.

Over half of lupus patients develop renal involvement, with 10%–30% eventually experiencing renal damage and, often, end-stage renal disease, she said.

A safe, inexpensive drug that could prevent a “very serious complication” in a substantial majority of patients would represent a highly significant improvement in their long-term care, she said.

Dr. Alarcón reported no financial conflicts of interest.

Use of hydroxy-chloroquine by lupus patients reduced their risk for early renal damage by about 70%. DR. ALARCÓN

Cardiac symptoms in a child should raise a high index of suspicion of hyperthyroidism, based on the results of a single-center study that also found prominent behavioral and mood issues in many children with the diagnosis.

Hyperthyroidism was diagnosed in more than half the children referred for a work-up for cardiac symptoms, based on a retrospective chart study conducted at the University of California, Davis, by Dr. Lindsey Loomba-Albrecht, of the department of pediatric endocrinology, and her associates.

Further, cardiac symptoms—tachycardia/heart palpitations, shortness of breath on exertion, chest pain, and/or syncope—were present in nearly a quarter of 68 children diagnosed with hyperthyroidism over an 8-year period.

Goiter, weight loss, gastrointestinal and neurologic symptoms, and fever or heat intolerance were also represented as common presenting complaints among the diagnosed children, who ranged in age up to 18 years. A few were diagnosed as a result of screening laboratory tests or exophthalmos, Dr. Loomba-Albrecht reported at the Western regional meeting of the American Federation for Medical Research.

In pediatric textbooks, cardiac indications are listed as possible symptoms of hyperthyroidism but they appear far down on a list of symptoms that typically includes heat intolerance, emotional lability, short attention span, tremors, increased appetite, ophthalmologic symptoms, flushed skin, sweating, and muscle weakness.

“Delayed diagnosis occurred in many due to the time spent evaluating suspected cardiac disease,” Dr. Loomba-Albrecht, said in an interview following the meeting.

Because of the high incidence of cardiac symptoms investigated in children with hyperthyroidism, Dr. Loomba-Albrecht and her associates are recommending that thyroid screening labs be considered in all children with cardiac symptoms.

Severe behavioral and mood symptoms were also strikingly common in the cohort, regardless of whether these symptoms brought the child to medical attention.

Mood and behavioral symptoms were the presenting concern in just 4 of 68 pediatric patients with hyperthyroidism, but 14 of the 68 (20.5%) had major psychological issues at the time of diagnosis, reported Dr. Loomba-Albrecht.

Four were in juvenile hall; seven had major depression, and three had demonstrated antisocial behavior (including one with concomitant severe anxiety).

The prevalence of mood and behavior disturbances in the children with hyperthyroidism was far greater than what was seen in gender-matched controls who were seen in the endocrinology clinic for pubertal or growth problems (20.5% vs. 1.5%), she noted.

“For comparison, 3% of children in the general population have a mood disorder and 1%-2% have generalized anxiety or panic disorder,” she said.

Dr. Loomba-Albrecht highlighted the case of a 13-year-old boy brought into the emergency department with multiple injuries sustained while “car surfing,” in which juveniles perform dangerous maneuvers while holding onto the outside of a vehicle.

During his stay in the emergency department, the teenager experienced sustained tachycardia “of unclear etiology.” A CT scan of the neck revealed an enlarged thyroid gland, previously unnoticed because he had been placed in a protective cervical spine collar during transport.

Graves' disease was confirmed by a laboratory work-up.

Looking back, the boy's parents noted that his behavior had become quite erratic over the previous several months, resulting in plummeting school grades.

“The percent with behavioral problems prior to development of the hyperthyroidism is unknown, but the timing of symptoms suggests that the hyperthyroidism caused the behavior manifestations in most cases.

“Hyperthyroidism should thus be considered whenever a child is evaluated for behavior change,” the team advised.

None of the researchers reported any conflicts of interest regarding the study.

Cardiac symptoms in a child should raise a high index of suspicion of hyperthyroidism, based on the results of a single-center study that also found prominent behavioral and mood issues in many children with the diagnosis.

Hyperthyroidism was diagnosed in more than half the children referred for a work-up for cardiac symptoms, based on a retrospective chart study conducted at the University of California, Davis, by Dr. Lindsey Loomba-Albrecht, of the department of pediatric endocrinology, and her associates.

Further, cardiac symptoms—tachycardia/heart palpitations, shortness of breath on exertion, chest pain, and/or syncope—were present in nearly a quarter of 68 children diagnosed with hyperthyroidism over an 8-year period.

Goiter, weight loss, gastrointestinal and neurologic symptoms, and fever or heat intolerance were also represented as common presenting complaints among the diagnosed children, who ranged in age up to 18 years. A few were diagnosed as a result of screening laboratory tests or exophthalmos, Dr. Loomba-Albrecht reported at the Western regional meeting of the American Federation for Medical Research.

In pediatric textbooks, cardiac indications are listed as possible symptoms of hyperthyroidism but they appear far down on a list of symptoms that typically includes heat intolerance, emotional lability, short attention span, tremors, increased appetite, ophthalmologic symptoms, flushed skin, sweating, and muscle weakness.

“Delayed diagnosis occurred in many due to the time spent evaluating suspected cardiac disease,” Dr. Loomba-Albrecht, said in an interview following the meeting.

Because of the high incidence of cardiac symptoms investigated in children with hyperthyroidism, Dr. Loomba-Albrecht and her associates are recommending that thyroid screening labs be considered in all children with cardiac symptoms.

Severe behavioral and mood symptoms were also strikingly common in the cohort, regardless of whether these symptoms brought the child to medical attention.

Mood and behavioral symptoms were the presenting concern in just 4 of 68 pediatric patients with hyperthyroidism, but 14 of the 68 (20.5%) had major psychological issues at the time of diagnosis, reported Dr. Loomba-Albrecht.

Four were in juvenile hall; seven had major depression, and three had demonstrated antisocial behavior (including one with concomitant severe anxiety).

The prevalence of mood and behavior disturbances in the children with hyperthyroidism was far greater than what was seen in gender-matched controls who were seen in the endocrinology clinic for pubertal or growth problems (20.5% vs. 1.5%), she noted.

“For comparison, 3% of children in the general population have a mood disorder and 1%-2% have generalized anxiety or panic disorder,” she said.

Dr. Loomba-Albrecht highlighted the case of a 13-year-old boy brought into the emergency department with multiple injuries sustained while “car surfing,” in which juveniles perform dangerous maneuvers while holding onto the outside of a vehicle.

During his stay in the emergency department, the teenager experienced sustained tachycardia “of unclear etiology.” A CT scan of the neck revealed an enlarged thyroid gland, previously unnoticed because he had been placed in a protective cervical spine collar during transport.

Graves' disease was confirmed by a laboratory work-up.

Looking back, the boy's parents noted that his behavior had become quite erratic over the previous several months, resulting in plummeting school grades.

“The percent with behavioral problems prior to development of the hyperthyroidism is unknown, but the timing of symptoms suggests that the hyperthyroidism caused the behavior manifestations in most cases.

“Hyperthyroidism should thus be considered whenever a child is evaluated for behavior change,” the team advised.

None of the researchers reported any conflicts of interest regarding the study.

Cardiac symptoms in a child should raise a high index of suspicion of hyperthyroidism, based on the results of a single-center study that also found prominent behavioral and mood issues in many children with the diagnosis.

Hyperthyroidism was diagnosed in more than half the children referred for a work-up for cardiac symptoms, based on a retrospective chart study conducted at the University of California, Davis, by Dr. Lindsey Loomba-Albrecht, of the department of pediatric endocrinology, and her associates.

Further, cardiac symptoms—tachycardia/heart palpitations, shortness of breath on exertion, chest pain, and/or syncope—were present in nearly a quarter of 68 children diagnosed with hyperthyroidism over an 8-year period.

Goiter, weight loss, gastrointestinal and neurologic symptoms, and fever or heat intolerance were also represented as common presenting complaints among the diagnosed children, who ranged in age up to 18 years. A few were diagnosed as a result of screening laboratory tests or exophthalmos, Dr. Loomba-Albrecht reported at the Western regional meeting of the American Federation for Medical Research.

In pediatric textbooks, cardiac indications are listed as possible symptoms of hyperthyroidism but they appear far down on a list of symptoms that typically includes heat intolerance, emotional lability, short attention span, tremors, increased appetite, ophthalmologic symptoms, flushed skin, sweating, and muscle weakness.

“Delayed diagnosis occurred in many due to the time spent evaluating suspected cardiac disease,” Dr. Loomba-Albrecht, said in an interview following the meeting.

Because of the high incidence of cardiac symptoms investigated in children with hyperthyroidism, Dr. Loomba-Albrecht and her associates are recommending that thyroid screening labs be considered in all children with cardiac symptoms.

Severe behavioral and mood symptoms were also strikingly common in the cohort, regardless of whether these symptoms brought the child to medical attention.

Mood and behavioral symptoms were the presenting concern in just 4 of 68 pediatric patients with hyperthyroidism, but 14 of the 68 (20.5%) had major psychological issues at the time of diagnosis, reported Dr. Loomba-Albrecht.

Four were in juvenile hall; seven had major depression, and three had demonstrated antisocial behavior (including one with concomitant severe anxiety).

The prevalence of mood and behavior disturbances in the children with hyperthyroidism was far greater than what was seen in gender-matched controls who were seen in the endocrinology clinic for pubertal or growth problems (20.5% vs. 1.5%), she noted.

“For comparison, 3% of children in the general population have a mood disorder and 1%-2% have generalized anxiety or panic disorder,” she said.

Dr. Loomba-Albrecht highlighted the case of a 13-year-old boy brought into the emergency department with multiple injuries sustained while “car surfing,” in which juveniles perform dangerous maneuvers while holding onto the outside of a vehicle.

During his stay in the emergency department, the teenager experienced sustained tachycardia “of unclear etiology.” A CT scan of the neck revealed an enlarged thyroid gland, previously unnoticed because he had been placed in a protective cervical spine collar during transport.

Graves' disease was confirmed by a laboratory work-up.

Looking back, the boy's parents noted that his behavior had become quite erratic over the previous several months, resulting in plummeting school grades.

“The percent with behavioral problems prior to development of the hyperthyroidism is unknown, but the timing of symptoms suggests that the hyperthyroidism caused the behavior manifestations in most cases.

“Hyperthyroidism should thus be considered whenever a child is evaluated for behavior change,” the team advised.

None of the researchers reported any conflicts of interest regarding the study.

Insulin clearance is a highly heritable trait that has now been tracked to specific regions of two chromosomes, a finding that may have important implications for risk assessment in diabetes, polycystic ovary syndrome, and the metabolic syndrome.

Although it has been “virtually neglected” in studies of insulin metabolism, insulin clearance may strongly impact an individual's risk of diabetes and response to the diabetic state, Dr. Mark Goodarzi reported at the Western regional meeting of the American Federation for Medical Research in Carmel, Calif.

In previous work, Dr. Goodarzi and associates had raised the possibility that the metabolic clearance rate of insulin was largely an inherited trait, because of patterns seen in a cohort of 403 Mexican American subjects (Diabetes 2005;54:1222–7).

Their current study of a second cohort of 536 individuals from 162 Hispanic families found that insulin clearance was indeed a highly heritable trait, with an age-, sex-, and body mass index-adjusted heritability rate of 70.5%.

A genome-wide linkage scan applied to samples from the same population identified candidate regions on chromosomes 15 and 20 that may harbor genes influencing insulin clearance, Dr. Goodarzi in an interview.

Insulin clearance is a relatively unknown player in the sequence of events leading to diabetes.

A recent Medline search revealed more than 35,000 references to insulin resistance, more than 16,000 references to insulin secretion, but just 424 references to insulin clearance.

Although underappreciated, insulin clearance may prove to have an important role as a marker of risk or a target for intervention not only for diabetes, but for other disorders characterized by hyperinsulinemia, such as polycystic ovary syndrome.

“It appears that a reduction in insulin clearance may be a compensatory response to the insulin resistant state, acting in concert with increased insulin secretion to increase insulin levels,” Dr. Goodarzi explained.

“If insulin levels increase sufficiently, the insulin resistance may be overcome and blood sugars will be maintained in the normal range. However, if there is a failure to adequately increase insulin levels in the face of insulin resistance (either by failing to increase insulin secretion, or, theoretically, failing to reduce insulin clearance), then diabetes will develop,” said Dr. Goodarzi, associate director of the division of endocrinology at Cedars-Sinai Medical Center, Los Angeles.

To test for heritability, subjects were drawn from the offspring generation within MA-HTN, a Mexican American Hypertension study of 939 subjects from 162 families.

Mexican Americans were chosen for the study because of their high prevalence of insulin resistance and high age-specific prevalence of the metabolic syndrome.

Euglycemic clamps were used to measure insulin sensitivity and clearance, keeping the insulin infusion rate steady for all subjects and obtaining a direct measure of insulin clearance via steady state plasma insulin (SSPI) levels achieved during the clamp study.

Once it was determined that more than 70% of the variation in insulin clearance was due to genetic factors, a genome-wide linkage scan utilizing 388 microsatellites resulted in the discovery of SSPI linkages on chromosomes 15 and 20.

Dr. Joseph M. Vinetz, AFMR western section president, said in a telephone interview that Dr. Goodarzi's study had the potential of “optimizing care in the exploding epidemic of type 2 diabetes,” with “huge ramifications for early prevention throughout society.”

To date, genetic studies of diabetes, insulin resistance, insulin secretion, and insulin clearance “have not yet translated to clinically useful tools,” said Dr. Goodarzi.

However, he predicted that the time is not far off—perhaps 5–10 years—when such a link can be made, perhaps by influencing clinical outcomes by implementing interventions once individuals at risk are identified through genetic testing.

Dr. Goodarzi and his associates did not disclose any conflicts of interest regarding their research.

To date, genetic studies of diabetes and insulin resistance have not yet translated to useful tools. DR. GOODARZI

Insulin clearance is a highly heritable trait that has now been tracked to specific regions of two chromosomes, a finding that may have important implications for risk assessment in diabetes, polycystic ovary syndrome, and the metabolic syndrome.

Although it has been “virtually neglected” in studies of insulin metabolism, insulin clearance may strongly impact an individual's risk of diabetes and response to the diabetic state, Dr. Mark Goodarzi reported at the Western regional meeting of the American Federation for Medical Research in Carmel, Calif.

In previous work, Dr. Goodarzi and associates had raised the possibility that the metabolic clearance rate of insulin was largely an inherited trait, because of patterns seen in a cohort of 403 Mexican American subjects (Diabetes 2005;54:1222–7).

Their current study of a second cohort of 536 individuals from 162 Hispanic families found that insulin clearance was indeed a highly heritable trait, with an age-, sex-, and body mass index-adjusted heritability rate of 70.5%.

A genome-wide linkage scan applied to samples from the same population identified candidate regions on chromosomes 15 and 20 that may harbor genes influencing insulin clearance, Dr. Goodarzi in an interview.

Insulin clearance is a relatively unknown player in the sequence of events leading to diabetes.

A recent Medline search revealed more than 35,000 references to insulin resistance, more than 16,000 references to insulin secretion, but just 424 references to insulin clearance.

Although underappreciated, insulin clearance may prove to have an important role as a marker of risk or a target for intervention not only for diabetes, but for other disorders characterized by hyperinsulinemia, such as polycystic ovary syndrome.

“It appears that a reduction in insulin clearance may be a compensatory response to the insulin resistant state, acting in concert with increased insulin secretion to increase insulin levels,” Dr. Goodarzi explained.

“If insulin levels increase sufficiently, the insulin resistance may be overcome and blood sugars will be maintained in the normal range. However, if there is a failure to adequately increase insulin levels in the face of insulin resistance (either by failing to increase insulin secretion, or, theoretically, failing to reduce insulin clearance), then diabetes will develop,” said Dr. Goodarzi, associate director of the division of endocrinology at Cedars-Sinai Medical Center, Los Angeles.

To test for heritability, subjects were drawn from the offspring generation within MA-HTN, a Mexican American Hypertension study of 939 subjects from 162 families.

Mexican Americans were chosen for the study because of their high prevalence of insulin resistance and high age-specific prevalence of the metabolic syndrome.

Euglycemic clamps were used to measure insulin sensitivity and clearance, keeping the insulin infusion rate steady for all subjects and obtaining a direct measure of insulin clearance via steady state plasma insulin (SSPI) levels achieved during the clamp study.

Once it was determined that more than 70% of the variation in insulin clearance was due to genetic factors, a genome-wide linkage scan utilizing 388 microsatellites resulted in the discovery of SSPI linkages on chromosomes 15 and 20.

Dr. Joseph M. Vinetz, AFMR western section president, said in a telephone interview that Dr. Goodarzi's study had the potential of “optimizing care in the exploding epidemic of type 2 diabetes,” with “huge ramifications for early prevention throughout society.”

To date, genetic studies of diabetes, insulin resistance, insulin secretion, and insulin clearance “have not yet translated to clinically useful tools,” said Dr. Goodarzi.

However, he predicted that the time is not far off—perhaps 5–10 years—when such a link can be made, perhaps by influencing clinical outcomes by implementing interventions once individuals at risk are identified through genetic testing.

Dr. Goodarzi and his associates did not disclose any conflicts of interest regarding their research.

To date, genetic studies of diabetes and insulin resistance have not yet translated to useful tools. DR. GOODARZI

Insulin clearance is a highly heritable trait that has now been tracked to specific regions of two chromosomes, a finding that may have important implications for risk assessment in diabetes, polycystic ovary syndrome, and the metabolic syndrome.

Although it has been “virtually neglected” in studies of insulin metabolism, insulin clearance may strongly impact an individual's risk of diabetes and response to the diabetic state, Dr. Mark Goodarzi reported at the Western regional meeting of the American Federation for Medical Research in Carmel, Calif.

In previous work, Dr. Goodarzi and associates had raised the possibility that the metabolic clearance rate of insulin was largely an inherited trait, because of patterns seen in a cohort of 403 Mexican American subjects (Diabetes 2005;54:1222–7).

Their current study of a second cohort of 536 individuals from 162 Hispanic families found that insulin clearance was indeed a highly heritable trait, with an age-, sex-, and body mass index-adjusted heritability rate of 70.5%.

A genome-wide linkage scan applied to samples from the same population identified candidate regions on chromosomes 15 and 20 that may harbor genes influencing insulin clearance, Dr. Goodarzi in an interview.

Insulin clearance is a relatively unknown player in the sequence of events leading to diabetes.

A recent Medline search revealed more than 35,000 references to insulin resistance, more than 16,000 references to insulin secretion, but just 424 references to insulin clearance.

Although underappreciated, insulin clearance may prove to have an important role as a marker of risk or a target for intervention not only for diabetes, but for other disorders characterized by hyperinsulinemia, such as polycystic ovary syndrome.

“It appears that a reduction in insulin clearance may be a compensatory response to the insulin resistant state, acting in concert with increased insulin secretion to increase insulin levels,” Dr. Goodarzi explained.

“If insulin levels increase sufficiently, the insulin resistance may be overcome and blood sugars will be maintained in the normal range. However, if there is a failure to adequately increase insulin levels in the face of insulin resistance (either by failing to increase insulin secretion, or, theoretically, failing to reduce insulin clearance), then diabetes will develop,” said Dr. Goodarzi, associate director of the division of endocrinology at Cedars-Sinai Medical Center, Los Angeles.

To test for heritability, subjects were drawn from the offspring generation within MA-HTN, a Mexican American Hypertension study of 939 subjects from 162 families.

Mexican Americans were chosen for the study because of their high prevalence of insulin resistance and high age-specific prevalence of the metabolic syndrome.

Euglycemic clamps were used to measure insulin sensitivity and clearance, keeping the insulin infusion rate steady for all subjects and obtaining a direct measure of insulin clearance via steady state plasma insulin (SSPI) levels achieved during the clamp study.

Once it was determined that more than 70% of the variation in insulin clearance was due to genetic factors, a genome-wide linkage scan utilizing 388 microsatellites resulted in the discovery of SSPI linkages on chromosomes 15 and 20.

Dr. Joseph M. Vinetz, AFMR western section president, said in a telephone interview that Dr. Goodarzi's study had the potential of “optimizing care in the exploding epidemic of type 2 diabetes,” with “huge ramifications for early prevention throughout society.”

To date, genetic studies of diabetes, insulin resistance, insulin secretion, and insulin clearance “have not yet translated to clinically useful tools,” said Dr. Goodarzi.

However, he predicted that the time is not far off—perhaps 5–10 years—when such a link can be made, perhaps by influencing clinical outcomes by implementing interventions once individuals at risk are identified through genetic testing.

Dr. Goodarzi and his associates did not disclose any conflicts of interest regarding their research.

To date, genetic studies of diabetes and insulin resistance have not yet translated to useful tools. DR. GOODARZI

“The response of the first patient was as dramatic as that of the first mouse. … Within 48 hours after the initiation of therapy, a softening of the tumor masses was detected. It soon became obvious that this was not just wishful thinking. “—Alfred Gilman, Ph.D., “The Initial Clinical Trial of Nitrogen Mustard” (Amer. J. Surg. 1963;105:574–8).

The top-secret intravenous administration of 0.1 mg/kg “Compound X” to an “x-ray resistant patient in the terminal stages of lymphosarcoma” in early December 1942 marked the quiet birth of chemotherapy in America.

The clandestine, government-sanctioned treatment of an anonymous patient at Yale University, New Haven, Conn., signified the first therapeutic use of nitrogen mustard, a mysterious compound that had been under investigation since its devastating use as a chemical weapon during World War I.

Dr. Gilman, Dr. Louis S. Goodman, and their team watched in amazement as obstructive symptoms associated with tumor masses involving the patient's face, mediastinum, and submental regions were eased within 4 days, and cervical and axillary masses receded soon after.

Ultimately, the first patient's course proved to be less miraculous than it first seemed. The person's bone marrow “slowly recovered” from toxic effects of the new treatment, but—“a great disappointment”—the tumors returned concomitantly.

Thus began the wrenching ups and downs of patient response to mustard gas in quiet experimental protocols at Yale, the University of Chicago, and the then-Sloan-Kettering Institute of Memorial Hospital in New York.

Until 1946, government secrecy restrictions prevented publication of small case series, but the experiments continued, and on March 15, 1949, mechlorethamine (Mustargen) became the first chemical agent to receive Food and Drug Administration approval for the treatment of cancer, transforming an agent of death into one that held the promise of extended life and launching a revolution.

“It is actually quite remarkable that it has only been 60 years since the first chemotherapy approval, considering where the field has gone in that time,” said Dr. Richard Schilsky, professor of medicine at the University of Chicago and president of the American Society of Clinical Oncology. “We now have probably 100 or more chemotherapy drugs for the treatment of a wide range of different malignancies.”

The journey has been anything but smooth, with strong early opposition documented by Yale oncologists Vincent T. DeVita Jr. and Edward Chu in a recent article, “A History of Cancer Chemotherapy” (Cancer Res. 2008;68:8643–53). “Remissions turned out to be brief and incomplete, and this realization then created an air of pessimism that pervaded the subsequent literature of the 1950s,” they noted. Some academic physicians “became harsh critics of a national drug development program and the effort to prove that drugs could cure advanced cancer.”

By the 1960s, “the main issue of the day was whether cancer drugs caused more harm than good, and talk of curing cancer with drugs was not considered compatible with sanity. The prevailing attitude toward the use of chemotherapy can only be described as hostile,” wrote Dr. DeVita and Dr. Chu.

In spite of it all, chemotherapy emerged as a trusted modality in the treatment of cancer. The drug that started it all, Mustargen, became a key element in the revolutionary MOPP (Mustargen, Oncovin, procarbazine, and prednisone) combination chemotherapy regimen pioneered by Dr. DeVita for advanced Hodgkin's disease in the mid-1960s. It still is used today for stage III and IV Hodgkin's disease and other hematologic cancers, including polycythemia vera and mycoses fungoides, and bronchogenic carcinoma.

Initial observations regarding Mustargen were made during World War I, “when thousands were gassed,” leading to recognition of profound lymph and bone marrow suppression in exposed soldiers and speculation that the agent might have therapeutic utility in diseases characterized by lymphoid and myeloid proliferation, said Dr. DeVita, former director of the National Cancer Institute.

By early 1942, the government's Office of Scientific Research and Development entrusted Dr. Goodman and Dr. Gilman of Yale University to shepherd a highly classified investigation of the deadly agent. After preliminary work in mice, they persuaded Dr. Gustav E. Lindskog, then assistant professor of surgery at the university, to supervise the first human clinical trial.

Detractors objected to the empiric manner in which the early drugs were investigated; the research partnerships that evolved among government, academic, and contracted pharmaceutical companies; and perhaps, most important, the terrible burden of side effects exacted from patients not assured of a cure.

“These drugs were highly experimental and used as a last resort. At first, they didn't work very well and made people who were already sick much sicker,” said Dr. Franco Muggia, director of medical oncology at New York University and chairman and medical director of the Chemotherapy Foundation.

But early believers pressed on, confident that the regimens could be fine-tuned, the toxicities tamed. In time, dramatic advances were made in dosages and treatment regimens, in combining chemotherapeutic agents and in using them in various ways with surgery, radiation, and biologic therapies. A better biologic understanding of cancer led to more precise targeting of chemotherapy. And progress was made in treating the side effects that once seemed to be chemotherapy's death knell, a point illustrated by Dr. Schilsky.

The experts consulted for this article have conducted research for pharmaceutical companies that manufacture various forms of chemotherapy.

ELSEVIER GLOBAL MEDICAL NEWS

Future of Cancer Treatment Includes Chemotherapy

People have been trying to write the epitaph for chemotherapy virtually since nitrogen mustard was approved in 1949. But the naysayers were shortsighted then, and still are today, a number of leading oncologists maintain.

For all the talk of “targeted” therapy taking center stage in cancer therapy, “chemotherapy is likely to be an important part of cancer treatment for some time to come,” Dr. Schilsky said.

The belief that chemotherapy is too toxic, and therefore should be replaced by “targeted therapy,” negates several truths; one, that chemotherapy isn't “targeted,” and two, that molecular-targeted therapies such as biologics and immunotherapy are capable of curing the solid tumors that afflict most patients with cancer.

“Methotrexate and 5-fluorouracil are among the most targeted drugs we've ever had,” Dr. Schilsky said. “They're more than 50 years old and have not been replaced.”

Although agents designed to target characteristics unique to tumor cells may be the hope of the future, to date they have matched chemotherapy's success only in a few rare tumor types, he added.

Empiric studies of early chemotherapeutic drugs may look “pretty unsophisticated” today, but the signals that resulted were strong, Dr. Muggia agreed. “There's no one way,” he said, predicting that chemotherapy will long play a key role in combination regimens that also may include molecular-targeted agents.

“As we get into targeted therapy, there are some problems with that as well,” he added.

Dr. DeVita echoed the notion that “targeted therapy is chemotherapy.”

“We always hoped, over time, that chemotherapy would become more specific and it has,” he said. “Nitrogen mustard was the first use of systemic therapy based on the premise that treatment failure was due to circulating cancer cells. All subsequent systemic therapy, including biologics, is based on that premise.”

Progress in cancer therapy, then, is likely to build on lessons of the past and encounter hurdles not foreseen, Dr. DeVita said.

“The response of the first patient was as dramatic as that of the first mouse. … Within 48 hours after the initiation of therapy, a softening of the tumor masses was detected. It soon became obvious that this was not just wishful thinking. “—Alfred Gilman, Ph.D., “The Initial Clinical Trial of Nitrogen Mustard” (Amer. J. Surg. 1963;105:574–8).

The top-secret intravenous administration of 0.1 mg/kg “Compound X” to an “x-ray resistant patient in the terminal stages of lymphosarcoma” in early December 1942 marked the quiet birth of chemotherapy in America.

The clandestine, government-sanctioned treatment of an anonymous patient at Yale University, New Haven, Conn., signified the first therapeutic use of nitrogen mustard, a mysterious compound that had been under investigation since its devastating use as a chemical weapon during World War I.

Dr. Gilman, Dr. Louis S. Goodman, and their team watched in amazement as obstructive symptoms associated with tumor masses involving the patient's face, mediastinum, and submental regions were eased within 4 days, and cervical and axillary masses receded soon after.

Ultimately, the first patient's course proved to be less miraculous than it first seemed. The person's bone marrow “slowly recovered” from toxic effects of the new treatment, but—“a great disappointment”—the tumors returned concomitantly.

Thus began the wrenching ups and downs of patient response to mustard gas in quiet experimental protocols at Yale, the University of Chicago, and the then-Sloan-Kettering Institute of Memorial Hospital in New York.

Until 1946, government secrecy restrictions prevented publication of small case series, but the experiments continued, and on March 15, 1949, mechlorethamine (Mustargen) became the first chemical agent to receive Food and Drug Administration approval for the treatment of cancer, transforming an agent of death into one that held the promise of extended life and launching a revolution.

“It is actually quite remarkable that it has only been 60 years since the first chemotherapy approval, considering where the field has gone in that time,” said Dr. Richard Schilsky, professor of medicine at the University of Chicago and president of the American Society of Clinical Oncology. “We now have probably 100 or more chemotherapy drugs for the treatment of a wide range of different malignancies.”

The journey has been anything but smooth, with strong early opposition documented by Yale oncologists Vincent T. DeVita Jr. and Edward Chu in a recent article, “A History of Cancer Chemotherapy” (Cancer Res. 2008;68:8643–53). “Remissions turned out to be brief and incomplete, and this realization then created an air of pessimism that pervaded the subsequent literature of the 1950s,” they noted. Some academic physicians “became harsh critics of a national drug development program and the effort to prove that drugs could cure advanced cancer.”

By the 1960s, “the main issue of the day was whether cancer drugs caused more harm than good, and talk of curing cancer with drugs was not considered compatible with sanity. The prevailing attitude toward the use of chemotherapy can only be described as hostile,” wrote Dr. DeVita and Dr. Chu.

In spite of it all, chemotherapy emerged as a trusted modality in the treatment of cancer. The drug that started it all, Mustargen, became a key element in the revolutionary MOPP (Mustargen, Oncovin, procarbazine, and prednisone) combination chemotherapy regimen pioneered by Dr. DeVita for advanced Hodgkin's disease in the mid-1960s. It still is used today for stage III and IV Hodgkin's disease and other hematologic cancers, including polycythemia vera and mycoses fungoides, and bronchogenic carcinoma.

Initial observations regarding Mustargen were made during World War I, “when thousands were gassed,” leading to recognition of profound lymph and bone marrow suppression in exposed soldiers and speculation that the agent might have therapeutic utility in diseases characterized by lymphoid and myeloid proliferation, said Dr. DeVita, former director of the National Cancer Institute.

By early 1942, the government's Office of Scientific Research and Development entrusted Dr. Goodman and Dr. Gilman of Yale University to shepherd a highly classified investigation of the deadly agent. After preliminary work in mice, they persuaded Dr. Gustav E. Lindskog, then assistant professor of surgery at the university, to supervise the first human clinical trial.

Detractors objected to the empiric manner in which the early drugs were investigated; the research partnerships that evolved among government, academic, and contracted pharmaceutical companies; and perhaps, most important, the terrible burden of side effects exacted from patients not assured of a cure.

“These drugs were highly experimental and used as a last resort. At first, they didn't work very well and made people who were already sick much sicker,” said Dr. Franco Muggia, director of medical oncology at New York University and chairman and medical director of the Chemotherapy Foundation.

But early believers pressed on, confident that the regimens could be fine-tuned, the toxicities tamed. In time, dramatic advances were made in dosages and treatment regimens, in combining chemotherapeutic agents and in using them in various ways with surgery, radiation, and biologic therapies. A better biologic understanding of cancer led to more precise targeting of chemotherapy. And progress was made in treating the side effects that once seemed to be chemotherapy's death knell, a point illustrated by Dr. Schilsky.

The experts consulted for this article have conducted research for pharmaceutical companies that manufacture various forms of chemotherapy.

ELSEVIER GLOBAL MEDICAL NEWS

Future of Cancer Treatment Includes Chemotherapy

People have been trying to write the epitaph for chemotherapy virtually since nitrogen mustard was approved in 1949. But the naysayers were shortsighted then, and still are today, a number of leading oncologists maintain.

For all the talk of “targeted” therapy taking center stage in cancer therapy, “chemotherapy is likely to be an important part of cancer treatment for some time to come,” Dr. Schilsky said.

The belief that chemotherapy is too toxic, and therefore should be replaced by “targeted therapy,” negates several truths; one, that chemotherapy isn't “targeted,” and two, that molecular-targeted therapies such as biologics and immunotherapy are capable of curing the solid tumors that afflict most patients with cancer.

“Methotrexate and 5-fluorouracil are among the most targeted drugs we've ever had,” Dr. Schilsky said. “They're more than 50 years old and have not been replaced.”

Although agents designed to target characteristics unique to tumor cells may be the hope of the future, to date they have matched chemotherapy's success only in a few rare tumor types, he added.

Empiric studies of early chemotherapeutic drugs may look “pretty unsophisticated” today, but the signals that resulted were strong, Dr. Muggia agreed. “There's no one way,” he said, predicting that chemotherapy will long play a key role in combination regimens that also may include molecular-targeted agents.

“As we get into targeted therapy, there are some problems with that as well,” he added.

Dr. DeVita echoed the notion that “targeted therapy is chemotherapy.”

“We always hoped, over time, that chemotherapy would become more specific and it has,” he said. “Nitrogen mustard was the first use of systemic therapy based on the premise that treatment failure was due to circulating cancer cells. All subsequent systemic therapy, including biologics, is based on that premise.”

Progress in cancer therapy, then, is likely to build on lessons of the past and encounter hurdles not foreseen, Dr. DeVita said.

“The response of the first patient was as dramatic as that of the first mouse. … Within 48 hours after the initiation of therapy, a softening of the tumor masses was detected. It soon became obvious that this was not just wishful thinking. “—Alfred Gilman, Ph.D., “The Initial Clinical Trial of Nitrogen Mustard” (Amer. J. Surg. 1963;105:574–8).

The top-secret intravenous administration of 0.1 mg/kg “Compound X” to an “x-ray resistant patient in the terminal stages of lymphosarcoma” in early December 1942 marked the quiet birth of chemotherapy in America.

The clandestine, government-sanctioned treatment of an anonymous patient at Yale University, New Haven, Conn., signified the first therapeutic use of nitrogen mustard, a mysterious compound that had been under investigation since its devastating use as a chemical weapon during World War I.

Dr. Gilman, Dr. Louis S. Goodman, and their team watched in amazement as obstructive symptoms associated with tumor masses involving the patient's face, mediastinum, and submental regions were eased within 4 days, and cervical and axillary masses receded soon after.

Ultimately, the first patient's course proved to be less miraculous than it first seemed. The person's bone marrow “slowly recovered” from toxic effects of the new treatment, but—“a great disappointment”—the tumors returned concomitantly.

Thus began the wrenching ups and downs of patient response to mustard gas in quiet experimental protocols at Yale, the University of Chicago, and the then-Sloan-Kettering Institute of Memorial Hospital in New York.

Until 1946, government secrecy restrictions prevented publication of small case series, but the experiments continued, and on March 15, 1949, mechlorethamine (Mustargen) became the first chemical agent to receive Food and Drug Administration approval for the treatment of cancer, transforming an agent of death into one that held the promise of extended life and launching a revolution.

“It is actually quite remarkable that it has only been 60 years since the first chemotherapy approval, considering where the field has gone in that time,” said Dr. Richard Schilsky, professor of medicine at the University of Chicago and president of the American Society of Clinical Oncology. “We now have probably 100 or more chemotherapy drugs for the treatment of a wide range of different malignancies.”

The journey has been anything but smooth, with strong early opposition documented by Yale oncologists Vincent T. DeVita Jr. and Edward Chu in a recent article, “A History of Cancer Chemotherapy” (Cancer Res. 2008;68:8643–53). “Remissions turned out to be brief and incomplete, and this realization then created an air of pessimism that pervaded the subsequent literature of the 1950s,” they noted. Some academic physicians “became harsh critics of a national drug development program and the effort to prove that drugs could cure advanced cancer.”

By the 1960s, “the main issue of the day was whether cancer drugs caused more harm than good, and talk of curing cancer with drugs was not considered compatible with sanity. The prevailing attitude toward the use of chemotherapy can only be described as hostile,” wrote Dr. DeVita and Dr. Chu.

In spite of it all, chemotherapy emerged as a trusted modality in the treatment of cancer. The drug that started it all, Mustargen, became a key element in the revolutionary MOPP (Mustargen, Oncovin, procarbazine, and prednisone) combination chemotherapy regimen pioneered by Dr. DeVita for advanced Hodgkin's disease in the mid-1960s. It still is used today for stage III and IV Hodgkin's disease and other hematologic cancers, including polycythemia vera and mycoses fungoides, and bronchogenic carcinoma.

Initial observations regarding Mustargen were made during World War I, “when thousands were gassed,” leading to recognition of profound lymph and bone marrow suppression in exposed soldiers and speculation that the agent might have therapeutic utility in diseases characterized by lymphoid and myeloid proliferation, said Dr. DeVita, former director of the National Cancer Institute.

By early 1942, the government's Office of Scientific Research and Development entrusted Dr. Goodman and Dr. Gilman of Yale University to shepherd a highly classified investigation of the deadly agent. After preliminary work in mice, they persuaded Dr. Gustav E. Lindskog, then assistant professor of surgery at the university, to supervise the first human clinical trial.

Detractors objected to the empiric manner in which the early drugs were investigated; the research partnerships that evolved among government, academic, and contracted pharmaceutical companies; and perhaps, most important, the terrible burden of side effects exacted from patients not assured of a cure.

“These drugs were highly experimental and used as a last resort. At first, they didn't work very well and made people who were already sick much sicker,” said Dr. Franco Muggia, director of medical oncology at New York University and chairman and medical director of the Chemotherapy Foundation.

But early believers pressed on, confident that the regimens could be fine-tuned, the toxicities tamed. In time, dramatic advances were made in dosages and treatment regimens, in combining chemotherapeutic agents and in using them in various ways with surgery, radiation, and biologic therapies. A better biologic understanding of cancer led to more precise targeting of chemotherapy. And progress was made in treating the side effects that once seemed to be chemotherapy's death knell, a point illustrated by Dr. Schilsky.

The experts consulted for this article have conducted research for pharmaceutical companies that manufacture various forms of chemotherapy.

ELSEVIER GLOBAL MEDICAL NEWS

Future of Cancer Treatment Includes Chemotherapy

People have been trying to write the epitaph for chemotherapy virtually since nitrogen mustard was approved in 1949. But the naysayers were shortsighted then, and still are today, a number of leading oncologists maintain.

For all the talk of “targeted” therapy taking center stage in cancer therapy, “chemotherapy is likely to be an important part of cancer treatment for some time to come,” Dr. Schilsky said.

The belief that chemotherapy is too toxic, and therefore should be replaced by “targeted therapy,” negates several truths; one, that chemotherapy isn't “targeted,” and two, that molecular-targeted therapies such as biologics and immunotherapy are capable of curing the solid tumors that afflict most patients with cancer.

“Methotrexate and 5-fluorouracil are among the most targeted drugs we've ever had,” Dr. Schilsky said. “They're more than 50 years old and have not been replaced.”

Although agents designed to target characteristics unique to tumor cells may be the hope of the future, to date they have matched chemotherapy's success only in a few rare tumor types, he added.

Empiric studies of early chemotherapeutic drugs may look “pretty unsophisticated” today, but the signals that resulted were strong, Dr. Muggia agreed. “There's no one way,” he said, predicting that chemotherapy will long play a key role in combination regimens that also may include molecular-targeted agents.

“As we get into targeted therapy, there are some problems with that as well,” he added.

Dr. DeVita echoed the notion that “targeted therapy is chemotherapy.”

“We always hoped, over time, that chemotherapy would become more specific and it has,” he said. “Nitrogen mustard was the first use of systemic therapy based on the premise that treatment failure was due to circulating cancer cells. All subsequent systemic therapy, including biologics, is based on that premise.”

Progress in cancer therapy, then, is likely to build on lessons of the past and encounter hurdles not foreseen, Dr. DeVita said.

Insulin clearance is a highly heritable trait that has now been tracked to specific regions of two chromosomes, a finding that may have important implications for risk assessment in diabetes, polycystic ovary syndrome, and metabolic syndrome.

Although it has been “virtually neglected” in studies of insulin metabolism, insulin clearance may strongly influence an individual's risk of diabetes and response to the diabetic state, Dr. Mark Goodarzi reported at the Western regional meeting of the American Federation for Medical Research in Carmel, Calif.

In previous work, Dr. Goodarzi and his associates had raised the possibility that the metabolic clearance rate of insulin was largely an inherited trait, because of patterns seen in a cohort of 403 Mexican American subjects (Diabetes 2005;54:1222–7).

The current study by these investigators of a second cohort of 536 individuals from 162 Hispanic families found that insulin clearance was indeed a highly heritable trait, with an age-, sex- and body mass index-adjusted heritability rate of 70.5%.

A genomewide linkage scan applied to samples from the same population identified candidate regions on chromosomes 15 and 20 that may harbor genes that influence insulin clearance, Dr. Goodarzi said in an interview.

Insulin clearance is a relatively unknown player in the sequence of events leading to diabetes.

A recent Medline search revealed more than 35,000 references to insulin resistance and more than 16,000 references to insulin secretion, but just 424 references to insulin clearance.

Although the significance of insulin clearance is underappreciated, it may prove to have an important role as a marker of risk or a target for intervention not only for diabetes, but also for other disorders characterized by hyperinsulinemia, such as polycystic ovary syndrome.

“It appears that a reduction in insulin clearance may be a compensatory response to the insulin resistant state, acting in concert with increased insulin secretion to increase insulin levels,” Dr. Goodarzi explained.

“If insulin levels increase sufficiently, the insulin resistance may be overcome and blood sugars will be maintained in the normal range. However, if there is a failure to adequately increase insulin levels in the face of insulin resistance—either by failing to increase insulin secretion, or, theoretically, failing to reduce insulin clearance—then diabetes will develop,” said Dr. Goodarzi, associate director of the division of endocrinology at Cedars-Sinai Medical Center, Los Angeles.

To test for heritability, subjects were drawn from the offspring generation within MA-HTN, a Mexican American Hypertension study of 939 subjects from 162 families.

Mexican Americans were chosen to participate in the study because of their high prevalence of insulin resistance and high age-specific prevalence of metabolic syndrome.

To date, genetic studies of diabetes, insulin resistance, insulin secretion, and insulin clearance “have not yet translated to clinically useful tools,” Dr. Goodarzi said.

However, he predicted that the time is not far off—perhaps 5–10 years—when such a link can be made, perhaps by influencing clinical outcomes by implementing interventions once individuals at risk are identified through genetic testing.

Dr. Goodarzi and his associates did not disclose any potential conflicts of interest regarding their research.

Insulin clearance may strongly influence an individual's risk of diabetes and response to the diabetic state. DR. GOODARZI

Insulin clearance is a highly heritable trait that has now been tracked to specific regions of two chromosomes, a finding that may have important implications for risk assessment in diabetes, polycystic ovary syndrome, and metabolic syndrome.

Although it has been “virtually neglected” in studies of insulin metabolism, insulin clearance may strongly influence an individual's risk of diabetes and response to the diabetic state, Dr. Mark Goodarzi reported at the Western regional meeting of the American Federation for Medical Research in Carmel, Calif.

In previous work, Dr. Goodarzi and his associates had raised the possibility that the metabolic clearance rate of insulin was largely an inherited trait, because of patterns seen in a cohort of 403 Mexican American subjects (Diabetes 2005;54:1222–7).

The current study by these investigators of a second cohort of 536 individuals from 162 Hispanic families found that insulin clearance was indeed a highly heritable trait, with an age-, sex- and body mass index-adjusted heritability rate of 70.5%.

A genomewide linkage scan applied to samples from the same population identified candidate regions on chromosomes 15 and 20 that may harbor genes that influence insulin clearance, Dr. Goodarzi said in an interview.

Insulin clearance is a relatively unknown player in the sequence of events leading to diabetes.

A recent Medline search revealed more than 35,000 references to insulin resistance and more than 16,000 references to insulin secretion, but just 424 references to insulin clearance.

Although the significance of insulin clearance is underappreciated, it may prove to have an important role as a marker of risk or a target for intervention not only for diabetes, but also for other disorders characterized by hyperinsulinemia, such as polycystic ovary syndrome.

“It appears that a reduction in insulin clearance may be a compensatory response to the insulin resistant state, acting in concert with increased insulin secretion to increase insulin levels,” Dr. Goodarzi explained.

“If insulin levels increase sufficiently, the insulin resistance may be overcome and blood sugars will be maintained in the normal range. However, if there is a failure to adequately increase insulin levels in the face of insulin resistance—either by failing to increase insulin secretion, or, theoretically, failing to reduce insulin clearance—then diabetes will develop,” said Dr. Goodarzi, associate director of the division of endocrinology at Cedars-Sinai Medical Center, Los Angeles.

To test for heritability, subjects were drawn from the offspring generation within MA-HTN, a Mexican American Hypertension study of 939 subjects from 162 families.

Mexican Americans were chosen to participate in the study because of their high prevalence of insulin resistance and high age-specific prevalence of metabolic syndrome.

To date, genetic studies of diabetes, insulin resistance, insulin secretion, and insulin clearance “have not yet translated to clinically useful tools,” Dr. Goodarzi said.

However, he predicted that the time is not far off—perhaps 5–10 years—when such a link can be made, perhaps by influencing clinical outcomes by implementing interventions once individuals at risk are identified through genetic testing.

Dr. Goodarzi and his associates did not disclose any potential conflicts of interest regarding their research.

Insulin clearance may strongly influence an individual's risk of diabetes and response to the diabetic state. DR. GOODARZI

Insulin clearance is a highly heritable trait that has now been tracked to specific regions of two chromosomes, a finding that may have important implications for risk assessment in diabetes, polycystic ovary syndrome, and metabolic syndrome.

Although it has been “virtually neglected” in studies of insulin metabolism, insulin clearance may strongly influence an individual's risk of diabetes and response to the diabetic state, Dr. Mark Goodarzi reported at the Western regional meeting of the American Federation for Medical Research in Carmel, Calif.

In previous work, Dr. Goodarzi and his associates had raised the possibility that the metabolic clearance rate of insulin was largely an inherited trait, because of patterns seen in a cohort of 403 Mexican American subjects (Diabetes 2005;54:1222–7).

The current study by these investigators of a second cohort of 536 individuals from 162 Hispanic families found that insulin clearance was indeed a highly heritable trait, with an age-, sex- and body mass index-adjusted heritability rate of 70.5%.

A genomewide linkage scan applied to samples from the same population identified candidate regions on chromosomes 15 and 20 that may harbor genes that influence insulin clearance, Dr. Goodarzi said in an interview.

Insulin clearance is a relatively unknown player in the sequence of events leading to diabetes.

A recent Medline search revealed more than 35,000 references to insulin resistance and more than 16,000 references to insulin secretion, but just 424 references to insulin clearance.

Although the significance of insulin clearance is underappreciated, it may prove to have an important role as a marker of risk or a target for intervention not only for diabetes, but also for other disorders characterized by hyperinsulinemia, such as polycystic ovary syndrome.

“It appears that a reduction in insulin clearance may be a compensatory response to the insulin resistant state, acting in concert with increased insulin secretion to increase insulin levels,” Dr. Goodarzi explained.

“If insulin levels increase sufficiently, the insulin resistance may be overcome and blood sugars will be maintained in the normal range. However, if there is a failure to adequately increase insulin levels in the face of insulin resistance—either by failing to increase insulin secretion, or, theoretically, failing to reduce insulin clearance—then diabetes will develop,” said Dr. Goodarzi, associate director of the division of endocrinology at Cedars-Sinai Medical Center, Los Angeles.

To test for heritability, subjects were drawn from the offspring generation within MA-HTN, a Mexican American Hypertension study of 939 subjects from 162 families.

Mexican Americans were chosen to participate in the study because of their high prevalence of insulin resistance and high age-specific prevalence of metabolic syndrome.

To date, genetic studies of diabetes, insulin resistance, insulin secretion, and insulin clearance “have not yet translated to clinically useful tools,” Dr. Goodarzi said.

However, he predicted that the time is not far off—perhaps 5–10 years—when such a link can be made, perhaps by influencing clinical outcomes by implementing interventions once individuals at risk are identified through genetic testing.

Dr. Goodarzi and his associates did not disclose any potential conflicts of interest regarding their research.

Insulin clearance may strongly influence an individual's risk of diabetes and response to the diabetic state. DR. GOODARZI

LAS VEGAS — Early-stage mycosis fungoides appears to be a lympho-accumulative disorder, driven by defects in apoptosis mechanisms designed to regulate T-cell populations in the skin, according to Dr. Gary Wood.

Cell cycle defects that lead to the classic "unchecked growth" that characterizes lymphoproliferative diseases do occur in mycosis fungoides, but likely not until its later stages, Dr. Wood, who is chairman of dermatology at the University of Wisconsin, Madison, said during a dermatology seminar that was sponsored by Skin Disease Education Foundation.

In the beginning, mycosis fungoides demonstrate a low rate of apoptosis, with "cells not growing particularly quickly, but also not dying—like guests that you invite that don't go home," he commented.

Many additional clues point to early mycosis fungoides as a lympho-accumulative, rather than a lympho-proliferative, disorder, he said, including:

▸ An indolent clinical course.

▸ Development of patches, not tumor masses.

▸ Low proliferative rate and mitotic counts.

▸ Relative resistance to chemotherapy, because mycosis fungoides cells are "quite similar to normal T cells. Anything that will kill them will kill the rest of the patient."

▸ Poor growth in vitro.

Research of late has buoyed the theory of lympho-accumulation.

One or more death receptor defects have been identified in the majority of patients with cutaneous T-cell lymphoma, including defects in FAS; TNFR (R1, R2, or the antiapoptotic TRAF1 receptor); or TRAIL (DR4, DR5, DcR1, or DcR2).

Dr. Wood's team and others have found further defects in the death receptor antagonist cFLIP, which is a key player in the death receptor pathway, he noted.

He and his colleagues found low FAS expression in 30 of the 31 patients with cutaneous T-cell lymphoma and in 5 of the 6 patients with large plaque parapsoriasis, a precursor of mycosis fungoides or Sézary syndrome (J. Invest. Dermatol. 2008 Oct. 16 [Epub doi:10.1038/jid.2008.309

No such abnormality was seen in the 15 patients with chronic dermatoses, he noted at the meeting.

A more targeted look identified four cutaneous T-cell lymphoma cell lines (MyLa, HH, SZ4, and SeAx) in which resistance to apoptosis correlated with levels of FAS transcripts and proteins.

Taking it one step further, Dr. Woods and his associates found that, when they triggered FAS upregulation by transfecting genes with a wild-type FAS construct, apoptosis was restored, including spontaneous FAS pathway apoptosis, in which FAS ligands, in essence, self-destruct.

"You can see a big uptake in the amount of killing," he pointed out, demonstrating the effect in each of the four tested cell lines using real time polymerase chain reaction (RT/PCR) technology.

While Dr. Wood's team has focused on FAS transfection to prime FAS and cutaneous T-cell lymphoma cells to self-destruct or to become targets of tumor-infiltrating lymphocytes, there are other ways to upregulate FAS as well.

These include interleukin-2 and bryostatin; interferon-α and -γ; and even epigallocatechin gallate (EGCG), which is the polyphenol antioxidant in green tea, he said.

"In the future, these may be useful therapeutic targets," Dr. Wood said.

SDEF and this newspaper are owned by Elsevier.

LAS VEGAS — Early-stage mycosis fungoides appears to be a lympho-accumulative disorder, driven by defects in apoptosis mechanisms designed to regulate T-cell populations in the skin, according to Dr. Gary Wood.

Cell cycle defects that lead to the classic "unchecked growth" that characterizes lymphoproliferative diseases do occur in mycosis fungoides, but likely not until its later stages, Dr. Wood, who is chairman of dermatology at the University of Wisconsin, Madison, said during a dermatology seminar that was sponsored by Skin Disease Education Foundation.

In the beginning, mycosis fungoides demonstrate a low rate of apoptosis, with "cells not growing particularly quickly, but also not dying—like guests that you invite that don't go home," he commented.

Many additional clues point to early mycosis fungoides as a lympho-accumulative, rather than a lympho-proliferative, disorder, he said, including:

▸ An indolent clinical course.

▸ Development of patches, not tumor masses.

▸ Low proliferative rate and mitotic counts.

▸ Relative resistance to chemotherapy, because mycosis fungoides cells are "quite similar to normal T cells. Anything that will kill them will kill the rest of the patient."

▸ Poor growth in vitro.

Research of late has buoyed the theory of lympho-accumulation.

One or more death receptor defects have been identified in the majority of patients with cutaneous T-cell lymphoma, including defects in FAS; TNFR (R1, R2, or the antiapoptotic TRAF1 receptor); or TRAIL (DR4, DR5, DcR1, or DcR2).

Dr. Wood's team and others have found further defects in the death receptor antagonist cFLIP, which is a key player in the death receptor pathway, he noted.

He and his colleagues found low FAS expression in 30 of the 31 patients with cutaneous T-cell lymphoma and in 5 of the 6 patients with large plaque parapsoriasis, a precursor of mycosis fungoides or Sézary syndrome (J. Invest. Dermatol. 2008 Oct. 16 [Epub doi:10.1038/jid.2008.309

No such abnormality was seen in the 15 patients with chronic dermatoses, he noted at the meeting.

A more targeted look identified four cutaneous T-cell lymphoma cell lines (MyLa, HH, SZ4, and SeAx) in which resistance to apoptosis correlated with levels of FAS transcripts and proteins.

Taking it one step further, Dr. Woods and his associates found that, when they triggered FAS upregulation by transfecting genes with a wild-type FAS construct, apoptosis was restored, including spontaneous FAS pathway apoptosis, in which FAS ligands, in essence, self-destruct.

"You can see a big uptake in the amount of killing," he pointed out, demonstrating the effect in each of the four tested cell lines using real time polymerase chain reaction (RT/PCR) technology.

While Dr. Wood's team has focused on FAS transfection to prime FAS and cutaneous T-cell lymphoma cells to self-destruct or to become targets of tumor-infiltrating lymphocytes, there are other ways to upregulate FAS as well.

These include interleukin-2 and bryostatin; interferon-α and -γ; and even epigallocatechin gallate (EGCG), which is the polyphenol antioxidant in green tea, he said.

"In the future, these may be useful therapeutic targets," Dr. Wood said.

SDEF and this newspaper are owned by Elsevier.

LAS VEGAS — Early-stage mycosis fungoides appears to be a lympho-accumulative disorder, driven by defects in apoptosis mechanisms designed to regulate T-cell populations in the skin, according to Dr. Gary Wood.

Cell cycle defects that lead to the classic "unchecked growth" that characterizes lymphoproliferative diseases do occur in mycosis fungoides, but likely not until its later stages, Dr. Wood, who is chairman of dermatology at the University of Wisconsin, Madison, said during a dermatology seminar that was sponsored by Skin Disease Education Foundation.

In the beginning, mycosis fungoides demonstrate a low rate of apoptosis, with "cells not growing particularly quickly, but also not dying—like guests that you invite that don't go home," he commented.

Many additional clues point to early mycosis fungoides as a lympho-accumulative, rather than a lympho-proliferative, disorder, he said, including:

▸ An indolent clinical course.

▸ Development of patches, not tumor masses.

▸ Low proliferative rate and mitotic counts.

▸ Relative resistance to chemotherapy, because mycosis fungoides cells are "quite similar to normal T cells. Anything that will kill them will kill the rest of the patient."

▸ Poor growth in vitro.

Research of late has buoyed the theory of lympho-accumulation.

One or more death receptor defects have been identified in the majority of patients with cutaneous T-cell lymphoma, including defects in FAS; TNFR (R1, R2, or the antiapoptotic TRAF1 receptor); or TRAIL (DR4, DR5, DcR1, or DcR2).

Dr. Wood's team and others have found further defects in the death receptor antagonist cFLIP, which is a key player in the death receptor pathway, he noted.

He and his colleagues found low FAS expression in 30 of the 31 patients with cutaneous T-cell lymphoma and in 5 of the 6 patients with large plaque parapsoriasis, a precursor of mycosis fungoides or Sézary syndrome (J. Invest. Dermatol. 2008 Oct. 16 [Epub doi:10.1038/jid.2008.309

No such abnormality was seen in the 15 patients with chronic dermatoses, he noted at the meeting.

A more targeted look identified four cutaneous T-cell lymphoma cell lines (MyLa, HH, SZ4, and SeAx) in which resistance to apoptosis correlated with levels of FAS transcripts and proteins.

Taking it one step further, Dr. Woods and his associates found that, when they triggered FAS upregulation by transfecting genes with a wild-type FAS construct, apoptosis was restored, including spontaneous FAS pathway apoptosis, in which FAS ligands, in essence, self-destruct.

"You can see a big uptake in the amount of killing," he pointed out, demonstrating the effect in each of the four tested cell lines using real time polymerase chain reaction (RT/PCR) technology.

While Dr. Wood's team has focused on FAS transfection to prime FAS and cutaneous T-cell lymphoma cells to self-destruct or to become targets of tumor-infiltrating lymphocytes, there are other ways to upregulate FAS as well.

These include interleukin-2 and bryostatin; interferon-α and -γ; and even epigallocatechin gallate (EGCG), which is the polyphenol antioxidant in green tea, he said.

"In the future, these may be useful therapeutic targets," Dr. Wood said.

SDEF and this newspaper are owned by Elsevier.

LAS VEGAS — After years of delay, topical dapsone gel 5% can now be prescribed for patients with mild to moderate acne, marking the first new chemically based drug treatment for acne in a decade.

A sulfone drug, Aczone 5% gel has anti-inflammatory and antimicrobial properties. “It's a drug we know well from dermatitis herpetiformis and other diseases,” said Dr. Guy Webster at a dermatology seminar sponsored by Skin Disease Education Foundation.

However, the topical gel form appears to be much safer, free from the hemolysis, hemolytic anemia, and peripheral neuropathy that can result from oral administration of the drug for Hansen's disease or serious skin disorders, said Dr. Webster, a dermatologist in private practice in Hockessin, Del.

No blood tests will be required for patients receiving topical dapsone, based on an FDA revision of drug labeling for the product last March.

In clinical trials involving more than 3,000 patients, the inflammatory lesion count among patients receiving active dapsone gel declined 24% within 2 weeks.

The total lesion count declined 48% in patients receiving dapsone gel by week 12, a statistically superior result to the 42% lesion count reduction seen in patients who received the vehicle alone.

Side effects were mostly mild and similar to the profile seen with other topical acne products. They included erythema, dryness, oiliness, and peeling. “This is going to be a very, very safe drug, very well tolerated,” Dr. Webster said.

He predicted the gel will be prescribed as a first-line treatment for patients with mild to moderate acne but said it remains to be seen whether topical dapsone will ultimately play a role in treating patients with severe acne, either alone or in combination with other drugs.

“My suspicion is that at the very least, it will be competitive with clindamycin monotherapy or benzoyl peroxide monotherapy,” he said.

Dr. Webster disclosed that he is a consultant to Allergan.

SDEF and this news organization are wholly owned subsidiaries of Elsevier.

LAS VEGAS — After years of delay, topical dapsone gel 5% can now be prescribed for patients with mild to moderate acne, marking the first new chemically based drug treatment for acne in a decade.

A sulfone drug, Aczone 5% gel has anti-inflammatory and antimicrobial properties. “It's a drug we know well from dermatitis herpetiformis and other diseases,” said Dr. Guy Webster at a dermatology seminar sponsored by Skin Disease Education Foundation.

However, the topical gel form appears to be much safer, free from the hemolysis, hemolytic anemia, and peripheral neuropathy that can result from oral administration of the drug for Hansen's disease or serious skin disorders, said Dr. Webster, a dermatologist in private practice in Hockessin, Del.

No blood tests will be required for patients receiving topical dapsone, based on an FDA revision of drug labeling for the product last March.

In clinical trials involving more than 3,000 patients, the inflammatory lesion count among patients receiving active dapsone gel declined 24% within 2 weeks.

The total lesion count declined 48% in patients receiving dapsone gel by week 12, a statistically superior result to the 42% lesion count reduction seen in patients who received the vehicle alone.

Side effects were mostly mild and similar to the profile seen with other topical acne products. They included erythema, dryness, oiliness, and peeling. “This is going to be a very, very safe drug, very well tolerated,” Dr. Webster said.

He predicted the gel will be prescribed as a first-line treatment for patients with mild to moderate acne but said it remains to be seen whether topical dapsone will ultimately play a role in treating patients with severe acne, either alone or in combination with other drugs.

“My suspicion is that at the very least, it will be competitive with clindamycin monotherapy or benzoyl peroxide monotherapy,” he said.

Dr. Webster disclosed that he is a consultant to Allergan.

SDEF and this news organization are wholly owned subsidiaries of Elsevier.

LAS VEGAS — After years of delay, topical dapsone gel 5% can now be prescribed for patients with mild to moderate acne, marking the first new chemically based drug treatment for acne in a decade.

A sulfone drug, Aczone 5% gel has anti-inflammatory and antimicrobial properties. “It's a drug we know well from dermatitis herpetiformis and other diseases,” said Dr. Guy Webster at a dermatology seminar sponsored by Skin Disease Education Foundation.

However, the topical gel form appears to be much safer, free from the hemolysis, hemolytic anemia, and peripheral neuropathy that can result from oral administration of the drug for Hansen's disease or serious skin disorders, said Dr. Webster, a dermatologist in private practice in Hockessin, Del.

No blood tests will be required for patients receiving topical dapsone, based on an FDA revision of drug labeling for the product last March.

In clinical trials involving more than 3,000 patients, the inflammatory lesion count among patients receiving active dapsone gel declined 24% within 2 weeks.

The total lesion count declined 48% in patients receiving dapsone gel by week 12, a statistically superior result to the 42% lesion count reduction seen in patients who received the vehicle alone.

Side effects were mostly mild and similar to the profile seen with other topical acne products. They included erythema, dryness, oiliness, and peeling. “This is going to be a very, very safe drug, very well tolerated,” Dr. Webster said.

He predicted the gel will be prescribed as a first-line treatment for patients with mild to moderate acne but said it remains to be seen whether topical dapsone will ultimately play a role in treating patients with severe acne, either alone or in combination with other drugs.

“My suspicion is that at the very least, it will be competitive with clindamycin monotherapy or benzoyl peroxide monotherapy,” he said.

Dr. Webster disclosed that he is a consultant to Allergan.

SDEF and this news organization are wholly owned subsidiaries of Elsevier.

LAS VEGAS — Profoundly severe, sudden-onset acne in adolescents should be treated right away, Dr. Fred Ghali said.

These patients exhibit inflammatory and ulcerative acne lesions, often with large, nodular cysts, Dr. Ghali said at a dermatology seminar sponsored by Skin Disease Education Foundation. The face, chest, back, and shoulders are typically involved. And bleeding and associated tenderness are common complaints.

When you see such a patient from across the room, your first inclination may be to wonder why the patient waited so long to seek help, but in fact, these cases may have a sudden onset, said Dr. Ghali, a pediatric dermatologist in private practice in Grapevine, Tex.

For unknown reasons, these extreme acne blowouts tend to occur predominantly in boys about 10-15 years old.

Although isotretinoin will ultimately be the choice of therapy, management of such patients should start with oral prednisone to reduce the inflammation and potential for granulation tissue, he said.

In such cases, Dr. Ghali said he typically prescribes 40-50 mg of prednisone daily, tapering the dose over a period of several weeks. For more localized lesions, intralesional steroids can be used as well, he added.

Given either adjunctly or after a few weeks, low-dose isotretinoin can be initiated at 10-20 mg/day. This lower-than-standard daily dose of isotretinoin will hopefully avoid a further flare of inflammatory lesions and typically should be maintained for a few months; after that, step-up therapy to 20-40 mg/day can be used, followed by higher doses, introduced gradually as tolerated by the patient, Dr. Ghali said.

To achieve long-standing improvement, acne patients typically require a total isotretinoin course of 150 mg/kg. Patients with severe, sudden-onset inflammatory acne are no different and should receive at least the standard total course or sometimes even greater amounts over time if necessary, depending on the severity of the case and the patient's response.

“What if it takes 8-10 months to complete the course in some patients? So be it,” Dr. Ghali said. For these severely inflamed acne patients, the main issue is ensuring they receive an adequate cumulative course of isotretinoin, rather than attempting to complete the treatment within the 5-month treatment window that applies to most acne patients.

If the diagnosis is truly acne fulminans, arthralgia can be treated with NSAIDs. A longer course of oral prednisone may be required, he said. Again, isotretinoin should be initiated at a low dose for best results, and gradually increased over time.

Dr. Ghali reported no relevant conflicts of interest in regard to his presentation.

SDEF and this news organization are owned by Elsevier.

Inflamed lesions may appear explosively, as on the chest of this teenage boy. Lesions are usually tender and bleed. Courtesy Dr. Fred Ghali

LAS VEGAS — Profoundly severe, sudden-onset acne in adolescents should be treated right away, Dr. Fred Ghali said.

These patients exhibit inflammatory and ulcerative acne lesions, often with large, nodular cysts, Dr. Ghali said at a dermatology seminar sponsored by Skin Disease Education Foundation. The face, chest, back, and shoulders are typically involved. And bleeding and associated tenderness are common complaints.

When you see such a patient from across the room, your first inclination may be to wonder why the patient waited so long to seek help, but in fact, these cases may have a sudden onset, said Dr. Ghali, a pediatric dermatologist in private practice in Grapevine, Tex.

For unknown reasons, these extreme acne blowouts tend to occur predominantly in boys about 10-15 years old.

Although isotretinoin will ultimately be the choice of therapy, management of such patients should start with oral prednisone to reduce the inflammation and potential for granulation tissue, he said.

In such cases, Dr. Ghali said he typically prescribes 40-50 mg of prednisone daily, tapering the dose over a period of several weeks. For more localized lesions, intralesional steroids can be used as well, he added.

Given either adjunctly or after a few weeks, low-dose isotretinoin can be initiated at 10-20 mg/day. This lower-than-standard daily dose of isotretinoin will hopefully avoid a further flare of inflammatory lesions and typically should be maintained for a few months; after that, step-up therapy to 20-40 mg/day can be used, followed by higher doses, introduced gradually as tolerated by the patient, Dr. Ghali said.

To achieve long-standing improvement, acne patients typically require a total isotretinoin course of 150 mg/kg. Patients with severe, sudden-onset inflammatory acne are no different and should receive at least the standard total course or sometimes even greater amounts over time if necessary, depending on the severity of the case and the patient's response.

“What if it takes 8-10 months to complete the course in some patients? So be it,” Dr. Ghali said. For these severely inflamed acne patients, the main issue is ensuring they receive an adequate cumulative course of isotretinoin, rather than attempting to complete the treatment within the 5-month treatment window that applies to most acne patients.

If the diagnosis is truly acne fulminans, arthralgia can be treated with NSAIDs. A longer course of oral prednisone may be required, he said. Again, isotretinoin should be initiated at a low dose for best results, and gradually increased over time.

Dr. Ghali reported no relevant conflicts of interest in regard to his presentation.

SDEF and this news organization are owned by Elsevier.

Inflamed lesions may appear explosively, as on the chest of this teenage boy. Lesions are usually tender and bleed. Courtesy Dr. Fred Ghali

LAS VEGAS — Profoundly severe, sudden-onset acne in adolescents should be treated right away, Dr. Fred Ghali said.

These patients exhibit inflammatory and ulcerative acne lesions, often with large, nodular cysts, Dr. Ghali said at a dermatology seminar sponsored by Skin Disease Education Foundation. The face, chest, back, and shoulders are typically involved. And bleeding and associated tenderness are common complaints.

When you see such a patient from across the room, your first inclination may be to wonder why the patient waited so long to seek help, but in fact, these cases may have a sudden onset, said Dr. Ghali, a pediatric dermatologist in private practice in Grapevine, Tex.

For unknown reasons, these extreme acne blowouts tend to occur predominantly in boys about 10-15 years old.

Although isotretinoin will ultimately be the choice of therapy, management of such patients should start with oral prednisone to reduce the inflammation and potential for granulation tissue, he said.

In such cases, Dr. Ghali said he typically prescribes 40-50 mg of prednisone daily, tapering the dose over a period of several weeks. For more localized lesions, intralesional steroids can be used as well, he added.

Given either adjunctly or after a few weeks, low-dose isotretinoin can be initiated at 10-20 mg/day. This lower-than-standard daily dose of isotretinoin will hopefully avoid a further flare of inflammatory lesions and typically should be maintained for a few months; after that, step-up therapy to 20-40 mg/day can be used, followed by higher doses, introduced gradually as tolerated by the patient, Dr. Ghali said.

To achieve long-standing improvement, acne patients typically require a total isotretinoin course of 150 mg/kg. Patients with severe, sudden-onset inflammatory acne are no different and should receive at least the standard total course or sometimes even greater amounts over time if necessary, depending on the severity of the case and the patient's response.

“What if it takes 8-10 months to complete the course in some patients? So be it,” Dr. Ghali said. For these severely inflamed acne patients, the main issue is ensuring they receive an adequate cumulative course of isotretinoin, rather than attempting to complete the treatment within the 5-month treatment window that applies to most acne patients.

If the diagnosis is truly acne fulminans, arthralgia can be treated with NSAIDs. A longer course of oral prednisone may be required, he said. Again, isotretinoin should be initiated at a low dose for best results, and gradually increased over time.

Dr. Ghali reported no relevant conflicts of interest in regard to his presentation.

SDEF and this news organization are owned by Elsevier.

Inflamed lesions may appear explosively, as on the chest of this teenage boy. Lesions are usually tender and bleed. Courtesy Dr. Fred Ghali

SALT LAKE CITY — The risk of permanent disability from a multiple sclerosis attack is extremely rare and does not appear to be tied to drug holidays, data on more than 1,000 MS patients showed.

A catastrophic attack of multiple sclerosis is feared by patients and physicians alike, sometimes influencing treatment decisions, said Dr. Loren A. Rolak, a neurologist at the Marshfield (Wis.) Clinic in an interview. “The debate still simmers a bit in MS circles about how disabling attacks are in general, as opposed to the progressive, neurodegenerative atrophic process of MS, where people sort of slowly get worse,” he said.

Dr. Rolak and his associates analyzed data from 1,078 MS patients who had a total of 2,587 attacks over a 34-year period. They reported their findings in a poster at the annual meeting of the American Neurological Association.

Seven patients had a disabling attack, defined as a relapse that resulted in a permanent Expanded Disability Status Scale score of 6 or greater. That level of impairment is associated with the loss of unaided mobility.

“It was extremely rare … 1 in 369 attacks,” Dr. Rolak said. In two of the seven cases, the disabling attack was the result of de novo tumefactive MS; another two patients were on interferon therapy.

Physicians who want to wait before prescribing medication to a newly diagnosed MS patient, or to approve a drug holiday in a woman who wants to become pregnant, may find reassurance in the study, Dr. Rolak suggested.

Dr. Rolak's study was not funded by a pharmaceutical company.

SALT LAKE CITY — The risk of permanent disability from a multiple sclerosis attack is extremely rare and does not appear to be tied to drug holidays, data on more than 1,000 MS patients showed.

A catastrophic attack of multiple sclerosis is feared by patients and physicians alike, sometimes influencing treatment decisions, said Dr. Loren A. Rolak, a neurologist at the Marshfield (Wis.) Clinic in an interview. “The debate still simmers a bit in MS circles about how disabling attacks are in general, as opposed to the progressive, neurodegenerative atrophic process of MS, where people sort of slowly get worse,” he said.

Dr. Rolak and his associates analyzed data from 1,078 MS patients who had a total of 2,587 attacks over a 34-year period. They reported their findings in a poster at the annual meeting of the American Neurological Association.

Seven patients had a disabling attack, defined as a relapse that resulted in a permanent Expanded Disability Status Scale score of 6 or greater. That level of impairment is associated with the loss of unaided mobility.

“It was extremely rare … 1 in 369 attacks,” Dr. Rolak said. In two of the seven cases, the disabling attack was the result of de novo tumefactive MS; another two patients were on interferon therapy.

Physicians who want to wait before prescribing medication to a newly diagnosed MS patient, or to approve a drug holiday in a woman who wants to become pregnant, may find reassurance in the study, Dr. Rolak suggested.

Dr. Rolak's study was not funded by a pharmaceutical company.

SALT LAKE CITY — The risk of permanent disability from a multiple sclerosis attack is extremely rare and does not appear to be tied to drug holidays, data on more than 1,000 MS patients showed.

A catastrophic attack of multiple sclerosis is feared by patients and physicians alike, sometimes influencing treatment decisions, said Dr. Loren A. Rolak, a neurologist at the Marshfield (Wis.) Clinic in an interview. “The debate still simmers a bit in MS circles about how disabling attacks are in general, as opposed to the progressive, neurodegenerative atrophic process of MS, where people sort of slowly get worse,” he said.

Dr. Rolak and his associates analyzed data from 1,078 MS patients who had a total of 2,587 attacks over a 34-year period. They reported their findings in a poster at the annual meeting of the American Neurological Association.

Seven patients had a disabling attack, defined as a relapse that resulted in a permanent Expanded Disability Status Scale score of 6 or greater. That level of impairment is associated with the loss of unaided mobility.

“It was extremely rare … 1 in 369 attacks,” Dr. Rolak said. In two of the seven cases, the disabling attack was the result of de novo tumefactive MS; another two patients were on interferon therapy.

Physicians who want to wait before prescribing medication to a newly diagnosed MS patient, or to approve a drug holiday in a woman who wants to become pregnant, may find reassurance in the study, Dr. Rolak suggested.

Dr. Rolak's study was not funded by a pharmaceutical company.

LAS VEGAS — After years of delay, topical dapsone gel 5% can now be prescribed for patients with mild to moderate acne, marking the first new chemically based drug treatment for acne in a decade.

A sulfone drug, Aczone 5% gel has anti-inflammatory and antimicrobial properties.

“It's a drug we know well from dermatitis herpetiformis and other diseases,” said Dr. Guy Webster at a dermatology seminar sponsored by Skin Disease Education Foundation.

However, the topical gel form appears to be a much safer drug, free from the hemolysis, hemolytic anemia, and peripheral neuropathy that can result from oral administration of the drug for Hansen's disease or serious skin disorders, he said.

No blood tests will be required for patients receiving topical dapsone, based on an FDA revision of drug labeling for the product last March.

In clinical trials involving more than 3,000 patients, the inflammatory lesion count among patients receiving active dapsone gel declined 24% within 2 weeks.

The total lesion count declined 48% in patients receiving dapsone gel by week 12, a statistically superior result to the 42% lesion count reduction seen in patients who received the vehicle alone.

Side effects were mostly mild and similar to the profile seen with other topical acne products. They included erythema, dryness, oiliness, and peeling.

“This is going to be a very, very safe drug, very well tolerated,” said Dr. Webster days before the drug was launched. “There are no safety worries.”

He predicted the gel will be prescribed as a first-line treatment for patients with mild to moderate acne but said it remains to be seen whether topical dapsone will ultimately play a role in treating patients with severe acne, either alone or in combination with other drugs.

Dr. Webster disclosed that he is a consultant to Allergan.

SDEF and this news organization are wholly owned subsidiaries of Elsevier.

LAS VEGAS — After years of delay, topical dapsone gel 5% can now be prescribed for patients with mild to moderate acne, marking the first new chemically based drug treatment for acne in a decade.

A sulfone drug, Aczone 5% gel has anti-inflammatory and antimicrobial properties.

“It's a drug we know well from dermatitis herpetiformis and other diseases,” said Dr. Guy Webster at a dermatology seminar sponsored by Skin Disease Education Foundation.

However, the topical gel form appears to be a much safer drug, free from the hemolysis, hemolytic anemia, and peripheral neuropathy that can result from oral administration of the drug for Hansen's disease or serious skin disorders, he said.

No blood tests will be required for patients receiving topical dapsone, based on an FDA revision of drug labeling for the product last March.

In clinical trials involving more than 3,000 patients, the inflammatory lesion count among patients receiving active dapsone gel declined 24% within 2 weeks.

The total lesion count declined 48% in patients receiving dapsone gel by week 12, a statistically superior result to the 42% lesion count reduction seen in patients who received the vehicle alone.

Side effects were mostly mild and similar to the profile seen with other topical acne products. They included erythema, dryness, oiliness, and peeling.

“This is going to be a very, very safe drug, very well tolerated,” said Dr. Webster days before the drug was launched. “There are no safety worries.”

He predicted the gel will be prescribed as a first-line treatment for patients with mild to moderate acne but said it remains to be seen whether topical dapsone will ultimately play a role in treating patients with severe acne, either alone or in combination with other drugs.

Dr. Webster disclosed that he is a consultant to Allergan.

SDEF and this news organization are wholly owned subsidiaries of Elsevier.

LAS VEGAS — After years of delay, topical dapsone gel 5% can now be prescribed for patients with mild to moderate acne, marking the first new chemically based drug treatment for acne in a decade.

A sulfone drug, Aczone 5% gel has anti-inflammatory and antimicrobial properties.

“It's a drug we know well from dermatitis herpetiformis and other diseases,” said Dr. Guy Webster at a dermatology seminar sponsored by Skin Disease Education Foundation.

However, the topical gel form appears to be a much safer drug, free from the hemolysis, hemolytic anemia, and peripheral neuropathy that can result from oral administration of the drug for Hansen's disease or serious skin disorders, he said.

No blood tests will be required for patients receiving topical dapsone, based on an FDA revision of drug labeling for the product last March.

In clinical trials involving more than 3,000 patients, the inflammatory lesion count among patients receiving active dapsone gel declined 24% within 2 weeks.

The total lesion count declined 48% in patients receiving dapsone gel by week 12, a statistically superior result to the 42% lesion count reduction seen in patients who received the vehicle alone.

Side effects were mostly mild and similar to the profile seen with other topical acne products. They included erythema, dryness, oiliness, and peeling.

“This is going to be a very, very safe drug, very well tolerated,” said Dr. Webster days before the drug was launched. “There are no safety worries.”

He predicted the gel will be prescribed as a first-line treatment for patients with mild to moderate acne but said it remains to be seen whether topical dapsone will ultimately play a role in treating patients with severe acne, either alone or in combination with other drugs.

Dr. Webster disclosed that he is a consultant to Allergan.

SDEF and this news organization are wholly owned subsidiaries of Elsevier.