Diana Mahoney

BOSTON — Treatment with metformin significantly improves body mass index and other metabolic parameters in women with polycystic ovary syndrome and significantly decreases the prevalence of metabolic syndrome in this population, a retrospective study has shown.

The findings confirm the utility of metformin, coupled with diet and exercise, as a primary therapy for minimizing the long-term risks of developing metabolic syndrome-associated cardiovascular disease and diabetes in women with the hormonal disorder, Kai I. Cheang, Pharm.D., said at the Fifth Annual World Congress on the Insulin Resistance Syndrome.

To date, short-term studies have demonstrated beneficial metabolic effects associated with metformin in women with polycystic ovary syndrome (PCOS), but long-term data have been lacking, according to Dr. Cheang, of Virginia Commonwealth University, Richmond.

To assess the impact of long-term metformin use, Dr. Cheang and colleagues reviewed the charts of consecutive PCOS patients treated at the university-affiliated clinic from 2000 to 2005. Patients with more than 6 months of treatment with metformin were included in the final analysis if baseline and follow-up assessments of metabolic syndrome parameters were available. Those patients with diabetes at baseline and those taking other medications that would affect metabolic parameters, such as thiazolidinediones, weight-loss agents, antihypertensives, lipid-lowering agents, or antidiabetic agents, were excluded.

Of the nearly 250 PCOS patients treated with metformin during the study period, 71 met the inclusion criteria; their mean age was 31.2 years. For the purposes of the investigation, metabolic syndrome was defined by National Cholesterol Education Program Adult Treatment Panel III (ATP-III) criteria, with the exception of waist circumference; body mass index (BMI) was substituted for that criterion.

“This is because waist circumference was not available for most of the patients,” Dr. Cheang noted. “Based on correlation between BMI and waist circumference of local PCOS women with PCOS women who entered into our clinical studies, we determined the BMI cut-off value corresponding to a waist circumference of 88 cm was 32 kg/m

The average period from initiation of metformin therapy to the most recent assessment for the study population was 31 months. The data for those patients who began lipid-lowering or antihypertensive therapy during follow-up were analyzed up until the beginning of such therapy, according to Dr. Cheang.

The investigators assessed baseline and follow-up metabolic syndrome parameters using a two-sided student's paired t test and observed that, compared with baseline, follow-up values for BMI, diastolic blood pressure, and high-density lipoprotein were significantly improved with metformin therapy, Dr. Cheang reported.

Additionally, metformin therapy significantly decreased the overall prevalence of metabolic syndrome from 31% at baseline to 14% following 31 months of treatment. Observed improvements in systolic blood pressure, triglycerides, and fasting glucose measures did not reach statistical significance.

The findings were limited by the study's retrospective design, Dr. Cheang said. “As information was not being collected specifically for the study, certain data [were] not available for all patients.” Additionally, the time between patient visits was inconsistent, and there is a possibility of selection bias because the clinic from which the patient pool was collected specializes in PCOS care, she said.

According to study coauthor Dr. John E. Nestler, chair of the university's division of endocrinology and metabolism, previous studies have shown that treatment with metformin, coupled with diet and exercise, improves ovulation and lowers androgens in PCOS women and possibly prevents or retards progression to glucose intolerance. With these new data, “[metformin treatment] also appears to ameliorate several components of the metabolic syndrome,” he said in an interview.

The clinical significance of these findings is substantial, given the extremely high risk for the metabolic disorder in PCOS, he added.

None of the investigators reported conflicts of interest relative to this study.

BOSTON — Treatment with metformin significantly improves body mass index and other metabolic parameters in women with polycystic ovary syndrome and significantly decreases the prevalence of metabolic syndrome in this population, a retrospective study has shown.

The findings confirm the utility of metformin, coupled with diet and exercise, as a primary therapy for minimizing the long-term risks of developing metabolic syndrome-associated cardiovascular disease and diabetes in women with the hormonal disorder, Kai I. Cheang, Pharm.D., said at the Fifth Annual World Congress on the Insulin Resistance Syndrome.

To date, short-term studies have demonstrated beneficial metabolic effects associated with metformin in women with polycystic ovary syndrome (PCOS), but long-term data have been lacking, according to Dr. Cheang, of Virginia Commonwealth University, Richmond.

To assess the impact of long-term metformin use, Dr. Cheang and colleagues reviewed the charts of consecutive PCOS patients treated at the university-affiliated clinic from 2000 to 2005. Patients with more than 6 months of treatment with metformin were included in the final analysis if baseline and follow-up assessments of metabolic syndrome parameters were available. Those patients with diabetes at baseline and those taking other medications that would affect metabolic parameters, such as thiazolidinediones, weight-loss agents, antihypertensives, lipid-lowering agents, or antidiabetic agents, were excluded.

Of the nearly 250 PCOS patients treated with metformin during the study period, 71 met the inclusion criteria; their mean age was 31.2 years. For the purposes of the investigation, metabolic syndrome was defined by National Cholesterol Education Program Adult Treatment Panel III (ATP-III) criteria, with the exception of waist circumference; body mass index (BMI) was substituted for that criterion.

“This is because waist circumference was not available for most of the patients,” Dr. Cheang noted. “Based on correlation between BMI and waist circumference of local PCOS women with PCOS women who entered into our clinical studies, we determined the BMI cut-off value corresponding to a waist circumference of 88 cm was 32 kg/m

The average period from initiation of metformin therapy to the most recent assessment for the study population was 31 months. The data for those patients who began lipid-lowering or antihypertensive therapy during follow-up were analyzed up until the beginning of such therapy, according to Dr. Cheang.

The investigators assessed baseline and follow-up metabolic syndrome parameters using a two-sided student's paired t test and observed that, compared with baseline, follow-up values for BMI, diastolic blood pressure, and high-density lipoprotein were significantly improved with metformin therapy, Dr. Cheang reported.

Additionally, metformin therapy significantly decreased the overall prevalence of metabolic syndrome from 31% at baseline to 14% following 31 months of treatment. Observed improvements in systolic blood pressure, triglycerides, and fasting glucose measures did not reach statistical significance.

The findings were limited by the study's retrospective design, Dr. Cheang said. “As information was not being collected specifically for the study, certain data [were] not available for all patients.” Additionally, the time between patient visits was inconsistent, and there is a possibility of selection bias because the clinic from which the patient pool was collected specializes in PCOS care, she said.

According to study coauthor Dr. John E. Nestler, chair of the university's division of endocrinology and metabolism, previous studies have shown that treatment with metformin, coupled with diet and exercise, improves ovulation and lowers androgens in PCOS women and possibly prevents or retards progression to glucose intolerance. With these new data, “[metformin treatment] also appears to ameliorate several components of the metabolic syndrome,” he said in an interview.

The clinical significance of these findings is substantial, given the extremely high risk for the metabolic disorder in PCOS, he added.

None of the investigators reported conflicts of interest relative to this study.

BOSTON — Treatment with metformin significantly improves body mass index and other metabolic parameters in women with polycystic ovary syndrome and significantly decreases the prevalence of metabolic syndrome in this population, a retrospective study has shown.

The findings confirm the utility of metformin, coupled with diet and exercise, as a primary therapy for minimizing the long-term risks of developing metabolic syndrome-associated cardiovascular disease and diabetes in women with the hormonal disorder, Kai I. Cheang, Pharm.D., said at the Fifth Annual World Congress on the Insulin Resistance Syndrome.

To date, short-term studies have demonstrated beneficial metabolic effects associated with metformin in women with polycystic ovary syndrome (PCOS), but long-term data have been lacking, according to Dr. Cheang, of Virginia Commonwealth University, Richmond.

To assess the impact of long-term metformin use, Dr. Cheang and colleagues reviewed the charts of consecutive PCOS patients treated at the university-affiliated clinic from 2000 to 2005. Patients with more than 6 months of treatment with metformin were included in the final analysis if baseline and follow-up assessments of metabolic syndrome parameters were available. Those patients with diabetes at baseline and those taking other medications that would affect metabolic parameters, such as thiazolidinediones, weight-loss agents, antihypertensives, lipid-lowering agents, or antidiabetic agents, were excluded.

Of the nearly 250 PCOS patients treated with metformin during the study period, 71 met the inclusion criteria; their mean age was 31.2 years. For the purposes of the investigation, metabolic syndrome was defined by National Cholesterol Education Program Adult Treatment Panel III (ATP-III) criteria, with the exception of waist circumference; body mass index (BMI) was substituted for that criterion.

“This is because waist circumference was not available for most of the patients,” Dr. Cheang noted. “Based on correlation between BMI and waist circumference of local PCOS women with PCOS women who entered into our clinical studies, we determined the BMI cut-off value corresponding to a waist circumference of 88 cm was 32 kg/m

The average period from initiation of metformin therapy to the most recent assessment for the study population was 31 months. The data for those patients who began lipid-lowering or antihypertensive therapy during follow-up were analyzed up until the beginning of such therapy, according to Dr. Cheang.

The investigators assessed baseline and follow-up metabolic syndrome parameters using a two-sided student's paired t test and observed that, compared with baseline, follow-up values for BMI, diastolic blood pressure, and high-density lipoprotein were significantly improved with metformin therapy, Dr. Cheang reported.

Additionally, metformin therapy significantly decreased the overall prevalence of metabolic syndrome from 31% at baseline to 14% following 31 months of treatment. Observed improvements in systolic blood pressure, triglycerides, and fasting glucose measures did not reach statistical significance.

The findings were limited by the study's retrospective design, Dr. Cheang said. “As information was not being collected specifically for the study, certain data [were] not available for all patients.” Additionally, the time between patient visits was inconsistent, and there is a possibility of selection bias because the clinic from which the patient pool was collected specializes in PCOS care, she said.

According to study coauthor Dr. John E. Nestler, chair of the university's division of endocrinology and metabolism, previous studies have shown that treatment with metformin, coupled with diet and exercise, improves ovulation and lowers androgens in PCOS women and possibly prevents or retards progression to glucose intolerance. With these new data, “[metformin treatment] also appears to ameliorate several components of the metabolic syndrome,” he said in an interview.

The clinical significance of these findings is substantial, given the extremely high risk for the metabolic disorder in PCOS, he added.

None of the investigators reported conflicts of interest relative to this study.

BOSTON — Small joint involvement and symptoms that last for more than 2 weeks are among the most important early predictors of the evolution of juvenile idiopathic arthritis in children with acute recent onset of the disease, according to findings from a Norwegian study.

A significant percentage of what appears to be juvenile idiopathic arthritis (JIA) actually is transient arthritis, according to the findings.

Knee joint involvement, a neutrophile white blood cell count within the normal range, and a platelet count above the normal limit are also significant predictors of the chronic inflammatory arthritis in children with early symptoms, Dr. Kai S. Handeland reported at the annual meeting of the American College of Rheumatology.

The inability to distinguish between JIA and other types of recent-onset childhood arthritis at an early stage limits the degree to which aggressive management can be carried forth, said Dr. Handeland of Rikshospitalet-Radiumhospitalet medical center, Oslo.

To determine whether any clinical or laboratory features in children with recent-onset arthritis might predict the diagnosis of JIA, Dr. Handeland and colleagues conducted a multicenter population-based study in three Norwegian counties between May 2004 and June 2005. During this period, the investigators asked all primary care physicians in the region to refer for study inclusion all children aged younger than 16 years with symptoms consistent with recent-onset arthritis or osteomyelitis, confirmed by clinical or radiological examination. In addition to prospectively enrolled patients, children who met inclusion criteria were identified retrospectively by searching electronic medical records for relevant diagnoses.

Of the region's 255,303 children, 504 were referred for possible inclusion in the study. A total of 214 patients were enrolled in the study and followed up for a minimum of 6 months, at which point a final diagnosis was made. The investigators reevaluated the diagnoses by chart review after 2 years.

Of the 214 children with confirmed arthritis symptoms, 40 had JIA, 8 had septic arthritis, 5 had osteomyelitis with coexisting arthritis, 21 had poststreptococcal reactive arthritis, 2 had acute rheumatic fever, 4 had Borrelia-arthritis, 1 had enteropathic arthritis, 61 had transient synovitis of the hip, and 72 had other types of transient arthritis, Dr. Handeland said in a poster presentation.

To identify predictors of JIA, the investigators used multiple logistic regression analyses with JIA diagnosis as the dependent variable. Of the factors identified as statistically significant predictors of JIA, the presence of small joint involvement at presentation was the most common, with an odds ratio of 14.1. The odds ratios for symptom duration of 14 days or more, normal neutrophile count, knee-joint involvement, and elevated platelet count, were, respectively, 13.3, 6.2, 4.1, and 3.4, reported Dr. Handeland. Patient gender, monoarthritis, hip-joint involvement, and elevated temperature were not significantly predictive of a JIA diagnosis, he said.

The investigators also conducted subsequent analyses to determine predictors of JIA versus transient/postinfectious arthritis and predictors of JIA versus infectious arthritis.

With respect to the former, the same determinants that discriminate JIA from all arthritis discriminate between JIA and transient/postinfectious arthritis, according to Dr. Handeland.

The determinants that discriminate JIA from infectious arthritis at the time of symptom presentation are the absence of fever and a low occurrence of hip-joint involvement, he said.

Dr. Handeland reported having no conflicts of interest to disclose relative to this presentation.

BOSTON — Small joint involvement and symptoms that last for more than 2 weeks are among the most important early predictors of the evolution of juvenile idiopathic arthritis in children with acute recent onset of the disease, according to findings from a Norwegian study.

A significant percentage of what appears to be juvenile idiopathic arthritis (JIA) actually is transient arthritis, according to the findings.

Knee joint involvement, a neutrophile white blood cell count within the normal range, and a platelet count above the normal limit are also significant predictors of the chronic inflammatory arthritis in children with early symptoms, Dr. Kai S. Handeland reported at the annual meeting of the American College of Rheumatology.

The inability to distinguish between JIA and other types of recent-onset childhood arthritis at an early stage limits the degree to which aggressive management can be carried forth, said Dr. Handeland of Rikshospitalet-Radiumhospitalet medical center, Oslo.

To determine whether any clinical or laboratory features in children with recent-onset arthritis might predict the diagnosis of JIA, Dr. Handeland and colleagues conducted a multicenter population-based study in three Norwegian counties between May 2004 and June 2005. During this period, the investigators asked all primary care physicians in the region to refer for study inclusion all children aged younger than 16 years with symptoms consistent with recent-onset arthritis or osteomyelitis, confirmed by clinical or radiological examination. In addition to prospectively enrolled patients, children who met inclusion criteria were identified retrospectively by searching electronic medical records for relevant diagnoses.

Of the region's 255,303 children, 504 were referred for possible inclusion in the study. A total of 214 patients were enrolled in the study and followed up for a minimum of 6 months, at which point a final diagnosis was made. The investigators reevaluated the diagnoses by chart review after 2 years.

Of the 214 children with confirmed arthritis symptoms, 40 had JIA, 8 had septic arthritis, 5 had osteomyelitis with coexisting arthritis, 21 had poststreptococcal reactive arthritis, 2 had acute rheumatic fever, 4 had Borrelia-arthritis, 1 had enteropathic arthritis, 61 had transient synovitis of the hip, and 72 had other types of transient arthritis, Dr. Handeland said in a poster presentation.

To identify predictors of JIA, the investigators used multiple logistic regression analyses with JIA diagnosis as the dependent variable. Of the factors identified as statistically significant predictors of JIA, the presence of small joint involvement at presentation was the most common, with an odds ratio of 14.1. The odds ratios for symptom duration of 14 days or more, normal neutrophile count, knee-joint involvement, and elevated platelet count, were, respectively, 13.3, 6.2, 4.1, and 3.4, reported Dr. Handeland. Patient gender, monoarthritis, hip-joint involvement, and elevated temperature were not significantly predictive of a JIA diagnosis, he said.

The investigators also conducted subsequent analyses to determine predictors of JIA versus transient/postinfectious arthritis and predictors of JIA versus infectious arthritis.

With respect to the former, the same determinants that discriminate JIA from all arthritis discriminate between JIA and transient/postinfectious arthritis, according to Dr. Handeland.

The determinants that discriminate JIA from infectious arthritis at the time of symptom presentation are the absence of fever and a low occurrence of hip-joint involvement, he said.

Dr. Handeland reported having no conflicts of interest to disclose relative to this presentation.

BOSTON — Small joint involvement and symptoms that last for more than 2 weeks are among the most important early predictors of the evolution of juvenile idiopathic arthritis in children with acute recent onset of the disease, according to findings from a Norwegian study.

A significant percentage of what appears to be juvenile idiopathic arthritis (JIA) actually is transient arthritis, according to the findings.

Knee joint involvement, a neutrophile white blood cell count within the normal range, and a platelet count above the normal limit are also significant predictors of the chronic inflammatory arthritis in children with early symptoms, Dr. Kai S. Handeland reported at the annual meeting of the American College of Rheumatology.

The inability to distinguish between JIA and other types of recent-onset childhood arthritis at an early stage limits the degree to which aggressive management can be carried forth, said Dr. Handeland of Rikshospitalet-Radiumhospitalet medical center, Oslo.

To determine whether any clinical or laboratory features in children with recent-onset arthritis might predict the diagnosis of JIA, Dr. Handeland and colleagues conducted a multicenter population-based study in three Norwegian counties between May 2004 and June 2005. During this period, the investigators asked all primary care physicians in the region to refer for study inclusion all children aged younger than 16 years with symptoms consistent with recent-onset arthritis or osteomyelitis, confirmed by clinical or radiological examination. In addition to prospectively enrolled patients, children who met inclusion criteria were identified retrospectively by searching electronic medical records for relevant diagnoses.

Of the region's 255,303 children, 504 were referred for possible inclusion in the study. A total of 214 patients were enrolled in the study and followed up for a minimum of 6 months, at which point a final diagnosis was made. The investigators reevaluated the diagnoses by chart review after 2 years.

Of the 214 children with confirmed arthritis symptoms, 40 had JIA, 8 had septic arthritis, 5 had osteomyelitis with coexisting arthritis, 21 had poststreptococcal reactive arthritis, 2 had acute rheumatic fever, 4 had Borrelia-arthritis, 1 had enteropathic arthritis, 61 had transient synovitis of the hip, and 72 had other types of transient arthritis, Dr. Handeland said in a poster presentation.

To identify predictors of JIA, the investigators used multiple logistic regression analyses with JIA diagnosis as the dependent variable. Of the factors identified as statistically significant predictors of JIA, the presence of small joint involvement at presentation was the most common, with an odds ratio of 14.1. The odds ratios for symptom duration of 14 days or more, normal neutrophile count, knee-joint involvement, and elevated platelet count, were, respectively, 13.3, 6.2, 4.1, and 3.4, reported Dr. Handeland. Patient gender, monoarthritis, hip-joint involvement, and elevated temperature were not significantly predictive of a JIA diagnosis, he said.

The investigators also conducted subsequent analyses to determine predictors of JIA versus transient/postinfectious arthritis and predictors of JIA versus infectious arthritis.

With respect to the former, the same determinants that discriminate JIA from all arthritis discriminate between JIA and transient/postinfectious arthritis, according to Dr. Handeland.

The determinants that discriminate JIA from infectious arthritis at the time of symptom presentation are the absence of fever and a low occurrence of hip-joint involvement, he said.

Dr. Handeland reported having no conflicts of interest to disclose relative to this presentation.

BOSTON — Rheumatologists must rethink their reflex to prescribe methotrexate for psoriatic arthritis, given data showing anti-tumor necrosis factor agents are more effective for this indication, Dr. Christopher Ritchlin said at a rheumatology conference sponsored by Harvard Medical School.

“About 70%-80% of clinicians around the world who treat psoriatic arthritis say methotrexate is the first drug that they use, yet the only double-blind randomized controlled trial addressing the question was too underpowered and underdosed to make any conclusions regarding efficacy,” he added.

Another concern is liver toxicity with methotrexate, since psoriasis patients tend to have higher alcoholism rates. And there is evidence of progression of fibrosis in psoriatic arthritis patients on methotrexate, said Dr. Ritchlin, of the University of Rochester, N.Y. Also, unlike rheumatoid arthritis, there is no evidence that methotrexate is synergistic with other disease-modifying antirheumatic drugs (DMARDs) in psoriatic arthritis.

In contrast, the production of TNF-α has been shown to play a central role in the development of psoriasis and psoriatic arthritis by sustaining the inflammatory process in the skin and the joints, and anti-TNF-α agents appear to effectively block that activity, said Dr. Ritchlin. Dr. Marte Schrumpf Heiberg of Diakonhjemmet Hospital, Oslo, has reported data from 526 patients with psoriatic arthritis. After 6 months, patients on anti-TNF-α treatment demonstrated significantly greater clinical improvement in disease measures, versus those on methotrexate monotherapy (Ann. Rheum. Dis. 2007;66:1038–42).

And Dr. Filip van den Bosch of University Hospital, in Gent (Belgium), and colleagues presented data showing adalimumab in 414 patients with psoriatic arthritis resulted in clinically meaningful joint and skin improvements at 12 weeks and was well tolerated. In a separate study, the researchers linked adalimumab with clinically important gains in psoriatic nail disease.

Anti-TNF-α therapy also seems to impact the enthesopathic pathology of psoriatic arthritis. Dr. Helena Marzo-Ortega of Chapel Allerton Hospital in Leeds (England), and colleagues have shown infliximab is tied to improvements in MRI-determined bone edema in psoriatic arthritis (Ann. Rheum. Dis. 2007;66:778–81).

Other potential therapeutic targets for psoriatic arthritis include B cells and T cells, as well as the interleukin-23/Th17 pathway, which is directly tied to psoriasis. Anti-p40 therapy targets an interleukin-23 subunit.

“Psoriatic arthritis, unlike rheumatoid arthritis, is quite complex in its disease manifestation,” Dr. Ritchlin. “Traditionally, psoriatic arthritis was defined as an inflammatory arthritis associated with psoriasis. More and more, however, it has become clear that psoriasis is a systemic disease.”

Anti-TNF-α agents come closest to achieving the goal of a treatment that is as simple and minimally toxic as possible, said Dr Ritchlin.

Anti-TNF-α agents come closest to achieving the goal of a treatment that is as simple and minimally toxic as possible. DR. RITCHLIN

BOSTON — Rheumatologists must rethink their reflex to prescribe methotrexate for psoriatic arthritis, given data showing anti-tumor necrosis factor agents are more effective for this indication, Dr. Christopher Ritchlin said at a rheumatology conference sponsored by Harvard Medical School.

“About 70%-80% of clinicians around the world who treat psoriatic arthritis say methotrexate is the first drug that they use, yet the only double-blind randomized controlled trial addressing the question was too underpowered and underdosed to make any conclusions regarding efficacy,” he added.

Another concern is liver toxicity with methotrexate, since psoriasis patients tend to have higher alcoholism rates. And there is evidence of progression of fibrosis in psoriatic arthritis patients on methotrexate, said Dr. Ritchlin, of the University of Rochester, N.Y. Also, unlike rheumatoid arthritis, there is no evidence that methotrexate is synergistic with other disease-modifying antirheumatic drugs (DMARDs) in psoriatic arthritis.

In contrast, the production of TNF-α has been shown to play a central role in the development of psoriasis and psoriatic arthritis by sustaining the inflammatory process in the skin and the joints, and anti-TNF-α agents appear to effectively block that activity, said Dr. Ritchlin. Dr. Marte Schrumpf Heiberg of Diakonhjemmet Hospital, Oslo, has reported data from 526 patients with psoriatic arthritis. After 6 months, patients on anti-TNF-α treatment demonstrated significantly greater clinical improvement in disease measures, versus those on methotrexate monotherapy (Ann. Rheum. Dis. 2007;66:1038–42).

And Dr. Filip van den Bosch of University Hospital, in Gent (Belgium), and colleagues presented data showing adalimumab in 414 patients with psoriatic arthritis resulted in clinically meaningful joint and skin improvements at 12 weeks and was well tolerated. In a separate study, the researchers linked adalimumab with clinically important gains in psoriatic nail disease.

Anti-TNF-α therapy also seems to impact the enthesopathic pathology of psoriatic arthritis. Dr. Helena Marzo-Ortega of Chapel Allerton Hospital in Leeds (England), and colleagues have shown infliximab is tied to improvements in MRI-determined bone edema in psoriatic arthritis (Ann. Rheum. Dis. 2007;66:778–81).

Other potential therapeutic targets for psoriatic arthritis include B cells and T cells, as well as the interleukin-23/Th17 pathway, which is directly tied to psoriasis. Anti-p40 therapy targets an interleukin-23 subunit.

“Psoriatic arthritis, unlike rheumatoid arthritis, is quite complex in its disease manifestation,” Dr. Ritchlin. “Traditionally, psoriatic arthritis was defined as an inflammatory arthritis associated with psoriasis. More and more, however, it has become clear that psoriasis is a systemic disease.”

Anti-TNF-α agents come closest to achieving the goal of a treatment that is as simple and minimally toxic as possible, said Dr Ritchlin.

Anti-TNF-α agents come closest to achieving the goal of a treatment that is as simple and minimally toxic as possible. DR. RITCHLIN

BOSTON — Rheumatologists must rethink their reflex to prescribe methotrexate for psoriatic arthritis, given data showing anti-tumor necrosis factor agents are more effective for this indication, Dr. Christopher Ritchlin said at a rheumatology conference sponsored by Harvard Medical School.

“About 70%-80% of clinicians around the world who treat psoriatic arthritis say methotrexate is the first drug that they use, yet the only double-blind randomized controlled trial addressing the question was too underpowered and underdosed to make any conclusions regarding efficacy,” he added.

Another concern is liver toxicity with methotrexate, since psoriasis patients tend to have higher alcoholism rates. And there is evidence of progression of fibrosis in psoriatic arthritis patients on methotrexate, said Dr. Ritchlin, of the University of Rochester, N.Y. Also, unlike rheumatoid arthritis, there is no evidence that methotrexate is synergistic with other disease-modifying antirheumatic drugs (DMARDs) in psoriatic arthritis.

In contrast, the production of TNF-α has been shown to play a central role in the development of psoriasis and psoriatic arthritis by sustaining the inflammatory process in the skin and the joints, and anti-TNF-α agents appear to effectively block that activity, said Dr. Ritchlin. Dr. Marte Schrumpf Heiberg of Diakonhjemmet Hospital, Oslo, has reported data from 526 patients with psoriatic arthritis. After 6 months, patients on anti-TNF-α treatment demonstrated significantly greater clinical improvement in disease measures, versus those on methotrexate monotherapy (Ann. Rheum. Dis. 2007;66:1038–42).

And Dr. Filip van den Bosch of University Hospital, in Gent (Belgium), and colleagues presented data showing adalimumab in 414 patients with psoriatic arthritis resulted in clinically meaningful joint and skin improvements at 12 weeks and was well tolerated. In a separate study, the researchers linked adalimumab with clinically important gains in psoriatic nail disease.

Anti-TNF-α therapy also seems to impact the enthesopathic pathology of psoriatic arthritis. Dr. Helena Marzo-Ortega of Chapel Allerton Hospital in Leeds (England), and colleagues have shown infliximab is tied to improvements in MRI-determined bone edema in psoriatic arthritis (Ann. Rheum. Dis. 2007;66:778–81).

Other potential therapeutic targets for psoriatic arthritis include B cells and T cells, as well as the interleukin-23/Th17 pathway, which is directly tied to psoriasis. Anti-p40 therapy targets an interleukin-23 subunit.

“Psoriatic arthritis, unlike rheumatoid arthritis, is quite complex in its disease manifestation,” Dr. Ritchlin. “Traditionally, psoriatic arthritis was defined as an inflammatory arthritis associated with psoriasis. More and more, however, it has become clear that psoriasis is a systemic disease.”

Anti-TNF-α agents come closest to achieving the goal of a treatment that is as simple and minimally toxic as possible, said Dr Ritchlin.

Anti-TNF-α agents come closest to achieving the goal of a treatment that is as simple and minimally toxic as possible. DR. RITCHLIN

BOSTON — Rheumatologists need to rethink their reflex to prescribe methotrexate for psoriatic arthritis given mounting data showing that anti-tumor necrosis factor agents are more effective for this indication, Dr. Christopher Ritchlin said at a rheumatology conference sponsored by Harvard Medical School.

Although methotrexate is often the treatment of choice, “we really don't have evidence that it works for psoriatic arthritis,” Dr. Ritchlin stated. “This is a very large problem. About 70%–80% of clinicians around the world who treat psoriatic arthritis say methotrexate is the first drug that they use, yet the only double-blind randomized controlled trial addressing the question was too underpowered and underdosed to make any conclusions regarding efficacy.”

In addition, there is concern about liver toxicity in psoriasis patients on methotrexate—particularly because psoriasis patients tend to have higher rates of alcoholism—and there is evidence of progression of fibrosis in psoriatic arthritis patients on methotrexate, said Dr. Ritchlin of the University of Rochester (N.Y.). And, unlike with rheumatoid arthritis, there is no evidence that methotrexate is synergistic with other disease-modifying antirheumatic drugs (DMARDs) in psoriatic arthritis, he said, noting that “this is an area in which we are in desperate need of data, but it's hard to get clinical trials designed and funded.”

In contrast, there is a growing body of evidence demonstrating that treatment of psoriatic arthritis with tumor necrosis factor-α (TNF-α) inhibitors safely and effectively controls disease activity at a variety of involved sites. The production of TNF-α has been shown to play a central role in the development of psoriasis and psoriatic arthritis by sustaining the inflammatory process in the skin and the joints, and anti-TNF-α agents appear to effectively block that activity, said Dr. Ritchlin.

Dr. Marte Schrumpf Heiberg of Diakonhjemmet Hospital, Oslo, Norway, has reported data from an ongoing study of the effectiveness of therapy with anti-TNF-α agents infliximab, etanercept, and adalimumab, compared with that of methotrexate in 526 patients with psoriatic arthritis. After 6 months of treatment, patients undergoing anti-TNF-α treatment showed significantly greater clinical improvement in disease measures, compared with those who received metho- trexate mono- therapy (Ann. Rheum. Dis. 2007;66:1038–42). Multiple studies presented at the European League Against Rheumatism meeting in June added to the growing cache of literature supporting anti-TNF-α therapy.

Additional potential therapeutic targets for psoriatic arthritis include both B cells and T cells, as well as the interleukin-23/Th17 pathway, which is directly associated with psoriasis. Specifically, anti-p40 therapy targets an interleukin-23 subunit and has proven very effective in psoriasis treatment, according to Dr. Ritchlin

“Psoriatic arthritis, unlike rheumatoid arthritis, is quite complex in its disease manifestation,” said Dr. Ritchlin. “Traditionally, it was defined as an inflammatory arthritis associated with psoriasis. However, it has become clear [it] is a systemic disease that can involve joints, gut mucosa, the uveal tract, and the endothelium, with associated cardiovascular and vascular issues.”

In terms of patient management, “not only do we have to worry about peripheral arthritis, but we also have to be concerned with skin and nail disease, axial disease, dactylitis, and enthesitis,” said Dr. Ritchlin. “It is critical that we approach the therapy of this disease from a global perspective, addressing all of these cardinal issues.”

Clinically, however, such an approach is challenging, as the degree of involvement of each of the heterogenous areas of disease can vary substantially. Anti-TNF-α agents come closer than does methotrexate to achieving the goal of a treatment regimen that is as simple and minimally toxic as possible, said Dr Ritchlin.

BOSTON — Rheumatologists need to rethink their reflex to prescribe methotrexate for psoriatic arthritis given mounting data showing that anti-tumor necrosis factor agents are more effective for this indication, Dr. Christopher Ritchlin said at a rheumatology conference sponsored by Harvard Medical School.

Although methotrexate is often the treatment of choice, “we really don't have evidence that it works for psoriatic arthritis,” Dr. Ritchlin stated. “This is a very large problem. About 70%–80% of clinicians around the world who treat psoriatic arthritis say methotrexate is the first drug that they use, yet the only double-blind randomized controlled trial addressing the question was too underpowered and underdosed to make any conclusions regarding efficacy.”

In addition, there is concern about liver toxicity in psoriasis patients on methotrexate—particularly because psoriasis patients tend to have higher rates of alcoholism—and there is evidence of progression of fibrosis in psoriatic arthritis patients on methotrexate, said Dr. Ritchlin of the University of Rochester (N.Y.). And, unlike with rheumatoid arthritis, there is no evidence that methotrexate is synergistic with other disease-modifying antirheumatic drugs (DMARDs) in psoriatic arthritis, he said, noting that “this is an area in which we are in desperate need of data, but it's hard to get clinical trials designed and funded.”

In contrast, there is a growing body of evidence demonstrating that treatment of psoriatic arthritis with tumor necrosis factor-α (TNF-α) inhibitors safely and effectively controls disease activity at a variety of involved sites. The production of TNF-α has been shown to play a central role in the development of psoriasis and psoriatic arthritis by sustaining the inflammatory process in the skin and the joints, and anti-TNF-α agents appear to effectively block that activity, said Dr. Ritchlin.

Dr. Marte Schrumpf Heiberg of Diakonhjemmet Hospital, Oslo, Norway, has reported data from an ongoing study of the effectiveness of therapy with anti-TNF-α agents infliximab, etanercept, and adalimumab, compared with that of methotrexate in 526 patients with psoriatic arthritis. After 6 months of treatment, patients undergoing anti-TNF-α treatment showed significantly greater clinical improvement in disease measures, compared with those who received metho- trexate mono- therapy (Ann. Rheum. Dis. 2007;66:1038–42). Multiple studies presented at the European League Against Rheumatism meeting in June added to the growing cache of literature supporting anti-TNF-α therapy.

Additional potential therapeutic targets for psoriatic arthritis include both B cells and T cells, as well as the interleukin-23/Th17 pathway, which is directly associated with psoriasis. Specifically, anti-p40 therapy targets an interleukin-23 subunit and has proven very effective in psoriasis treatment, according to Dr. Ritchlin

“Psoriatic arthritis, unlike rheumatoid arthritis, is quite complex in its disease manifestation,” said Dr. Ritchlin. “Traditionally, it was defined as an inflammatory arthritis associated with psoriasis. However, it has become clear [it] is a systemic disease that can involve joints, gut mucosa, the uveal tract, and the endothelium, with associated cardiovascular and vascular issues.”

In terms of patient management, “not only do we have to worry about peripheral arthritis, but we also have to be concerned with skin and nail disease, axial disease, dactylitis, and enthesitis,” said Dr. Ritchlin. “It is critical that we approach the therapy of this disease from a global perspective, addressing all of these cardinal issues.”

Clinically, however, such an approach is challenging, as the degree of involvement of each of the heterogenous areas of disease can vary substantially. Anti-TNF-α agents come closer than does methotrexate to achieving the goal of a treatment regimen that is as simple and minimally toxic as possible, said Dr Ritchlin.

BOSTON — Rheumatologists need to rethink their reflex to prescribe methotrexate for psoriatic arthritis given mounting data showing that anti-tumor necrosis factor agents are more effective for this indication, Dr. Christopher Ritchlin said at a rheumatology conference sponsored by Harvard Medical School.

Although methotrexate is often the treatment of choice, “we really don't have evidence that it works for psoriatic arthritis,” Dr. Ritchlin stated. “This is a very large problem. About 70%–80% of clinicians around the world who treat psoriatic arthritis say methotrexate is the first drug that they use, yet the only double-blind randomized controlled trial addressing the question was too underpowered and underdosed to make any conclusions regarding efficacy.”

In addition, there is concern about liver toxicity in psoriasis patients on methotrexate—particularly because psoriasis patients tend to have higher rates of alcoholism—and there is evidence of progression of fibrosis in psoriatic arthritis patients on methotrexate, said Dr. Ritchlin of the University of Rochester (N.Y.). And, unlike with rheumatoid arthritis, there is no evidence that methotrexate is synergistic with other disease-modifying antirheumatic drugs (DMARDs) in psoriatic arthritis, he said, noting that “this is an area in which we are in desperate need of data, but it's hard to get clinical trials designed and funded.”

In contrast, there is a growing body of evidence demonstrating that treatment of psoriatic arthritis with tumor necrosis factor-α (TNF-α) inhibitors safely and effectively controls disease activity at a variety of involved sites. The production of TNF-α has been shown to play a central role in the development of psoriasis and psoriatic arthritis by sustaining the inflammatory process in the skin and the joints, and anti-TNF-α agents appear to effectively block that activity, said Dr. Ritchlin.

Dr. Marte Schrumpf Heiberg of Diakonhjemmet Hospital, Oslo, Norway, has reported data from an ongoing study of the effectiveness of therapy with anti-TNF-α agents infliximab, etanercept, and adalimumab, compared with that of methotrexate in 526 patients with psoriatic arthritis. After 6 months of treatment, patients undergoing anti-TNF-α treatment showed significantly greater clinical improvement in disease measures, compared with those who received metho- trexate mono- therapy (Ann. Rheum. Dis. 2007;66:1038–42). Multiple studies presented at the European League Against Rheumatism meeting in June added to the growing cache of literature supporting anti-TNF-α therapy.

Additional potential therapeutic targets for psoriatic arthritis include both B cells and T cells, as well as the interleukin-23/Th17 pathway, which is directly associated with psoriasis. Specifically, anti-p40 therapy targets an interleukin-23 subunit and has proven very effective in psoriasis treatment, according to Dr. Ritchlin

“Psoriatic arthritis, unlike rheumatoid arthritis, is quite complex in its disease manifestation,” said Dr. Ritchlin. “Traditionally, it was defined as an inflammatory arthritis associated with psoriasis. However, it has become clear [it] is a systemic disease that can involve joints, gut mucosa, the uveal tract, and the endothelium, with associated cardiovascular and vascular issues.”

In terms of patient management, “not only do we have to worry about peripheral arthritis, but we also have to be concerned with skin and nail disease, axial disease, dactylitis, and enthesitis,” said Dr. Ritchlin. “It is critical that we approach the therapy of this disease from a global perspective, addressing all of these cardinal issues.”

Clinically, however, such an approach is challenging, as the degree of involvement of each of the heterogenous areas of disease can vary substantially. Anti-TNF-α agents come closer than does methotrexate to achieving the goal of a treatment regimen that is as simple and minimally toxic as possible, said Dr Ritchlin.

BOSTON – Adolescent girls with polycystic ovary morphology have severe hyperinsulinemia after glucose stimulation, and the degree of insulin elevation is correlated with obesity, a study has shown. The findings emphasize the role of obesity and hyperinsulinemia in the pathophysiology of polycystic ovary syndrome, Dr. Marianna I. Bak said at the Fifth Annual World Congress on the Insulin Resistance Syndrome.

“Hyperinsulinemia directly influences the ovary function by potentialization of [luteinizing hormone] secretion and, as a consequence, may lead to increased ovarian androgen production,” said Dr. Bak of the Medical University of Warsaw. It has been suggested that hyperinsulinemia and luteinizing hormone together could induce the changes that lead to polycystic ovary morphology, such as ovarian stroma and theca interna hyperplasia, and could contribute to menstrual dysfunction in adolescent girls, she said.

For this reason, Dr. Bak and colleagues hypothesized that identifying the subset of adolescent girls with polycystic ovary morphology could provide important information for the role of obesity and hyperinsulinemia in polycystic ovary syndrome (PCOS). Toward this end, the investigators evaluated the insulin resistance, glucose, and insulinogenic response to glucose stimulation in a sample of 13- to 18-year-old girls with clinical manifestations of irregular menstrual cycles and various degrees of polycysticlike ovary morphology on ultrasound, and they correlated circulating insulinemia with ovarian morphology and clinical features.

From a sample of 114 girls who met the study criteria, 36 with a body mass index (BMI) in the normal range (less than 25 kg/m2) and 42 with a BMI in the obese range (greater than 27) were included in the final analysis.

“In all of the studied ovaries, we observed small subcapsular follicles and increased stromal score,” Dr. Bak reported. She noted, however, that the degree of advanced morphologic changes was differentiated based on BMI status. “In 50% of the obese girls, the stromal score was moderately increased [compared with the normal BMI group] and in 30% it was markedly increased,” she said.

All of the girls had biochemical features of various degrees of hyperandrogenemia, and all had normal fasting glucose regardless of their BMI. Although fasting and stimulated insulinemia were increased in both groups, “insulin levels during [OGTT] were markedly higher in obese girls relative to normal BMI subjects,” said Dr. Bak. In fact, “the obese girls had a threefold higher frequency of prediabetes based on oral glucose tolerance testing relative to normal-weight girls with similar ovarian changes.” The latter finding suggests that the measure of insulin with the OGTT should be considered in all obese girls with irregular menstrual cycles, even in the presence of normal fasting plasma glucose “in order to implement the proper early therapy against hyperinsulinemia,” said Dr. Bak. Early intervention is important, she said, because the correlation between hyperinsulinemia and PCOS-like ovarian changes in this population suggests that hyperinsulinemia in adolescent girls could have a significant effect on their fertility.

BOSTON – Adolescent girls with polycystic ovary morphology have severe hyperinsulinemia after glucose stimulation, and the degree of insulin elevation is correlated with obesity, a study has shown. The findings emphasize the role of obesity and hyperinsulinemia in the pathophysiology of polycystic ovary syndrome, Dr. Marianna I. Bak said at the Fifth Annual World Congress on the Insulin Resistance Syndrome.

“Hyperinsulinemia directly influences the ovary function by potentialization of [luteinizing hormone] secretion and, as a consequence, may lead to increased ovarian androgen production,” said Dr. Bak of the Medical University of Warsaw. It has been suggested that hyperinsulinemia and luteinizing hormone together could induce the changes that lead to polycystic ovary morphology, such as ovarian stroma and theca interna hyperplasia, and could contribute to menstrual dysfunction in adolescent girls, she said.

For this reason, Dr. Bak and colleagues hypothesized that identifying the subset of adolescent girls with polycystic ovary morphology could provide important information for the role of obesity and hyperinsulinemia in polycystic ovary syndrome (PCOS). Toward this end, the investigators evaluated the insulin resistance, glucose, and insulinogenic response to glucose stimulation in a sample of 13- to 18-year-old girls with clinical manifestations of irregular menstrual cycles and various degrees of polycysticlike ovary morphology on ultrasound, and they correlated circulating insulinemia with ovarian morphology and clinical features.

From a sample of 114 girls who met the study criteria, 36 with a body mass index (BMI) in the normal range (less than 25 kg/m2) and 42 with a BMI in the obese range (greater than 27) were included in the final analysis.

“In all of the studied ovaries, we observed small subcapsular follicles and increased stromal score,” Dr. Bak reported. She noted, however, that the degree of advanced morphologic changes was differentiated based on BMI status. “In 50% of the obese girls, the stromal score was moderately increased [compared with the normal BMI group] and in 30% it was markedly increased,” she said.

All of the girls had biochemical features of various degrees of hyperandrogenemia, and all had normal fasting glucose regardless of their BMI. Although fasting and stimulated insulinemia were increased in both groups, “insulin levels during [OGTT] were markedly higher in obese girls relative to normal BMI subjects,” said Dr. Bak. In fact, “the obese girls had a threefold higher frequency of prediabetes based on oral glucose tolerance testing relative to normal-weight girls with similar ovarian changes.” The latter finding suggests that the measure of insulin with the OGTT should be considered in all obese girls with irregular menstrual cycles, even in the presence of normal fasting plasma glucose “in order to implement the proper early therapy against hyperinsulinemia,” said Dr. Bak. Early intervention is important, she said, because the correlation between hyperinsulinemia and PCOS-like ovarian changes in this population suggests that hyperinsulinemia in adolescent girls could have a significant effect on their fertility.

BOSTON – Adolescent girls with polycystic ovary morphology have severe hyperinsulinemia after glucose stimulation, and the degree of insulin elevation is correlated with obesity, a study has shown. The findings emphasize the role of obesity and hyperinsulinemia in the pathophysiology of polycystic ovary syndrome, Dr. Marianna I. Bak said at the Fifth Annual World Congress on the Insulin Resistance Syndrome.

“Hyperinsulinemia directly influences the ovary function by potentialization of [luteinizing hormone] secretion and, as a consequence, may lead to increased ovarian androgen production,” said Dr. Bak of the Medical University of Warsaw. It has been suggested that hyperinsulinemia and luteinizing hormone together could induce the changes that lead to polycystic ovary morphology, such as ovarian stroma and theca interna hyperplasia, and could contribute to menstrual dysfunction in adolescent girls, she said.

For this reason, Dr. Bak and colleagues hypothesized that identifying the subset of adolescent girls with polycystic ovary morphology could provide important information for the role of obesity and hyperinsulinemia in polycystic ovary syndrome (PCOS). Toward this end, the investigators evaluated the insulin resistance, glucose, and insulinogenic response to glucose stimulation in a sample of 13- to 18-year-old girls with clinical manifestations of irregular menstrual cycles and various degrees of polycysticlike ovary morphology on ultrasound, and they correlated circulating insulinemia with ovarian morphology and clinical features.

From a sample of 114 girls who met the study criteria, 36 with a body mass index (BMI) in the normal range (less than 25 kg/m2) and 42 with a BMI in the obese range (greater than 27) were included in the final analysis.

“In all of the studied ovaries, we observed small subcapsular follicles and increased stromal score,” Dr. Bak reported. She noted, however, that the degree of advanced morphologic changes was differentiated based on BMI status. “In 50% of the obese girls, the stromal score was moderately increased [compared with the normal BMI group] and in 30% it was markedly increased,” she said.

All of the girls had biochemical features of various degrees of hyperandrogenemia, and all had normal fasting glucose regardless of their BMI. Although fasting and stimulated insulinemia were increased in both groups, “insulin levels during [OGTT] were markedly higher in obese girls relative to normal BMI subjects,” said Dr. Bak. In fact, “the obese girls had a threefold higher frequency of prediabetes based on oral glucose tolerance testing relative to normal-weight girls with similar ovarian changes.” The latter finding suggests that the measure of insulin with the OGTT should be considered in all obese girls with irregular menstrual cycles, even in the presence of normal fasting plasma glucose “in order to implement the proper early therapy against hyperinsulinemia,” said Dr. Bak. Early intervention is important, she said, because the correlation between hyperinsulinemia and PCOS-like ovarian changes in this population suggests that hyperinsulinemia in adolescent girls could have a significant effect on their fertility.

BOSTON — Women with bacterial vaginosis who fail initial treatment with either metronidazole or clindamycin may respond favorably to subsequent treatment with the same medication, results of a small study have shown.

Using data from 119 nonpregnant women with bacterial vaginosis who participated in a randomized controlled trial comparing topical metronidazole with topical clindamycin for the treatment of bacterial vaginosis, Dr. Katherine E. Bunge of the University of Pittsburgh Magee-Womens Research Institute and her colleagues conducted a nested cohort investigation to compare retreatment cure rates in women who failed initial treatment with either of these drugs. For the purposes of this study, bacterial vaginosis was defined clinically as the presence of at least three of the four Amsel's criteria.

Participants were randomized to receive metronidazole for 5 days or clindamycin for 3 days and were asked to return for follow-up visits at 7–12 days post treatment, 35–45 days post treatment, and 70–90 days post treatment. “At each [follow-up visit], the women were assessed for clinical cure of bacterial vaginosis, defined as less than two Amsel's criteria,” Dr. Bunge said at the annual meeting of the Infectious Diseases Society for Obstetrics and Gynecology.

Study protocol dictated that women with early treatment failure, defined as clinical evidence of bacterial vaginosis at either the second or third follow-up visit, should be prescribed a second course of the medication to which they were initially randomized.

Of the initial 119 patients enrolled in the larger randomized controlled trial study, 104 had adequate clinical data for inclusion in the subgroup analysis. Of these women, 51 had evidence of failed initial treatment at follow-up visit two or three and 33 were retreated with the same medication they were initially randomized to receive, said Dr. Bunge. “These 33 women make up the cohort in this study,” she said, noting that 19 of the women had been randomized initially to metronidazole treatment and 14 to clindamycin treatment. The mean age of the predominantly nonwhite cohort was 27 years.

Overall, 21 of the 33 women with a single early clinical failure responded successfully to retreatment, “giving a cure rate of 64%,” Dr. Bunge reported. Retreatment resulted in 11 cures in the metronidazole arm and 10 in the clindamycin arm. There was no statistical significance in the difference between the respective cure rates of 58% and 71%, she said.

While the study was not powered to detect differences between women in whom retreatment was and was not successful, said Dr. Bunge, “there were no obvious differences between the two groups in terms of therapy, smoking, age, race, or bacterial vaginosis history.”

Of the 12 women who experienced a second treatment failure, only 2 received a third course of the same medication to which they were initially randomized and neither had clinical evidence of cure at the subsequent follow-up. The remaining 10 women with two treatment failures were retreated with a different medication, “but only 2 experienced cure at follow-up,” said Dr. Bunge. “This suggests that women who experience repetitive early treatment failures are unlikely to respond favorably to retreatment.”

The study is limited by its small size, Dr. Bunge noted. “Unfortunately, only 65% of the early treatment failures were retreated with the same medication, as had been our intention.” In addition, she said, “long-term follow-up data were not available.”

Despite the limitations, the findings do lead to the conclusion that for women who experience a single early treatment failure, “retreatment with the same medication is a reasonable approach,” said Dr. Bunge. This is important, she added, “because early treatment failure of bacterial vaginosis is a common problem, and there is [a scarcity of] data that remotely touch on the best management course.”

BOSTON — Women with bacterial vaginosis who fail initial treatment with either metronidazole or clindamycin may respond favorably to subsequent treatment with the same medication, results of a small study have shown.

Using data from 119 nonpregnant women with bacterial vaginosis who participated in a randomized controlled trial comparing topical metronidazole with topical clindamycin for the treatment of bacterial vaginosis, Dr. Katherine E. Bunge of the University of Pittsburgh Magee-Womens Research Institute and her colleagues conducted a nested cohort investigation to compare retreatment cure rates in women who failed initial treatment with either of these drugs. For the purposes of this study, bacterial vaginosis was defined clinically as the presence of at least three of the four Amsel's criteria.

Participants were randomized to receive metronidazole for 5 days or clindamycin for 3 days and were asked to return for follow-up visits at 7–12 days post treatment, 35–45 days post treatment, and 70–90 days post treatment. “At each [follow-up visit], the women were assessed for clinical cure of bacterial vaginosis, defined as less than two Amsel's criteria,” Dr. Bunge said at the annual meeting of the Infectious Diseases Society for Obstetrics and Gynecology.

Study protocol dictated that women with early treatment failure, defined as clinical evidence of bacterial vaginosis at either the second or third follow-up visit, should be prescribed a second course of the medication to which they were initially randomized.

Of the initial 119 patients enrolled in the larger randomized controlled trial study, 104 had adequate clinical data for inclusion in the subgroup analysis. Of these women, 51 had evidence of failed initial treatment at follow-up visit two or three and 33 were retreated with the same medication they were initially randomized to receive, said Dr. Bunge. “These 33 women make up the cohort in this study,” she said, noting that 19 of the women had been randomized initially to metronidazole treatment and 14 to clindamycin treatment. The mean age of the predominantly nonwhite cohort was 27 years.

Overall, 21 of the 33 women with a single early clinical failure responded successfully to retreatment, “giving a cure rate of 64%,” Dr. Bunge reported. Retreatment resulted in 11 cures in the metronidazole arm and 10 in the clindamycin arm. There was no statistical significance in the difference between the respective cure rates of 58% and 71%, she said.

While the study was not powered to detect differences between women in whom retreatment was and was not successful, said Dr. Bunge, “there were no obvious differences between the two groups in terms of therapy, smoking, age, race, or bacterial vaginosis history.”

Of the 12 women who experienced a second treatment failure, only 2 received a third course of the same medication to which they were initially randomized and neither had clinical evidence of cure at the subsequent follow-up. The remaining 10 women with two treatment failures were retreated with a different medication, “but only 2 experienced cure at follow-up,” said Dr. Bunge. “This suggests that women who experience repetitive early treatment failures are unlikely to respond favorably to retreatment.”

The study is limited by its small size, Dr. Bunge noted. “Unfortunately, only 65% of the early treatment failures were retreated with the same medication, as had been our intention.” In addition, she said, “long-term follow-up data were not available.”

Despite the limitations, the findings do lead to the conclusion that for women who experience a single early treatment failure, “retreatment with the same medication is a reasonable approach,” said Dr. Bunge. This is important, she added, “because early treatment failure of bacterial vaginosis is a common problem, and there is [a scarcity of] data that remotely touch on the best management course.”

BOSTON — Women with bacterial vaginosis who fail initial treatment with either metronidazole or clindamycin may respond favorably to subsequent treatment with the same medication, results of a small study have shown.

Using data from 119 nonpregnant women with bacterial vaginosis who participated in a randomized controlled trial comparing topical metronidazole with topical clindamycin for the treatment of bacterial vaginosis, Dr. Katherine E. Bunge of the University of Pittsburgh Magee-Womens Research Institute and her colleagues conducted a nested cohort investigation to compare retreatment cure rates in women who failed initial treatment with either of these drugs. For the purposes of this study, bacterial vaginosis was defined clinically as the presence of at least three of the four Amsel's criteria.

Participants were randomized to receive metronidazole for 5 days or clindamycin for 3 days and were asked to return for follow-up visits at 7–12 days post treatment, 35–45 days post treatment, and 70–90 days post treatment. “At each [follow-up visit], the women were assessed for clinical cure of bacterial vaginosis, defined as less than two Amsel's criteria,” Dr. Bunge said at the annual meeting of the Infectious Diseases Society for Obstetrics and Gynecology.

Study protocol dictated that women with early treatment failure, defined as clinical evidence of bacterial vaginosis at either the second or third follow-up visit, should be prescribed a second course of the medication to which they were initially randomized.

Of the initial 119 patients enrolled in the larger randomized controlled trial study, 104 had adequate clinical data for inclusion in the subgroup analysis. Of these women, 51 had evidence of failed initial treatment at follow-up visit two or three and 33 were retreated with the same medication they were initially randomized to receive, said Dr. Bunge. “These 33 women make up the cohort in this study,” she said, noting that 19 of the women had been randomized initially to metronidazole treatment and 14 to clindamycin treatment. The mean age of the predominantly nonwhite cohort was 27 years.

Overall, 21 of the 33 women with a single early clinical failure responded successfully to retreatment, “giving a cure rate of 64%,” Dr. Bunge reported. Retreatment resulted in 11 cures in the metronidazole arm and 10 in the clindamycin arm. There was no statistical significance in the difference between the respective cure rates of 58% and 71%, she said.

While the study was not powered to detect differences between women in whom retreatment was and was not successful, said Dr. Bunge, “there were no obvious differences between the two groups in terms of therapy, smoking, age, race, or bacterial vaginosis history.”

Of the 12 women who experienced a second treatment failure, only 2 received a third course of the same medication to which they were initially randomized and neither had clinical evidence of cure at the subsequent follow-up. The remaining 10 women with two treatment failures were retreated with a different medication, “but only 2 experienced cure at follow-up,” said Dr. Bunge. “This suggests that women who experience repetitive early treatment failures are unlikely to respond favorably to retreatment.”

The study is limited by its small size, Dr. Bunge noted. “Unfortunately, only 65% of the early treatment failures were retreated with the same medication, as had been our intention.” In addition, she said, “long-term follow-up data were not available.”

Despite the limitations, the findings do lead to the conclusion that for women who experience a single early treatment failure, “retreatment with the same medication is a reasonable approach,” said Dr. Bunge. This is important, she added, “because early treatment failure of bacterial vaginosis is a common problem, and there is [a scarcity of] data that remotely touch on the best management course.”

BOSTON — Adolescent girls with polycystic ovary morphology have severe hyperinsulinemia after glucose stimulation, and the degree of insulin elevation is correlated with obesity, a study has shown. The findings emphasize the role of obesity and hyperinsulinemia in the pathophysiology of polycystic ovary syndrome, Dr. Marianna I. Bak said at the Fifth Annual World Congress on the Insulin Resistance Syndrome.

“Hyperinsulinemia directly influences the ovary function by potentialization of [luteinizing hormone] secretion and, as a consequence, may lead to increased ovarian androgen production,” said Dr. Bak of the Medical University of Warsaw. It has been suggested that hyperinsulinemia and luteinizing hormone together could induce the changes that lead to polycystic ovary morphology, such as ovarian stroma and theca interna hyperplasia, and could contribute to menstrual dysfunction in adolescent girls, she said.

For this reason, Dr. Bak and colleagues hypothesized that identifying the subset of adolescent girls with polycystic ovary morphology could provide important information for the role of obesity and hyperinsulinemia in polycystic ovary syndrome (PCOS). They evaluated the insulin resistance, glucose, and insulinogenic response to glucose stimulation in a sample of 13- to 18-year-old girls with clinical manifestations of irregular menstrual cycles and various degrees of polycysticlike ovary morphology on ultrasound, and they correlated circulating insulinemia with ovarian morphology and clinical features.

Of the 114 girls who met the study criteria, 36 with a body mass index (BMI) in the normal range (less than 25 kg/m

“In all of the studied ovaries, we observed small subcapsular follicles and increased stromal score,” Dr. Bak reported. She noted, however, that the degree of advanced morphological changes was differentiated based on BMI status. “In 50% of the obese girls, the stromal score was moderately increased [compared with the normal BMI group] and in 30% it was markedly increased,” she said.

All of the girls had biochemical features of various degrees of hyperandrogenemia, and all had normal fasting glucose regardless of their BMI. In addition, although fasting and stimulated insulinemia were increased in both groups, “insulin levels during [OGTT] were markedly higher in obese girls relative to normal BMI subjects,” said Dr. Bak. In fact, “the obese girls had a threefold higher frequency of prediabetes based on oral glucose tolerance testing relative to normal-weight girls with similar ovarian changes.”

The latter finding suggests that the measure of insulin with the OGTT should be considered in all obese girls with irregular menstrual cycles, even in the presence of normal fasting plasma glucose “in order to implement the proper early therapy against hyperinsulinemia,” said Dr. Bak. Early intervention is important, she said, because the correlation between hyperinsulinemia and PCOS-like ovarian changes in this population suggests that hyperinsulinemia in adolescent girls could have a significant effect on their fertility.

BOSTON — Adolescent girls with polycystic ovary morphology have severe hyperinsulinemia after glucose stimulation, and the degree of insulin elevation is correlated with obesity, a study has shown. The findings emphasize the role of obesity and hyperinsulinemia in the pathophysiology of polycystic ovary syndrome, Dr. Marianna I. Bak said at the Fifth Annual World Congress on the Insulin Resistance Syndrome.

“Hyperinsulinemia directly influences the ovary function by potentialization of [luteinizing hormone] secretion and, as a consequence, may lead to increased ovarian androgen production,” said Dr. Bak of the Medical University of Warsaw. It has been suggested that hyperinsulinemia and luteinizing hormone together could induce the changes that lead to polycystic ovary morphology, such as ovarian stroma and theca interna hyperplasia, and could contribute to menstrual dysfunction in adolescent girls, she said.

For this reason, Dr. Bak and colleagues hypothesized that identifying the subset of adolescent girls with polycystic ovary morphology could provide important information for the role of obesity and hyperinsulinemia in polycystic ovary syndrome (PCOS). They evaluated the insulin resistance, glucose, and insulinogenic response to glucose stimulation in a sample of 13- to 18-year-old girls with clinical manifestations of irregular menstrual cycles and various degrees of polycysticlike ovary morphology on ultrasound, and they correlated circulating insulinemia with ovarian morphology and clinical features.

Of the 114 girls who met the study criteria, 36 with a body mass index (BMI) in the normal range (less than 25 kg/m

“In all of the studied ovaries, we observed small subcapsular follicles and increased stromal score,” Dr. Bak reported. She noted, however, that the degree of advanced morphological changes was differentiated based on BMI status. “In 50% of the obese girls, the stromal score was moderately increased [compared with the normal BMI group] and in 30% it was markedly increased,” she said.

All of the girls had biochemical features of various degrees of hyperandrogenemia, and all had normal fasting glucose regardless of their BMI. In addition, although fasting and stimulated insulinemia were increased in both groups, “insulin levels during [OGTT] were markedly higher in obese girls relative to normal BMI subjects,” said Dr. Bak. In fact, “the obese girls had a threefold higher frequency of prediabetes based on oral glucose tolerance testing relative to normal-weight girls with similar ovarian changes.”

The latter finding suggests that the measure of insulin with the OGTT should be considered in all obese girls with irregular menstrual cycles, even in the presence of normal fasting plasma glucose “in order to implement the proper early therapy against hyperinsulinemia,” said Dr. Bak. Early intervention is important, she said, because the correlation between hyperinsulinemia and PCOS-like ovarian changes in this population suggests that hyperinsulinemia in adolescent girls could have a significant effect on their fertility.

BOSTON — Adolescent girls with polycystic ovary morphology have severe hyperinsulinemia after glucose stimulation, and the degree of insulin elevation is correlated with obesity, a study has shown. The findings emphasize the role of obesity and hyperinsulinemia in the pathophysiology of polycystic ovary syndrome, Dr. Marianna I. Bak said at the Fifth Annual World Congress on the Insulin Resistance Syndrome.

“Hyperinsulinemia directly influences the ovary function by potentialization of [luteinizing hormone] secretion and, as a consequence, may lead to increased ovarian androgen production,” said Dr. Bak of the Medical University of Warsaw. It has been suggested that hyperinsulinemia and luteinizing hormone together could induce the changes that lead to polycystic ovary morphology, such as ovarian stroma and theca interna hyperplasia, and could contribute to menstrual dysfunction in adolescent girls, she said.

For this reason, Dr. Bak and colleagues hypothesized that identifying the subset of adolescent girls with polycystic ovary morphology could provide important information for the role of obesity and hyperinsulinemia in polycystic ovary syndrome (PCOS). They evaluated the insulin resistance, glucose, and insulinogenic response to glucose stimulation in a sample of 13- to 18-year-old girls with clinical manifestations of irregular menstrual cycles and various degrees of polycysticlike ovary morphology on ultrasound, and they correlated circulating insulinemia with ovarian morphology and clinical features.

Of the 114 girls who met the study criteria, 36 with a body mass index (BMI) in the normal range (less than 25 kg/m

“In all of the studied ovaries, we observed small subcapsular follicles and increased stromal score,” Dr. Bak reported. She noted, however, that the degree of advanced morphological changes was differentiated based on BMI status. “In 50% of the obese girls, the stromal score was moderately increased [compared with the normal BMI group] and in 30% it was markedly increased,” she said.

All of the girls had biochemical features of various degrees of hyperandrogenemia, and all had normal fasting glucose regardless of their BMI. In addition, although fasting and stimulated insulinemia were increased in both groups, “insulin levels during [OGTT] were markedly higher in obese girls relative to normal BMI subjects,” said Dr. Bak. In fact, “the obese girls had a threefold higher frequency of prediabetes based on oral glucose tolerance testing relative to normal-weight girls with similar ovarian changes.”

The latter finding suggests that the measure of insulin with the OGTT should be considered in all obese girls with irregular menstrual cycles, even in the presence of normal fasting plasma glucose “in order to implement the proper early therapy against hyperinsulinemia,” said Dr. Bak. Early intervention is important, she said, because the correlation between hyperinsulinemia and PCOS-like ovarian changes in this population suggests that hyperinsulinemia in adolescent girls could have a significant effect on their fertility.

BOSTON — Treatment with metformin significantly improves body mass index and other metabolic parameters in women with polycystic ovary syndrome and significantly decreases the prevalence of metabolic syndrome in this population, a retrospective study has shown.

The findings confirm the utility of metformin, coupled with diet and exercise, as a primary therapy for minimizing the long-term risks of developing metabolic syndrome-associated cardiovascular disease and diabetes in women with the hormonal disorder, Kai I. Cheang, Pharm.D., said at the Fifth Annual World Congress on the Insulin Resistance Syndrome.

To date, short-term studies have demonstrated beneficial metabolic effects associated with metformin in women with polycystic ovary syndrome (PCOS), but long-term data have been lacking, according to Dr. Cheang, of Virginia Commonwealth University, Richmond.

To assess the impact of long-term metformin use, Dr. Cheang and colleagues reviewed the charts of consecutive PCOS patients treated at the university-affiliated clinic from 2000 to 2005. Patients with more than 6 months of treatment with metformin were included in the final analysis if baseline and follow-up assessments of metabolic syndrome parameters were available. Those patients with diabetes at baseline and those taking other medications that would affect metabolic parameters, such as thiazolidinediones, weight-loss agents, antihypertensives, lipid- lowering agents, or antidiabetic agents, were excluded.

Of the nearly 250 PCOS patients treated with metformin during the study period, 71 met the inclusion criteria; their mean age was 31.2 years. For the purposes of the investigation, metabolic syndrome was defined by National Cholesterol Education Program Adult Treatment Panel III (ATP-III) criteria, with the exception of waist circumference; body mass index (BMI) was substituted for that criterion.

“This is because waist circumference was not available for most of the patients,” Dr. Cheang noted. “Based on correlation between BMI and waist circumference of local PCOS women with PCOS women who entered into our clinical studies, we determined the BMI cut-off value corresponding to a waist circumference of 88 cm was 32 kg/m

The average period from initiation of metformin therapy to the most recent assessment for the study population was 31 months. The data for those who began lipid-lowering or antihypertensive therapy during follow-up were analyzed up until the beginning of such therapy, said Dr. Cheang.

The investigators assessed baseline and follow-up metabolic syndrome parameters using a two-sided student's paired t test and observed that, compared with baseline, follow-up values for BMI, diastolic blood pressure, and high-density lipoprotein were significantly improved with metformin therapy, Dr. Cheang reported. Additionally, metformin therapy significantly decreased the overall prevalence of metabolic syndrome from 31% at baseline to 14% following 31 months of treatment. Observed improvements in systolic blood pressure, triglycerides, and fasting glucose measures did not reach statistical significance.

The findings were limited by the study's retrospective design, Dr. Cheang said. “As information was not being collected specifically for the study, certain data [were] not available for all patients.” The time between patient visits was inconsistent, and there is a possibility of selection bias because the clinic from which the patient pool was collected specializes in PCOS care, she said.

According to study coauthor Dr. John E. Nestler, chair of the university's division of endocrinology and metabolism, previous studies have shown that treatment with metformin, coupled with diet and exercise, improves ovulation and lowers androgens in PCOS women and possibly prevents or retards progression to glucose intolerance. With these new data, “[metformin treatment] also appears to ameliorate several components of the metabolic syndrome,” he said in an interview.

The clinical significance of these findings is substantial, given the extremely high risk for the metabolic disorder in PCOS, he said.

No conflicts of interest were reported relative to this study.

BOSTON — Treatment with metformin significantly improves body mass index and other metabolic parameters in women with polycystic ovary syndrome and significantly decreases the prevalence of metabolic syndrome in this population, a retrospective study has shown.

The findings confirm the utility of metformin, coupled with diet and exercise, as a primary therapy for minimizing the long-term risks of developing metabolic syndrome-associated cardiovascular disease and diabetes in women with the hormonal disorder, Kai I. Cheang, Pharm.D., said at the Fifth Annual World Congress on the Insulin Resistance Syndrome.

To date, short-term studies have demonstrated beneficial metabolic effects associated with metformin in women with polycystic ovary syndrome (PCOS), but long-term data have been lacking, according to Dr. Cheang, of Virginia Commonwealth University, Richmond.

To assess the impact of long-term metformin use, Dr. Cheang and colleagues reviewed the charts of consecutive PCOS patients treated at the university-affiliated clinic from 2000 to 2005. Patients with more than 6 months of treatment with metformin were included in the final analysis if baseline and follow-up assessments of metabolic syndrome parameters were available. Those patients with diabetes at baseline and those taking other medications that would affect metabolic parameters, such as thiazolidinediones, weight-loss agents, antihypertensives, lipid- lowering agents, or antidiabetic agents, were excluded.

Of the nearly 250 PCOS patients treated with metformin during the study period, 71 met the inclusion criteria; their mean age was 31.2 years. For the purposes of the investigation, metabolic syndrome was defined by National Cholesterol Education Program Adult Treatment Panel III (ATP-III) criteria, with the exception of waist circumference; body mass index (BMI) was substituted for that criterion.

“This is because waist circumference was not available for most of the patients,” Dr. Cheang noted. “Based on correlation between BMI and waist circumference of local PCOS women with PCOS women who entered into our clinical studies, we determined the BMI cut-off value corresponding to a waist circumference of 88 cm was 32 kg/m

The average period from initiation of metformin therapy to the most recent assessment for the study population was 31 months. The data for those who began lipid-lowering or antihypertensive therapy during follow-up were analyzed up until the beginning of such therapy, said Dr. Cheang.

The investigators assessed baseline and follow-up metabolic syndrome parameters using a two-sided student's paired t test and observed that, compared with baseline, follow-up values for BMI, diastolic blood pressure, and high-density lipoprotein were significantly improved with metformin therapy, Dr. Cheang reported. Additionally, metformin therapy significantly decreased the overall prevalence of metabolic syndrome from 31% at baseline to 14% following 31 months of treatment. Observed improvements in systolic blood pressure, triglycerides, and fasting glucose measures did not reach statistical significance.

The findings were limited by the study's retrospective design, Dr. Cheang said. “As information was not being collected specifically for the study, certain data [were] not available for all patients.” The time between patient visits was inconsistent, and there is a possibility of selection bias because the clinic from which the patient pool was collected specializes in PCOS care, she said.

According to study coauthor Dr. John E. Nestler, chair of the university's division of endocrinology and metabolism, previous studies have shown that treatment with metformin, coupled with diet and exercise, improves ovulation and lowers androgens in PCOS women and possibly prevents or retards progression to glucose intolerance. With these new data, “[metformin treatment] also appears to ameliorate several components of the metabolic syndrome,” he said in an interview.

The clinical significance of these findings is substantial, given the extremely high risk for the metabolic disorder in PCOS, he said.

No conflicts of interest were reported relative to this study.

BOSTON — Treatment with metformin significantly improves body mass index and other metabolic parameters in women with polycystic ovary syndrome and significantly decreases the prevalence of metabolic syndrome in this population, a retrospective study has shown.

The findings confirm the utility of metformin, coupled with diet and exercise, as a primary therapy for minimizing the long-term risks of developing metabolic syndrome-associated cardiovascular disease and diabetes in women with the hormonal disorder, Kai I. Cheang, Pharm.D., said at the Fifth Annual World Congress on the Insulin Resistance Syndrome.

To date, short-term studies have demonstrated beneficial metabolic effects associated with metformin in women with polycystic ovary syndrome (PCOS), but long-term data have been lacking, according to Dr. Cheang, of Virginia Commonwealth University, Richmond.

To assess the impact of long-term metformin use, Dr. Cheang and colleagues reviewed the charts of consecutive PCOS patients treated at the university-affiliated clinic from 2000 to 2005. Patients with more than 6 months of treatment with metformin were included in the final analysis if baseline and follow-up assessments of metabolic syndrome parameters were available. Those patients with diabetes at baseline and those taking other medications that would affect metabolic parameters, such as thiazolidinediones, weight-loss agents, antihypertensives, lipid- lowering agents, or antidiabetic agents, were excluded.

Of the nearly 250 PCOS patients treated with metformin during the study period, 71 met the inclusion criteria; their mean age was 31.2 years. For the purposes of the investigation, metabolic syndrome was defined by National Cholesterol Education Program Adult Treatment Panel III (ATP-III) criteria, with the exception of waist circumference; body mass index (BMI) was substituted for that criterion.

“This is because waist circumference was not available for most of the patients,” Dr. Cheang noted. “Based on correlation between BMI and waist circumference of local PCOS women with PCOS women who entered into our clinical studies, we determined the BMI cut-off value corresponding to a waist circumference of 88 cm was 32 kg/m

The average period from initiation of metformin therapy to the most recent assessment for the study population was 31 months. The data for those who began lipid-lowering or antihypertensive therapy during follow-up were analyzed up until the beginning of such therapy, said Dr. Cheang.

The investigators assessed baseline and follow-up metabolic syndrome parameters using a two-sided student's paired t test and observed that, compared with baseline, follow-up values for BMI, diastolic blood pressure, and high-density lipoprotein were significantly improved with metformin therapy, Dr. Cheang reported. Additionally, metformin therapy significantly decreased the overall prevalence of metabolic syndrome from 31% at baseline to 14% following 31 months of treatment. Observed improvements in systolic blood pressure, triglycerides, and fasting glucose measures did not reach statistical significance.

The findings were limited by the study's retrospective design, Dr. Cheang said. “As information was not being collected specifically for the study, certain data [were] not available for all patients.” The time between patient visits was inconsistent, and there is a possibility of selection bias because the clinic from which the patient pool was collected specializes in PCOS care, she said.

According to study coauthor Dr. John E. Nestler, chair of the university's division of endocrinology and metabolism, previous studies have shown that treatment with metformin, coupled with diet and exercise, improves ovulation and lowers androgens in PCOS women and possibly prevents or retards progression to glucose intolerance. With these new data, “[metformin treatment] also appears to ameliorate several components of the metabolic syndrome,” he said in an interview.

The clinical significance of these findings is substantial, given the extremely high risk for the metabolic disorder in PCOS, he said.

No conflicts of interest were reported relative to this study.

BOSTON — The current standard of care for initial treatment of severe Wegener's granulomatosis and microscopic polyangiitis—glucocorticoids plus daily oral or pulse intravenous cyclophosphamide—is far from perfect, according to Dr. Peter A. Merkel of Boston University Medical Center.

“In randomized controlled trials, the remission rate with severe disease associated with this treatment is less than 90%, and sometimes less than 80%, so there are still a substantial number of patients who never reach remission,” Dr. Merkel said at a meeting on rheumatology sponsored by Harvard Medical School. Even when initial treatment induces remission, the risk of relapse and retreatment is high. Moreover, prolonged cyclophosphamide use has been tied to ovarian/testicular failure, bladder carcinoma and hemorrhage, cystitis, infections, and myelodysplasia.

“Because most rheumatologists don't have a high volume of patients with these diseases, most don't have a lot of personal, anecdotal experience with cyclophosphamide treatment, which can lead to problems,” said Dr. Merkel.

“One of the biggest problems I see is undertreatment,” Dr. Merkel noted. “All of the studies and trials use 2 mg/kg per day as the treatment goal, adjusting for renal disease as necessary,” while in practice patients are often receiving less. “It's better to give the right dose up front and adjust down if need be. Many patients require dose reductions. That's fine. It doesn't mean the therapy is wrong.”

Overdosage is also common. “Often, adjustments for renal disease are not being made, and they must be,” said Dr. Merkel. “The goal is not neutropenia, although sustained lymphopenia is associated with prolonged remission.”

Another roadblock to optimal therapy is inadequate lab testing. “There should be labs done on these patients every week initially, certainly no less frequently than every 2 weeks,” said Dr. Merkel. “White count values can drop pretty quickly, which is typically what happens in those patients who end up with neutropenia and sepsis. Often those outcomes could have been prevented with proper monitoring.” Unfortunately, clinicians' tendency to become lax over the course of cyclophosphamide therapy coincides with a patient's most vulnerable period. “This is when steroids are being tapered and the risk of cumulative cyclophosphamide toxicity is greatest.”

With frequent lab testing, “you can anticipate white count drops, and when you see a trend, you can start adjusting, rather than waiting until the count has dropped so low that treatment has to be stopped entirely,” said Dr. Merkel.

Other tips include avoiding twice-daily or evening dosing, “because the cyclophosphamide can accumulate in the bladder overnight.” Encourage hyperhydration to prevent cyclophosphamide-induced cystitis, Dr. Merkel stated.

One of the most prevalent treatment inadequacies “is failing to spend enough time talking to patients about cyclophosphamide,” said Dr. Merkel. “This is a toxic drug and patients need to be educated about it. For example, they need not only to know that they have to drink water, but also why they must drink water and why they should take the drug early in the day. This should be a long conversation, not just an aside.”

BOSTON — The current standard of care for initial treatment of severe Wegener's granulomatosis and microscopic polyangiitis—glucocorticoids plus daily oral or pulse intravenous cyclophosphamide—is far from perfect, according to Dr. Peter A. Merkel of Boston University Medical Center.

“In randomized controlled trials, the remission rate with severe disease associated with this treatment is less than 90%, and sometimes less than 80%, so there are still a substantial number of patients who never reach remission,” Dr. Merkel said at a meeting on rheumatology sponsored by Harvard Medical School. Even when initial treatment induces remission, the risk of relapse and retreatment is high. Moreover, prolonged cyclophosphamide use has been tied to ovarian/testicular failure, bladder carcinoma and hemorrhage, cystitis, infections, and myelodysplasia.

“Because most rheumatologists don't have a high volume of patients with these diseases, most don't have a lot of personal, anecdotal experience with cyclophosphamide treatment, which can lead to problems,” said Dr. Merkel.

“One of the biggest problems I see is undertreatment,” Dr. Merkel noted. “All of the studies and trials use 2 mg/kg per day as the treatment goal, adjusting for renal disease as necessary,” while in practice patients are often receiving less. “It's better to give the right dose up front and adjust down if need be. Many patients require dose reductions. That's fine. It doesn't mean the therapy is wrong.”

Overdosage is also common. “Often, adjustments for renal disease are not being made, and they must be,” said Dr. Merkel. “The goal is not neutropenia, although sustained lymphopenia is associated with prolonged remission.”

Another roadblock to optimal therapy is inadequate lab testing. “There should be labs done on these patients every week initially, certainly no less frequently than every 2 weeks,” said Dr. Merkel. “White count values can drop pretty quickly, which is typically what happens in those patients who end up with neutropenia and sepsis. Often those outcomes could have been prevented with proper monitoring.” Unfortunately, clinicians' tendency to become lax over the course of cyclophosphamide therapy coincides with a patient's most vulnerable period. “This is when steroids are being tapered and the risk of cumulative cyclophosphamide toxicity is greatest.”

With frequent lab testing, “you can anticipate white count drops, and when you see a trend, you can start adjusting, rather than waiting until the count has dropped so low that treatment has to be stopped entirely,” said Dr. Merkel.

Other tips include avoiding twice-daily or evening dosing, “because the cyclophosphamide can accumulate in the bladder overnight.” Encourage hyperhydration to prevent cyclophosphamide-induced cystitis, Dr. Merkel stated.

One of the most prevalent treatment inadequacies “is failing to spend enough time talking to patients about cyclophosphamide,” said Dr. Merkel. “This is a toxic drug and patients need to be educated about it. For example, they need not only to know that they have to drink water, but also why they must drink water and why they should take the drug early in the day. This should be a long conversation, not just an aside.”

BOSTON — The current standard of care for initial treatment of severe Wegener's granulomatosis and microscopic polyangiitis—glucocorticoids plus daily oral or pulse intravenous cyclophosphamide—is far from perfect, according to Dr. Peter A. Merkel of Boston University Medical Center.

“In randomized controlled trials, the remission rate with severe disease associated with this treatment is less than 90%, and sometimes less than 80%, so there are still a substantial number of patients who never reach remission,” Dr. Merkel said at a meeting on rheumatology sponsored by Harvard Medical School. Even when initial treatment induces remission, the risk of relapse and retreatment is high. Moreover, prolonged cyclophosphamide use has been tied to ovarian/testicular failure, bladder carcinoma and hemorrhage, cystitis, infections, and myelodysplasia.

“Because most rheumatologists don't have a high volume of patients with these diseases, most don't have a lot of personal, anecdotal experience with cyclophosphamide treatment, which can lead to problems,” said Dr. Merkel.

“One of the biggest problems I see is undertreatment,” Dr. Merkel noted. “All of the studies and trials use 2 mg/kg per day as the treatment goal, adjusting for renal disease as necessary,” while in practice patients are often receiving less. “It's better to give the right dose up front and adjust down if need be. Many patients require dose reductions. That's fine. It doesn't mean the therapy is wrong.”

Overdosage is also common. “Often, adjustments for renal disease are not being made, and they must be,” said Dr. Merkel. “The goal is not neutropenia, although sustained lymphopenia is associated with prolonged remission.”

Another roadblock to optimal therapy is inadequate lab testing. “There should be labs done on these patients every week initially, certainly no less frequently than every 2 weeks,” said Dr. Merkel. “White count values can drop pretty quickly, which is typically what happens in those patients who end up with neutropenia and sepsis. Often those outcomes could have been prevented with proper monitoring.” Unfortunately, clinicians' tendency to become lax over the course of cyclophosphamide therapy coincides with a patient's most vulnerable period. “This is when steroids are being tapered and the risk of cumulative cyclophosphamide toxicity is greatest.”

With frequent lab testing, “you can anticipate white count drops, and when you see a trend, you can start adjusting, rather than waiting until the count has dropped so low that treatment has to be stopped entirely,” said Dr. Merkel.

Other tips include avoiding twice-daily or evening dosing, “because the cyclophosphamide can accumulate in the bladder overnight.” Encourage hyperhydration to prevent cyclophosphamide-induced cystitis, Dr. Merkel stated.

One of the most prevalent treatment inadequacies “is failing to spend enough time talking to patients about cyclophosphamide,” said Dr. Merkel. “This is a toxic drug and patients need to be educated about it. For example, they need not only to know that they have to drink water, but also why they must drink water and why they should take the drug early in the day. This should be a long conversation, not just an aside.”

BOSTON — Despite the availability of “pretty good therapies” for Wegener's granulomatosis and microscopic polyangiitis, “these forms of small-vessel vasculitis still regularly kill people, so do not underestimate the misery associated with them,” said Dr. Peter Merkel at a meeting on rheumatology sponsored by Harvard Medical School.

“These are bad diseases that cause major, permanent damage to multiple organ systems,” said Dr. Merkel of Boston University. “While the available treatments can effectively induce remission in some patients, many other patients die. Some die early from hemorrhage or other problems; some die later from concurrent disease or treatment toxicity. The important thing to remember is that these diseases kill.”

The first line of defense against such an outcome is the accurate diagnosis of acute disease, and early, aggressive therapy. Unfortunately, a number of obstacles can get in the way of both, Dr. Merkel said.

Because these conditions are relatively rare, “many rheumatologists don't see a lot of these patients and thus do not have a good sense of the spectrum of the disease and its presentations,” he noted.

When a patient presents with symptoms suggestive of acute vasculitis, “the first thing to do is look for trouble,” said Dr. Merkel. “There's always more to acute vasculitis than you think. If you look for trouble, you will almost certainly find it, and this is important because you want to find and treat the worst part of the disease first.” A good evaluation for potential small-vessel vasculitis should include a full medical history and physical. “This is not a 20-minute visit. It requires a long, comprehensive examination with a full set of labs,” Dr. Merkel stressed. “Certainly, one of the first things is to get a urine specimen to assess possible kidney involvement, and, for dipstick positive specimens, you have to be willing and able to do a microscopic examination of the urinary sediment right then and there,” he said. “Early changes in urine are critical to evaluating these patients, and in order to identify such changes, the specimen for microscopic examination has to be as fresh as possible. If you send the specimen to the lab, the red cells and formed solids will have disintegrated.”

Unfortunately, microscopic examination of urine sediment is a “lost art,” said Dr. Merkel. “It requires a degree of skill acquired through practice. It's hard to get used to doing if you're not seeing hundreds of patients with these diseases, and most rheumatologists are not seeing hundreds of these patients,” he said.

“However, if you're not comfortable doing this, you cannot take care of these patients on your own.”

Testing for antineutrophil cytoplasmic antibodies (ANCA) is also necessary. “Although there is a subset of patients who test negative for ANCA, a positive test is a useful diagnostic and prognostic marker for Wegener's granulomatosis and microscopic polyangiitis,” Dr. Merkel stressed.

Chest x-rays are also considered an essential diagnostic tool, “but they often miss things,” said Dr. Merkel. “Anyone being evaluated for possible Wegener's should have a CT scan of the chest—and often even the head and neck—to look for subparotid disease or tracheal narrowing.” Because upper-airway and lung involvement are devastating, “it's important to have a low threshold when looking for neck disease, so you can get it early,” he said.

Pulmonary function testing and an ophthalmological examination to identify inflammatory eye disease should be conducted, as should audiograms, said Dr. Merkel. “Hearing loss, in particular, is an underappreciated problem in small-vessel vasculitis. Audiograms are noninvasive and cheap, and should be standard practice in these patients.”

Although electromyography and nerve conduction studies may be useful for identifying and localizing neurologic involvement in these diseases, “they are painful, annoying, and expensive tests and generally unnecessary if you do a proper examination,” said Dr. Merkel.

Before making a diagnosis, “rule everything else out, particularly infections,” Dr. Merkel stressed. “Infections are the great mimicker and cotraveler of vasculitis, so be sure to look for them.”

As the diagnostic criteria for these conditions are fulfilled, get a good team together to address the multiple organ system assaults, said Dr. Merkel. And, in the case of acute disease, “jump right in with glucocorticoids, especially if you suspect acute glomerulonephritis or pulmonary hemorrhage. These are among the few true rheumatoid emergencies, and nothing works faster for acute ANCA-associated vasculitis than steroids.” Immunosuppressive therapy, which is the mainstay of treatment for these conditions, “can usually wait until the patient is more stable or the diagnosis has been confirmed, but you don't want to miss treating acute renal or pulmonary disease, or even bad eye disease, because the consequences can be devastating,” he said.

BOSTON — Despite the availability of “pretty good therapies” for Wegener's granulomatosis and microscopic polyangiitis, “these forms of small-vessel vasculitis still regularly kill people, so do not underestimate the misery associated with them,” said Dr. Peter Merkel at a meeting on rheumatology sponsored by Harvard Medical School.

“These are bad diseases that cause major, permanent damage to multiple organ systems,” said Dr. Merkel of Boston University. “While the available treatments can effectively induce remission in some patients, many other patients die. Some die early from hemorrhage or other problems; some die later from concurrent disease or treatment toxicity. The important thing to remember is that these diseases kill.”

The first line of defense against such an outcome is the accurate diagnosis of acute disease, and early, aggressive therapy. Unfortunately, a number of obstacles can get in the way of both, Dr. Merkel said.

Because these conditions are relatively rare, “many rheumatologists don't see a lot of these patients and thus do not have a good sense of the spectrum of the disease and its presentations,” he noted.

When a patient presents with symptoms suggestive of acute vasculitis, “the first thing to do is look for trouble,” said Dr. Merkel. “There's always more to acute vasculitis than you think. If you look for trouble, you will almost certainly find it, and this is important because you want to find and treat the worst part of the disease first.” A good evaluation for potential small-vessel vasculitis should include a full medical history and physical. “This is not a 20-minute visit. It requires a long, comprehensive examination with a full set of labs,” Dr. Merkel stressed. “Certainly, one of the first things is to get a urine specimen to assess possible kidney involvement, and, for dipstick positive specimens, you have to be willing and able to do a microscopic examination of the urinary sediment right then and there,” he said. “Early changes in urine are critical to evaluating these patients, and in order to identify such changes, the specimen for microscopic examination has to be as fresh as possible. If you send the specimen to the lab, the red cells and formed solids will have disintegrated.”

Unfortunately, microscopic examination of urine sediment is a “lost art,” said Dr. Merkel. “It requires a degree of skill acquired through practice. It's hard to get used to doing if you're not seeing hundreds of patients with these diseases, and most rheumatologists are not seeing hundreds of these patients,” he said.

“However, if you're not comfortable doing this, you cannot take care of these patients on your own.”

Testing for antineutrophil cytoplasmic antibodies (ANCA) is also necessary. “Although there is a subset of patients who test negative for ANCA, a positive test is a useful diagnostic and prognostic marker for Wegener's granulomatosis and microscopic polyangiitis,” Dr. Merkel stressed.

Chest x-rays are also considered an essential diagnostic tool, “but they often miss things,” said Dr. Merkel. “Anyone being evaluated for possible Wegener's should have a CT scan of the chest—and often even the head and neck—to look for subparotid disease or tracheal narrowing.” Because upper-airway and lung involvement are devastating, “it's important to have a low threshold when looking for neck disease, so you can get it early,” he said.

Pulmonary function testing and an ophthalmological examination to identify inflammatory eye disease should be conducted, as should audiograms, said Dr. Merkel. “Hearing loss, in particular, is an underappreciated problem in small-vessel vasculitis. Audiograms are noninvasive and cheap, and should be standard practice in these patients.”

Although electromyography and nerve conduction studies may be useful for identifying and localizing neurologic involvement in these diseases, “they are painful, annoying, and expensive tests and generally unnecessary if you do a proper examination,” said Dr. Merkel.

Before making a diagnosis, “rule everything else out, particularly infections,” Dr. Merkel stressed. “Infections are the great mimicker and cotraveler of vasculitis, so be sure to look for them.”

As the diagnostic criteria for these conditions are fulfilled, get a good team together to address the multiple organ system assaults, said Dr. Merkel. And, in the case of acute disease, “jump right in with glucocorticoids, especially if you suspect acute glomerulonephritis or pulmonary hemorrhage. These are among the few true rheumatoid emergencies, and nothing works faster for acute ANCA-associated vasculitis than steroids.” Immunosuppressive therapy, which is the mainstay of treatment for these conditions, “can usually wait until the patient is more stable or the diagnosis has been confirmed, but you don't want to miss treating acute renal or pulmonary disease, or even bad eye disease, because the consequences can be devastating,” he said.

BOSTON — Despite the availability of “pretty good therapies” for Wegener's granulomatosis and microscopic polyangiitis, “these forms of small-vessel vasculitis still regularly kill people, so do not underestimate the misery associated with them,” said Dr. Peter Merkel at a meeting on rheumatology sponsored by Harvard Medical School.

“These are bad diseases that cause major, permanent damage to multiple organ systems,” said Dr. Merkel of Boston University. “While the available treatments can effectively induce remission in some patients, many other patients die. Some die early from hemorrhage or other problems; some die later from concurrent disease or treatment toxicity. The important thing to remember is that these diseases kill.”

The first line of defense against such an outcome is the accurate diagnosis of acute disease, and early, aggressive therapy. Unfortunately, a number of obstacles can get in the way of both, Dr. Merkel said.

Because these conditions are relatively rare, “many rheumatologists don't see a lot of these patients and thus do not have a good sense of the spectrum of the disease and its presentations,” he noted.

When a patient presents with symptoms suggestive of acute vasculitis, “the first thing to do is look for trouble,” said Dr. Merkel. “There's always more to acute vasculitis than you think. If you look for trouble, you will almost certainly find it, and this is important because you want to find and treat the worst part of the disease first.” A good evaluation for potential small-vessel vasculitis should include a full medical history and physical. “This is not a 20-minute visit. It requires a long, comprehensive examination with a full set of labs,” Dr. Merkel stressed. “Certainly, one of the first things is to get a urine specimen to assess possible kidney involvement, and, for dipstick positive specimens, you have to be willing and able to do a microscopic examination of the urinary sediment right then and there,” he said. “Early changes in urine are critical to evaluating these patients, and in order to identify such changes, the specimen for microscopic examination has to be as fresh as possible. If you send the specimen to the lab, the red cells and formed solids will have disintegrated.”

Unfortunately, microscopic examination of urine sediment is a “lost art,” said Dr. Merkel. “It requires a degree of skill acquired through practice. It's hard to get used to doing if you're not seeing hundreds of patients with these diseases, and most rheumatologists are not seeing hundreds of these patients,” he said.

“However, if you're not comfortable doing this, you cannot take care of these patients on your own.”

Testing for antineutrophil cytoplasmic antibodies (ANCA) is also necessary. “Although there is a subset of patients who test negative for ANCA, a positive test is a useful diagnostic and prognostic marker for Wegener's granulomatosis and microscopic polyangiitis,” Dr. Merkel stressed.

Chest x-rays are also considered an essential diagnostic tool, “but they often miss things,” said Dr. Merkel. “Anyone being evaluated for possible Wegener's should have a CT scan of the chest—and often even the head and neck—to look for subparotid disease or tracheal narrowing.” Because upper-airway and lung involvement are devastating, “it's important to have a low threshold when looking for neck disease, so you can get it early,” he said.

Pulmonary function testing and an ophthalmological examination to identify inflammatory eye disease should be conducted, as should audiograms, said Dr. Merkel. “Hearing loss, in particular, is an underappreciated problem in small-vessel vasculitis. Audiograms are noninvasive and cheap, and should be standard practice in these patients.”

Although electromyography and nerve conduction studies may be useful for identifying and localizing neurologic involvement in these diseases, “they are painful, annoying, and expensive tests and generally unnecessary if you do a proper examination,” said Dr. Merkel.

Before making a diagnosis, “rule everything else out, particularly infections,” Dr. Merkel stressed. “Infections are the great mimicker and cotraveler of vasculitis, so be sure to look for them.”

As the diagnostic criteria for these conditions are fulfilled, get a good team together to address the multiple organ system assaults, said Dr. Merkel. And, in the case of acute disease, “jump right in with glucocorticoids, especially if you suspect acute glomerulonephritis or pulmonary hemorrhage. These are among the few true rheumatoid emergencies, and nothing works faster for acute ANCA-associated vasculitis than steroids.” Immunosuppressive therapy, which is the mainstay of treatment for these conditions, “can usually wait until the patient is more stable or the diagnosis has been confirmed, but you don't want to miss treating acute renal or pulmonary disease, or even bad eye disease, because the consequences can be devastating,” he said.