Bruce Jancin

Major Finding: The annual rate of bone loss during the late perimenopausal and early postmenopausal years is 1.8%–2.3% in the lumbar spine and 1.0%–1.4% in the hip. At those rates, 5 years of bone loss would translate to a 7%–10% drop in BMD at the spine in the average woman, along with a 5%–7% decline at the hip.

Data Source: SWAN, a long-term, longitudinal, observational study of 3,302 women from five ethnic groups at seven U.S. sites who were pre- or early perimenopausal at enrollment.

Disclosures: Dr. Santoro declared having no financial interests relevant to the National Institutes of Health–funded study.

DENVER – The Study of Women's Health Across the Nation has filled important knowledge gaps regarding bone loss rates at various stages of the menopausal transition, enabling physicians for the first time to make informed decisions about the appropriate time to screen for osteoporosis.

“Hypoestrogenic bone loss does not occur until the late transition. Duration of amenorrhea is the best predictor of when this process begins. There's no rationale to measure bone mineral density prior to 90 days of amenorrhea if postmenopausal osteoporosis is the clinical issue,” Dr. Nanette F. Santoro explained at the meeting.

“Bone mineral density at the lumbar spine and total hip starts dropping like a stone as soon as the women get to late menopause, so 3-11 months of amenorrhea is the tipping point for bone density. There is no point in assessing it sooner if you think they may have bone loss related to the menopause transition, because it's not going to be estrogen-related prior to this point,” said Dr. Santoro, a long-time SWAN (Study of Women's Health Across the Nation) investigator and chair of obstetrics and gynecology at the University of Colorado at Denver.

The SWAN findings have important clinical implications because most guidelines don't recommend routine screening of women for osteoporosis until age 65. That's too late. Since the rate of BMD loss accelerates markedly in late menopause, accompanied by an attendant increase in fracture risk, it makes sense to measure bone mineral density after a women has experienced 3 months of amenorrhea, and to intervene if she is beginning to lose bone rapidly, she continued.

SWAN showed that the annual rate of bone loss during the late perimenopausal and early postmenopausal years is 1.8%-2.3% in the lumbar spine and 1.0%-1.4% in the hip. At those rates, 5 years of bone loss would translate to a 7%-10% drop in BMD at the spine in the average woman, along with a 5%-7% decline at the hip. And that in turn foretells a 50%-100% higher fracture rate.

Another key SWAN finding regarding BMD changes during the menopausal transition is that rates of bone loss are markedly greater in women who are in the lowest tertile of body weight. Indeed, women in the top tertile for body weight had a 33%-55% slower rate of bone loss than did those in the lightest tertile. The apparent large ethnic differences in bone loss rates observed in SWAN turned out on closer inspection to be explained chiefly by ethnic differences in body weight.

SWAN is a long-term, longitudinal, observational study involving 3,302 women who were pre- or early perimenopausal at enrollment.

Participants were recruited from five ethnic groups – white, black, Hispanic, Japanese, and Chinese – at seven U.S. sites. The BMD substudy included 1,902 SWAN participants with BMD measurements obtained at up to six annual visits. The key findings of the BMD substudy have already been published (J. Clin. Endocrinol. Metab. 2008;93:861-8). Dr. Santoro, in her plenary lecture at the meeting, sought to spread the word.

Major Finding: The annual rate of bone loss during the late perimenopausal and early postmenopausal years is 1.8%–2.3% in the lumbar spine and 1.0%–1.4% in the hip. At those rates, 5 years of bone loss would translate to a 7%–10% drop in BMD at the spine in the average woman, along with a 5%–7% decline at the hip.

Data Source: SWAN, a long-term, longitudinal, observational study of 3,302 women from five ethnic groups at seven U.S. sites who were pre- or early perimenopausal at enrollment.

Disclosures: Dr. Santoro declared having no financial interests relevant to the National Institutes of Health–funded study.

DENVER – The Study of Women's Health Across the Nation has filled important knowledge gaps regarding bone loss rates at various stages of the menopausal transition, enabling physicians for the first time to make informed decisions about the appropriate time to screen for osteoporosis.

“Hypoestrogenic bone loss does not occur until the late transition. Duration of amenorrhea is the best predictor of when this process begins. There's no rationale to measure bone mineral density prior to 90 days of amenorrhea if postmenopausal osteoporosis is the clinical issue,” Dr. Nanette F. Santoro explained at the meeting.

“Bone mineral density at the lumbar spine and total hip starts dropping like a stone as soon as the women get to late menopause, so 3-11 months of amenorrhea is the tipping point for bone density. There is no point in assessing it sooner if you think they may have bone loss related to the menopause transition, because it's not going to be estrogen-related prior to this point,” said Dr. Santoro, a long-time SWAN (Study of Women's Health Across the Nation) investigator and chair of obstetrics and gynecology at the University of Colorado at Denver.

The SWAN findings have important clinical implications because most guidelines don't recommend routine screening of women for osteoporosis until age 65. That's too late. Since the rate of BMD loss accelerates markedly in late menopause, accompanied by an attendant increase in fracture risk, it makes sense to measure bone mineral density after a women has experienced 3 months of amenorrhea, and to intervene if she is beginning to lose bone rapidly, she continued.

SWAN showed that the annual rate of bone loss during the late perimenopausal and early postmenopausal years is 1.8%-2.3% in the lumbar spine and 1.0%-1.4% in the hip. At those rates, 5 years of bone loss would translate to a 7%-10% drop in BMD at the spine in the average woman, along with a 5%-7% decline at the hip. And that in turn foretells a 50%-100% higher fracture rate.

Another key SWAN finding regarding BMD changes during the menopausal transition is that rates of bone loss are markedly greater in women who are in the lowest tertile of body weight. Indeed, women in the top tertile for body weight had a 33%-55% slower rate of bone loss than did those in the lightest tertile. The apparent large ethnic differences in bone loss rates observed in SWAN turned out on closer inspection to be explained chiefly by ethnic differences in body weight.

SWAN is a long-term, longitudinal, observational study involving 3,302 women who were pre- or early perimenopausal at enrollment.

Participants were recruited from five ethnic groups – white, black, Hispanic, Japanese, and Chinese – at seven U.S. sites. The BMD substudy included 1,902 SWAN participants with BMD measurements obtained at up to six annual visits. The key findings of the BMD substudy have already been published (J. Clin. Endocrinol. Metab. 2008;93:861-8). Dr. Santoro, in her plenary lecture at the meeting, sought to spread the word.

Major Finding: The annual rate of bone loss during the late perimenopausal and early postmenopausal years is 1.8%–2.3% in the lumbar spine and 1.0%–1.4% in the hip. At those rates, 5 years of bone loss would translate to a 7%–10% drop in BMD at the spine in the average woman, along with a 5%–7% decline at the hip.

Data Source: SWAN, a long-term, longitudinal, observational study of 3,302 women from five ethnic groups at seven U.S. sites who were pre- or early perimenopausal at enrollment.

Disclosures: Dr. Santoro declared having no financial interests relevant to the National Institutes of Health–funded study.

DENVER – The Study of Women's Health Across the Nation has filled important knowledge gaps regarding bone loss rates at various stages of the menopausal transition, enabling physicians for the first time to make informed decisions about the appropriate time to screen for osteoporosis.

“Hypoestrogenic bone loss does not occur until the late transition. Duration of amenorrhea is the best predictor of when this process begins. There's no rationale to measure bone mineral density prior to 90 days of amenorrhea if postmenopausal osteoporosis is the clinical issue,” Dr. Nanette F. Santoro explained at the meeting.

“Bone mineral density at the lumbar spine and total hip starts dropping like a stone as soon as the women get to late menopause, so 3-11 months of amenorrhea is the tipping point for bone density. There is no point in assessing it sooner if you think they may have bone loss related to the menopause transition, because it's not going to be estrogen-related prior to this point,” said Dr. Santoro, a long-time SWAN (Study of Women's Health Across the Nation) investigator and chair of obstetrics and gynecology at the University of Colorado at Denver.

The SWAN findings have important clinical implications because most guidelines don't recommend routine screening of women for osteoporosis until age 65. That's too late. Since the rate of BMD loss accelerates markedly in late menopause, accompanied by an attendant increase in fracture risk, it makes sense to measure bone mineral density after a women has experienced 3 months of amenorrhea, and to intervene if she is beginning to lose bone rapidly, she continued.

SWAN showed that the annual rate of bone loss during the late perimenopausal and early postmenopausal years is 1.8%-2.3% in the lumbar spine and 1.0%-1.4% in the hip. At those rates, 5 years of bone loss would translate to a 7%-10% drop in BMD at the spine in the average woman, along with a 5%-7% decline at the hip. And that in turn foretells a 50%-100% higher fracture rate.

Another key SWAN finding regarding BMD changes during the menopausal transition is that rates of bone loss are markedly greater in women who are in the lowest tertile of body weight. Indeed, women in the top tertile for body weight had a 33%-55% slower rate of bone loss than did those in the lightest tertile. The apparent large ethnic differences in bone loss rates observed in SWAN turned out on closer inspection to be explained chiefly by ethnic differences in body weight.

SWAN is a long-term, longitudinal, observational study involving 3,302 women who were pre- or early perimenopausal at enrollment.

Participants were recruited from five ethnic groups – white, black, Hispanic, Japanese, and Chinese – at seven U.S. sites. The BMD substudy included 1,902 SWAN participants with BMD measurements obtained at up to six annual visits. The key findings of the BMD substudy have already been published (J. Clin. Endocrinol. Metab. 2008;93:861-8). Dr. Santoro, in her plenary lecture at the meeting, sought to spread the word.

Major Finding: Median time to the first on-study skeletal-related event was 32.4 months in the denosumab arm compared with 27.4 months in the zoledronic acid arm.

Data Source: Updated results on 2,046 patients with advanced breast cancer and bone metastases in a pivotal phase III trial.

Disclosures: Dr. Stopeck disclosed that she serves as a consultant to and has received research grants from both Amgen, which markets denosumab, and Novartis, which markets zoledronic acid. The trial was sponsored by Amgen in collaboration with Daiichi Sankyo.

SAN ANTONIO – Denosumab delayed time to a first skeletal-related adverse event by a median of 5 months longer than zoledronic acid in patients with advanced breast cancer and bone metastases, based on updated results from a landmark head-to-head comparative trial of the two osteoclast-inhibiting drugs.

Moreover, time to the composite secondary end point of a first skeletal-related event or hypercalcemia, a feared and life-threatening complication of metastatic bone disease, was prolonged by a median of 7.3 months in the denosumab (Xgeva) group compared with those on zoledronic acid (Zometa), Dr. Alison T. Stopeck reported.

“To put this in some perspective, the average life expectancy of these patients is 2½-3 years, so 7 additional months of freedom from these complications is a considerable period of their remaining time,” said Dr. Stopeck, director of the clinical breast cancer program at the Arizona Cancer Center at the University of Arizona, Tucson.

She presented a new extended analysis that included 4 more months of blinded treatment than previously reported in the recent publication of data from the pivotal phase III randomized, double-blind, double-dummy study (J. Clin. Oncol. 2010;28:5132-9).

The trial involved 2,046 patients with advanced breast cancer and bone metastases, 1% of them men, who were assigned to 120 mg of subcutaneous denosumab or 4 mg of intravenous zoledronic acid, with each drug given every 4 weeks.

In the extended analysis, the median time to the first on-study skeletal-related event, such as fracture, spinal cord compression, or radiotherapy or surgery to bone, was 32.4 months in the denosumab arm compared with 27.4 months in the zoledronic acid arm. This represented a highly significant 18% delay in the time to these serious events in the denosumab-treated group (P = .0096).

Median time to the first on-study skeletal-related event or hypercalcemia was 32.4 months in the denosumab group and 25.1 months with zoledronic acid (P = .0076).

At the time of the extended analysis out to 3 years, 32.9% of patients in the denosumab group had had one or more skeletal-related events compared with 38.9% in the zoledronic acid arm, for a 15.4% relative risk reduction. One hundred additional skeletal-related events occurred during the extra 4 months of blinded treatment, bringing the total number of such events to 526 in the denosumab arm and 669 with zoledronic acid; this represents a 22% risk reduction (P = .0008). And the event curves are continuing to separate over time, Dr. Stopeck noted.

Overall survival and disease progression rates were similar in the two study arms. In terms of adverse events, renal toxicity was significantly more common in the zoledronic acid arm (9.4% vs. 5.4%), as were acute phase reactions involving bone pain and/or flulike symptoms (28.2% vs. 10.7%).

Hypocalcemia occurred in 6.1% of the denosumab group compared with 3.7% on zoledronic acid. Osteonecrosis of the jaw occurred at similarly low rates − 2.5% or less – in both treatment arms.

On the strength of earlier data from this and two other phase III studies, in November the Food and Drug Administration approved denosumab, a fully human monoclonal antibody that acts as a RANK ligand inhibitor, for the prevention of skeletal-related events in patients with bone metastases from solid tumors.

Dr. Stopeck noted that denosumab offers significant advantages in terms of ease of use. It's given via a once-monthly subcutaneous injection rather than the intravenous infusion required with zoledronic acid.

Furthermore, unlike for zoledronic acid, there is no need for renal monitoring or dose adjustments with denosumab.

The next phase of development for denosumab will be to study it in the setting of early-stage breast cancer to see if it can prevent metastases to the bone and indeed any other part of the body. The rationale is that bone acts as a reservoir for circulating tumor cells, which may spread to other parts of the body and cause metastases.

“This is a trial I think we're all enthusiastic about, to see if we can actually prevent cancer from spreading at an earlier stage by manipulating the bone microenvironment. Preventing skeletal-related events is nice, but we'd like to move earlier,” Dr. Stopeck explained.

Toward this end, the D-CARE trial, a randomized, double-blind, placebo-controlled phase III study of denosumab as adjuvant treatment for women with early-stage breast cancer at high risk of recurrence, has begun enrolling a planned 4,500 patients. The Amgen-sponsored study is expected to run for 10 years, with bone metastasis–free survival as the primary end point, and overall and disease-free survival among the key secondary end points.

Major Finding: Median time to the first on-study skeletal-related event was 32.4 months in the denosumab arm compared with 27.4 months in the zoledronic acid arm.

Data Source: Updated results on 2,046 patients with advanced breast cancer and bone metastases in a pivotal phase III trial.

Disclosures: Dr. Stopeck disclosed that she serves as a consultant to and has received research grants from both Amgen, which markets denosumab, and Novartis, which markets zoledronic acid. The trial was sponsored by Amgen in collaboration with Daiichi Sankyo.

SAN ANTONIO – Denosumab delayed time to a first skeletal-related adverse event by a median of 5 months longer than zoledronic acid in patients with advanced breast cancer and bone metastases, based on updated results from a landmark head-to-head comparative trial of the two osteoclast-inhibiting drugs.

Moreover, time to the composite secondary end point of a first skeletal-related event or hypercalcemia, a feared and life-threatening complication of metastatic bone disease, was prolonged by a median of 7.3 months in the denosumab (Xgeva) group compared with those on zoledronic acid (Zometa), Dr. Alison T. Stopeck reported.

“To put this in some perspective, the average life expectancy of these patients is 2½-3 years, so 7 additional months of freedom from these complications is a considerable period of their remaining time,” said Dr. Stopeck, director of the clinical breast cancer program at the Arizona Cancer Center at the University of Arizona, Tucson.

She presented a new extended analysis that included 4 more months of blinded treatment than previously reported in the recent publication of data from the pivotal phase III randomized, double-blind, double-dummy study (J. Clin. Oncol. 2010;28:5132-9).

The trial involved 2,046 patients with advanced breast cancer and bone metastases, 1% of them men, who were assigned to 120 mg of subcutaneous denosumab or 4 mg of intravenous zoledronic acid, with each drug given every 4 weeks.

In the extended analysis, the median time to the first on-study skeletal-related event, such as fracture, spinal cord compression, or radiotherapy or surgery to bone, was 32.4 months in the denosumab arm compared with 27.4 months in the zoledronic acid arm. This represented a highly significant 18% delay in the time to these serious events in the denosumab-treated group (P = .0096).

Median time to the first on-study skeletal-related event or hypercalcemia was 32.4 months in the denosumab group and 25.1 months with zoledronic acid (P = .0076).

At the time of the extended analysis out to 3 years, 32.9% of patients in the denosumab group had had one or more skeletal-related events compared with 38.9% in the zoledronic acid arm, for a 15.4% relative risk reduction. One hundred additional skeletal-related events occurred during the extra 4 months of blinded treatment, bringing the total number of such events to 526 in the denosumab arm and 669 with zoledronic acid; this represents a 22% risk reduction (P = .0008). And the event curves are continuing to separate over time, Dr. Stopeck noted.

Overall survival and disease progression rates were similar in the two study arms. In terms of adverse events, renal toxicity was significantly more common in the zoledronic acid arm (9.4% vs. 5.4%), as were acute phase reactions involving bone pain and/or flulike symptoms (28.2% vs. 10.7%).

Hypocalcemia occurred in 6.1% of the denosumab group compared with 3.7% on zoledronic acid. Osteonecrosis of the jaw occurred at similarly low rates − 2.5% or less – in both treatment arms.

On the strength of earlier data from this and two other phase III studies, in November the Food and Drug Administration approved denosumab, a fully human monoclonal antibody that acts as a RANK ligand inhibitor, for the prevention of skeletal-related events in patients with bone metastases from solid tumors.

Dr. Stopeck noted that denosumab offers significant advantages in terms of ease of use. It's given via a once-monthly subcutaneous injection rather than the intravenous infusion required with zoledronic acid.

Furthermore, unlike for zoledronic acid, there is no need for renal monitoring or dose adjustments with denosumab.

The next phase of development for denosumab will be to study it in the setting of early-stage breast cancer to see if it can prevent metastases to the bone and indeed any other part of the body. The rationale is that bone acts as a reservoir for circulating tumor cells, which may spread to other parts of the body and cause metastases.

“This is a trial I think we're all enthusiastic about, to see if we can actually prevent cancer from spreading at an earlier stage by manipulating the bone microenvironment. Preventing skeletal-related events is nice, but we'd like to move earlier,” Dr. Stopeck explained.

Toward this end, the D-CARE trial, a randomized, double-blind, placebo-controlled phase III study of denosumab as adjuvant treatment for women with early-stage breast cancer at high risk of recurrence, has begun enrolling a planned 4,500 patients. The Amgen-sponsored study is expected to run for 10 years, with bone metastasis–free survival as the primary end point, and overall and disease-free survival among the key secondary end points.

Major Finding: Median time to the first on-study skeletal-related event was 32.4 months in the denosumab arm compared with 27.4 months in the zoledronic acid arm.

Data Source: Updated results on 2,046 patients with advanced breast cancer and bone metastases in a pivotal phase III trial.

Disclosures: Dr. Stopeck disclosed that she serves as a consultant to and has received research grants from both Amgen, which markets denosumab, and Novartis, which markets zoledronic acid. The trial was sponsored by Amgen in collaboration with Daiichi Sankyo.

SAN ANTONIO – Denosumab delayed time to a first skeletal-related adverse event by a median of 5 months longer than zoledronic acid in patients with advanced breast cancer and bone metastases, based on updated results from a landmark head-to-head comparative trial of the two osteoclast-inhibiting drugs.

Moreover, time to the composite secondary end point of a first skeletal-related event or hypercalcemia, a feared and life-threatening complication of metastatic bone disease, was prolonged by a median of 7.3 months in the denosumab (Xgeva) group compared with those on zoledronic acid (Zometa), Dr. Alison T. Stopeck reported.

“To put this in some perspective, the average life expectancy of these patients is 2½-3 years, so 7 additional months of freedom from these complications is a considerable period of their remaining time,” said Dr. Stopeck, director of the clinical breast cancer program at the Arizona Cancer Center at the University of Arizona, Tucson.

She presented a new extended analysis that included 4 more months of blinded treatment than previously reported in the recent publication of data from the pivotal phase III randomized, double-blind, double-dummy study (J. Clin. Oncol. 2010;28:5132-9).

The trial involved 2,046 patients with advanced breast cancer and bone metastases, 1% of them men, who were assigned to 120 mg of subcutaneous denosumab or 4 mg of intravenous zoledronic acid, with each drug given every 4 weeks.

In the extended analysis, the median time to the first on-study skeletal-related event, such as fracture, spinal cord compression, or radiotherapy or surgery to bone, was 32.4 months in the denosumab arm compared with 27.4 months in the zoledronic acid arm. This represented a highly significant 18% delay in the time to these serious events in the denosumab-treated group (P = .0096).

Median time to the first on-study skeletal-related event or hypercalcemia was 32.4 months in the denosumab group and 25.1 months with zoledronic acid (P = .0076).

At the time of the extended analysis out to 3 years, 32.9% of patients in the denosumab group had had one or more skeletal-related events compared with 38.9% in the zoledronic acid arm, for a 15.4% relative risk reduction. One hundred additional skeletal-related events occurred during the extra 4 months of blinded treatment, bringing the total number of such events to 526 in the denosumab arm and 669 with zoledronic acid; this represents a 22% risk reduction (P = .0008). And the event curves are continuing to separate over time, Dr. Stopeck noted.

Overall survival and disease progression rates were similar in the two study arms. In terms of adverse events, renal toxicity was significantly more common in the zoledronic acid arm (9.4% vs. 5.4%), as were acute phase reactions involving bone pain and/or flulike symptoms (28.2% vs. 10.7%).

Hypocalcemia occurred in 6.1% of the denosumab group compared with 3.7% on zoledronic acid. Osteonecrosis of the jaw occurred at similarly low rates − 2.5% or less – in both treatment arms.

On the strength of earlier data from this and two other phase III studies, in November the Food and Drug Administration approved denosumab, a fully human monoclonal antibody that acts as a RANK ligand inhibitor, for the prevention of skeletal-related events in patients with bone metastases from solid tumors.

Dr. Stopeck noted that denosumab offers significant advantages in terms of ease of use. It's given via a once-monthly subcutaneous injection rather than the intravenous infusion required with zoledronic acid.

Furthermore, unlike for zoledronic acid, there is no need for renal monitoring or dose adjustments with denosumab.

The next phase of development for denosumab will be to study it in the setting of early-stage breast cancer to see if it can prevent metastases to the bone and indeed any other part of the body. The rationale is that bone acts as a reservoir for circulating tumor cells, which may spread to other parts of the body and cause metastases.

“This is a trial I think we're all enthusiastic about, to see if we can actually prevent cancer from spreading at an earlier stage by manipulating the bone microenvironment. Preventing skeletal-related events is nice, but we'd like to move earlier,” Dr. Stopeck explained.

Toward this end, the D-CARE trial, a randomized, double-blind, placebo-controlled phase III study of denosumab as adjuvant treatment for women with early-stage breast cancer at high risk of recurrence, has begun enrolling a planned 4,500 patients. The Amgen-sponsored study is expected to run for 10 years, with bone metastasis–free survival as the primary end point, and overall and disease-free survival among the key secondary end points.

DENVER – Chronic methotrexate therapy may harm the future fertility of girls and young women being treated for rheumatoid arthritis or juvenile idiopathic arthritis, based on preliminary findings from an observational study.

“The biggest issue is that rheumatologists have become much more aggressive in their therapy for these young girls with juvenile idiopathic arthritis in the last 5-10 years. As early as 1 year of age, these girls are placed on methotrexate weekly for years and years and years,” Dr. Amber R. Cooper said at the meeting.

The study findings suggest a need to alter how physicians counsel patients and their families on this score in light of emerging evidence that long-term cytotoxic therapy with methotrexate may threaten the oocyte pool, she said.

Thus far, 168 females aged 4-49 years have been recruited for the ongoing study from pediatric and adult rheumatology clinics. Every 3-4 months they undergo measurement of serum anti-Müllerian hormone (AMH), follicle-stimulating hormone (FSH), inhibin B, and other indicators of ovarian reserve. In addition, transabdominal ultrasound is performed annually by sonographers blinded as to the patients' treatment regimen in order to assess ovarian volume and antral follicle count, explained Dr. Cooper of Washington University in St. Louis.

Among the study participants, 55% have juvenile idiopathic arthritis, formerly called juvenile rheumatoid arthritis, and 43% have rheumatoid arthritis. The rest have psoriatic arthritis or undifferentiated spondyloarthropathies. The subjects' mean age at diagnosis was 18.6 years, while at enrollment in the fertility study they averaged 25.4 years of age. Forty-three percent were on methotrexate or the related drug leflunomide, 12% were on a tumor necrosis factor (TNF) antagonist, 30% were on both, and 15% were on other agents, mainly corticosteroids, hydroxychloroquine, or sulfasalazine.

The primary study end point was change over time in AMH level, widely considered to be the best indicator of ovarian reserve. At enrollment, the median AMH level was 2.25 ng/mL in patients on methotrexate or leflunomide, 1.65 ng/mL in those on a TNF antagonist, 2.42 ng/mL in patients on both, and 2.54 ng/mL in patients on other agents.

A multifactorial analysis showed that patients on methotrexate/leflunomide were the only ones who showed a progressive decline in AMH with increasing time on therapy. In addition, patients on methotrexate or methotrexate plus an anti-TNF biologic had significantly lower antral follicle counts than did other patients.

A key question is whether patients on chronic therapy take an irreversible hit to the primordial oocyte pool, or if their oocyte count will eventually recover after they come off methotrexate, Dr. Cooper said.

Dr. Cooper's study is funded by a grant from the Society for Reproductive Endocrinology and Infertility. She had no other relevant financial disclosures.

'As early as 1 year of age, these girls are placed on methotrexate weekly for years and years and years.'

Source DR. COOPER

DENVER – Chronic methotrexate therapy may harm the future fertility of girls and young women being treated for rheumatoid arthritis or juvenile idiopathic arthritis, based on preliminary findings from an observational study.

“The biggest issue is that rheumatologists have become much more aggressive in their therapy for these young girls with juvenile idiopathic arthritis in the last 5-10 years. As early as 1 year of age, these girls are placed on methotrexate weekly for years and years and years,” Dr. Amber R. Cooper said at the meeting.

The study findings suggest a need to alter how physicians counsel patients and their families on this score in light of emerging evidence that long-term cytotoxic therapy with methotrexate may threaten the oocyte pool, she said.

Thus far, 168 females aged 4-49 years have been recruited for the ongoing study from pediatric and adult rheumatology clinics. Every 3-4 months they undergo measurement of serum anti-Müllerian hormone (AMH), follicle-stimulating hormone (FSH), inhibin B, and other indicators of ovarian reserve. In addition, transabdominal ultrasound is performed annually by sonographers blinded as to the patients' treatment regimen in order to assess ovarian volume and antral follicle count, explained Dr. Cooper of Washington University in St. Louis.

Among the study participants, 55% have juvenile idiopathic arthritis, formerly called juvenile rheumatoid arthritis, and 43% have rheumatoid arthritis. The rest have psoriatic arthritis or undifferentiated spondyloarthropathies. The subjects' mean age at diagnosis was 18.6 years, while at enrollment in the fertility study they averaged 25.4 years of age. Forty-three percent were on methotrexate or the related drug leflunomide, 12% were on a tumor necrosis factor (TNF) antagonist, 30% were on both, and 15% were on other agents, mainly corticosteroids, hydroxychloroquine, or sulfasalazine.

The primary study end point was change over time in AMH level, widely considered to be the best indicator of ovarian reserve. At enrollment, the median AMH level was 2.25 ng/mL in patients on methotrexate or leflunomide, 1.65 ng/mL in those on a TNF antagonist, 2.42 ng/mL in patients on both, and 2.54 ng/mL in patients on other agents.

A multifactorial analysis showed that patients on methotrexate/leflunomide were the only ones who showed a progressive decline in AMH with increasing time on therapy. In addition, patients on methotrexate or methotrexate plus an anti-TNF biologic had significantly lower antral follicle counts than did other patients.

A key question is whether patients on chronic therapy take an irreversible hit to the primordial oocyte pool, or if their oocyte count will eventually recover after they come off methotrexate, Dr. Cooper said.

Dr. Cooper's study is funded by a grant from the Society for Reproductive Endocrinology and Infertility. She had no other relevant financial disclosures.

'As early as 1 year of age, these girls are placed on methotrexate weekly for years and years and years.'

Source DR. COOPER

DENVER – Chronic methotrexate therapy may harm the future fertility of girls and young women being treated for rheumatoid arthritis or juvenile idiopathic arthritis, based on preliminary findings from an observational study.

“The biggest issue is that rheumatologists have become much more aggressive in their therapy for these young girls with juvenile idiopathic arthritis in the last 5-10 years. As early as 1 year of age, these girls are placed on methotrexate weekly for years and years and years,” Dr. Amber R. Cooper said at the meeting.

The study findings suggest a need to alter how physicians counsel patients and their families on this score in light of emerging evidence that long-term cytotoxic therapy with methotrexate may threaten the oocyte pool, she said.

Thus far, 168 females aged 4-49 years have been recruited for the ongoing study from pediatric and adult rheumatology clinics. Every 3-4 months they undergo measurement of serum anti-Müllerian hormone (AMH), follicle-stimulating hormone (FSH), inhibin B, and other indicators of ovarian reserve. In addition, transabdominal ultrasound is performed annually by sonographers blinded as to the patients' treatment regimen in order to assess ovarian volume and antral follicle count, explained Dr. Cooper of Washington University in St. Louis.

Among the study participants, 55% have juvenile idiopathic arthritis, formerly called juvenile rheumatoid arthritis, and 43% have rheumatoid arthritis. The rest have psoriatic arthritis or undifferentiated spondyloarthropathies. The subjects' mean age at diagnosis was 18.6 years, while at enrollment in the fertility study they averaged 25.4 years of age. Forty-three percent were on methotrexate or the related drug leflunomide, 12% were on a tumor necrosis factor (TNF) antagonist, 30% were on both, and 15% were on other agents, mainly corticosteroids, hydroxychloroquine, or sulfasalazine.

The primary study end point was change over time in AMH level, widely considered to be the best indicator of ovarian reserve. At enrollment, the median AMH level was 2.25 ng/mL in patients on methotrexate or leflunomide, 1.65 ng/mL in those on a TNF antagonist, 2.42 ng/mL in patients on both, and 2.54 ng/mL in patients on other agents.

A multifactorial analysis showed that patients on methotrexate/leflunomide were the only ones who showed a progressive decline in AMH with increasing time on therapy. In addition, patients on methotrexate or methotrexate plus an anti-TNF biologic had significantly lower antral follicle counts than did other patients.

A key question is whether patients on chronic therapy take an irreversible hit to the primordial oocyte pool, or if their oocyte count will eventually recover after they come off methotrexate, Dr. Cooper said.

Dr. Cooper's study is funded by a grant from the Society for Reproductive Endocrinology and Infertility. She had no other relevant financial disclosures.

'As early as 1 year of age, these girls are placed on methotrexate weekly for years and years and years.'

Source DR. COOPER

Major Finding: The measure of fertility rate, consisting of the number of normal fertilized oocytes divided by the total number of oocytes collected, was 63% in the group given an FSH bolus as compared to 55% with placebo, a significant difference. The fertility rate in IVF cycles was 62% with FSH bolus and 48% in controls. In cycles involving intracytoplasmic sperm injection, the rates were 79% with FSH and 73% in controls.

Data Source: A double-blind clinical trial in which 188 IVF patients undergoing a long agonist suppression protocol were randomized to a 450-IU bolus of FSH or placebo at the time of hCG trigger, 36 hours before oocyte retrieval.

Disclosures: Dr. Lamb disclosed having received a research grant from Ferring Pharmaceuticals.

DENVER – A bolus of follicle stimulating hormone given at the time of the human chorionic gonadotropin trigger during in vitro fertilization improves the developmental competence of oocytes, a new randomized trial shows.

The result is improved oocyte recovery, a higher fertilization rate, and perhaps a higher pregnancy rate, Dr. Julie D. Lamb said at the meeting.

“These findings may change our current practice, and with further study may play a pivotal role in improving ART outcomes for our patients,” according to Dr. Lamb of the University of California, San Francisco.

She presented a double-blind clinical trial in which 188 IVF patients undergoing a long agonist suppression protocol were randomized to a 450-IU bolus of FSH or placebo at the time of hCG trigger, 36 hours before oocyte retrieval.

The study rationale was that spontaneous ovulation in most mammalian species is preceded by a surge in FSH and luteinizing hormone, a combined gonadotropin surge believed necessary to final oocyte maturation and follicular rupture.

However, in modern stimulation protocols the last dose of FSH is often given 2 days prior to egg retrieval, and with intentional pituitary suppression little endogenous FSH is present at the pivotal time.

The study hypothesis was that creating a more physiologic ovulation trigger process would improve the developmental competence of oocytes.

“The dramatically increased success in IVF in the last two decades has been attributed largely to improvement in the embryo culture, laboratory conditions, and optimization of different stimulation protocols. Less attention has been given to different methods of hCG induction of final oocyte maturation,” she said.

The study results indicate this is a fruitful new area. The primary outcome – a measure of fertility rate consisting of the number of normal fertilized oocytes divided by the total number of oocytes collected – was 63% in the FSH group compared with 55% with placebo, a significant difference. The FSH bolus improved the fertility rate in IVF cycles, where it was 62% compared with 48% in controls, but not in cycles involving intracytoplasmic sperm injection, where the rates were 79% with FSH and similar at 73% in controls.

Turning to secondary end points, Dr. Lamb reported that the oocyte recovery rate – the chance of obtaining an oocyte upon flushing or aspirating a mature follicle – was 70% in the FSH group, significantly better than the 57% with placebo.

The implantation rate was 40% in the FSH group compared with 35% in the placebo arm. Clinical pregnancy as defined by fetal heart motion on ultrasound occurred in 57% of women in the FSH group compared with 46% of controls. The composite rate of ongoing pregnancy beyond 24 weeks or live birth was 51% in the FSH group and 43% in controls. None of these differences were statistically significant. However, the trends consistently favored the FSH intervention. Since the study wasn't powered to show significant differences in pregnancy outcomes, a larger trial will be required to determine whether the FSH bolus truly does boost pregnancy rates, Dr. Lamb said.

Follicular fluid FSH levels on the day of oocyte retrieval were significantly higher in the bolus FSH recipients at 13.3 mIU/mL compared with 9.2 mIU/mL, confirming that the supplemental FSH reached the follicular fluid. The benefits of bolus FSH weren't due to a change in the broader intrafollicular hormone milieu, since follicular fluid levels of testosterone, estradiol, progesterone, and hCG were similar in the two study arms.

No cases of ovarian hyperstimulation syndrome occurred with the study protocol because women with a baseline estradiol level greater than 4,500 pg/mL were excluded from participation as a precautionary measure.

Dr. Lamb said the next step planned by the researchers is a dose-finding study to learn whether a smaller dose of FSH would be equally effective, or if perhaps a larger dose would bring a better response.

She disclosed having received a research grant from Ferring Pharmaceuticals.

A larger trial will be required to determine whether the FSH bolus truly does boost pregnancy rates.

Source DR. LAMB

Major Finding: The measure of fertility rate, consisting of the number of normal fertilized oocytes divided by the total number of oocytes collected, was 63% in the group given an FSH bolus as compared to 55% with placebo, a significant difference. The fertility rate in IVF cycles was 62% with FSH bolus and 48% in controls. In cycles involving intracytoplasmic sperm injection, the rates were 79% with FSH and 73% in controls.

Data Source: A double-blind clinical trial in which 188 IVF patients undergoing a long agonist suppression protocol were randomized to a 450-IU bolus of FSH or placebo at the time of hCG trigger, 36 hours before oocyte retrieval.

Disclosures: Dr. Lamb disclosed having received a research grant from Ferring Pharmaceuticals.

DENVER – A bolus of follicle stimulating hormone given at the time of the human chorionic gonadotropin trigger during in vitro fertilization improves the developmental competence of oocytes, a new randomized trial shows.

The result is improved oocyte recovery, a higher fertilization rate, and perhaps a higher pregnancy rate, Dr. Julie D. Lamb said at the meeting.

“These findings may change our current practice, and with further study may play a pivotal role in improving ART outcomes for our patients,” according to Dr. Lamb of the University of California, San Francisco.

She presented a double-blind clinical trial in which 188 IVF patients undergoing a long agonist suppression protocol were randomized to a 450-IU bolus of FSH or placebo at the time of hCG trigger, 36 hours before oocyte retrieval.

The study rationale was that spontaneous ovulation in most mammalian species is preceded by a surge in FSH and luteinizing hormone, a combined gonadotropin surge believed necessary to final oocyte maturation and follicular rupture.

However, in modern stimulation protocols the last dose of FSH is often given 2 days prior to egg retrieval, and with intentional pituitary suppression little endogenous FSH is present at the pivotal time.

The study hypothesis was that creating a more physiologic ovulation trigger process would improve the developmental competence of oocytes.

“The dramatically increased success in IVF in the last two decades has been attributed largely to improvement in the embryo culture, laboratory conditions, and optimization of different stimulation protocols. Less attention has been given to different methods of hCG induction of final oocyte maturation,” she said.

The study results indicate this is a fruitful new area. The primary outcome – a measure of fertility rate consisting of the number of normal fertilized oocytes divided by the total number of oocytes collected – was 63% in the FSH group compared with 55% with placebo, a significant difference. The FSH bolus improved the fertility rate in IVF cycles, where it was 62% compared with 48% in controls, but not in cycles involving intracytoplasmic sperm injection, where the rates were 79% with FSH and similar at 73% in controls.

Turning to secondary end points, Dr. Lamb reported that the oocyte recovery rate – the chance of obtaining an oocyte upon flushing or aspirating a mature follicle – was 70% in the FSH group, significantly better than the 57% with placebo.

The implantation rate was 40% in the FSH group compared with 35% in the placebo arm. Clinical pregnancy as defined by fetal heart motion on ultrasound occurred in 57% of women in the FSH group compared with 46% of controls. The composite rate of ongoing pregnancy beyond 24 weeks or live birth was 51% in the FSH group and 43% in controls. None of these differences were statistically significant. However, the trends consistently favored the FSH intervention. Since the study wasn't powered to show significant differences in pregnancy outcomes, a larger trial will be required to determine whether the FSH bolus truly does boost pregnancy rates, Dr. Lamb said.

Follicular fluid FSH levels on the day of oocyte retrieval were significantly higher in the bolus FSH recipients at 13.3 mIU/mL compared with 9.2 mIU/mL, confirming that the supplemental FSH reached the follicular fluid. The benefits of bolus FSH weren't due to a change in the broader intrafollicular hormone milieu, since follicular fluid levels of testosterone, estradiol, progesterone, and hCG were similar in the two study arms.

No cases of ovarian hyperstimulation syndrome occurred with the study protocol because women with a baseline estradiol level greater than 4,500 pg/mL were excluded from participation as a precautionary measure.

Dr. Lamb said the next step planned by the researchers is a dose-finding study to learn whether a smaller dose of FSH would be equally effective, or if perhaps a larger dose would bring a better response.

She disclosed having received a research grant from Ferring Pharmaceuticals.

A larger trial will be required to determine whether the FSH bolus truly does boost pregnancy rates.

Source DR. LAMB

Major Finding: The measure of fertility rate, consisting of the number of normal fertilized oocytes divided by the total number of oocytes collected, was 63% in the group given an FSH bolus as compared to 55% with placebo, a significant difference. The fertility rate in IVF cycles was 62% with FSH bolus and 48% in controls. In cycles involving intracytoplasmic sperm injection, the rates were 79% with FSH and 73% in controls.

Data Source: A double-blind clinical trial in which 188 IVF patients undergoing a long agonist suppression protocol were randomized to a 450-IU bolus of FSH or placebo at the time of hCG trigger, 36 hours before oocyte retrieval.

Disclosures: Dr. Lamb disclosed having received a research grant from Ferring Pharmaceuticals.

DENVER – A bolus of follicle stimulating hormone given at the time of the human chorionic gonadotropin trigger during in vitro fertilization improves the developmental competence of oocytes, a new randomized trial shows.

The result is improved oocyte recovery, a higher fertilization rate, and perhaps a higher pregnancy rate, Dr. Julie D. Lamb said at the meeting.

“These findings may change our current practice, and with further study may play a pivotal role in improving ART outcomes for our patients,” according to Dr. Lamb of the University of California, San Francisco.

She presented a double-blind clinical trial in which 188 IVF patients undergoing a long agonist suppression protocol were randomized to a 450-IU bolus of FSH or placebo at the time of hCG trigger, 36 hours before oocyte retrieval.

The study rationale was that spontaneous ovulation in most mammalian species is preceded by a surge in FSH and luteinizing hormone, a combined gonadotropin surge believed necessary to final oocyte maturation and follicular rupture.

However, in modern stimulation protocols the last dose of FSH is often given 2 days prior to egg retrieval, and with intentional pituitary suppression little endogenous FSH is present at the pivotal time.

The study hypothesis was that creating a more physiologic ovulation trigger process would improve the developmental competence of oocytes.

“The dramatically increased success in IVF in the last two decades has been attributed largely to improvement in the embryo culture, laboratory conditions, and optimization of different stimulation protocols. Less attention has been given to different methods of hCG induction of final oocyte maturation,” she said.

The study results indicate this is a fruitful new area. The primary outcome – a measure of fertility rate consisting of the number of normal fertilized oocytes divided by the total number of oocytes collected – was 63% in the FSH group compared with 55% with placebo, a significant difference. The FSH bolus improved the fertility rate in IVF cycles, where it was 62% compared with 48% in controls, but not in cycles involving intracytoplasmic sperm injection, where the rates were 79% with FSH and similar at 73% in controls.

Turning to secondary end points, Dr. Lamb reported that the oocyte recovery rate – the chance of obtaining an oocyte upon flushing or aspirating a mature follicle – was 70% in the FSH group, significantly better than the 57% with placebo.

The implantation rate was 40% in the FSH group compared with 35% in the placebo arm. Clinical pregnancy as defined by fetal heart motion on ultrasound occurred in 57% of women in the FSH group compared with 46% of controls. The composite rate of ongoing pregnancy beyond 24 weeks or live birth was 51% in the FSH group and 43% in controls. None of these differences were statistically significant. However, the trends consistently favored the FSH intervention. Since the study wasn't powered to show significant differences in pregnancy outcomes, a larger trial will be required to determine whether the FSH bolus truly does boost pregnancy rates, Dr. Lamb said.

Follicular fluid FSH levels on the day of oocyte retrieval were significantly higher in the bolus FSH recipients at 13.3 mIU/mL compared with 9.2 mIU/mL, confirming that the supplemental FSH reached the follicular fluid. The benefits of bolus FSH weren't due to a change in the broader intrafollicular hormone milieu, since follicular fluid levels of testosterone, estradiol, progesterone, and hCG were similar in the two study arms.

No cases of ovarian hyperstimulation syndrome occurred with the study protocol because women with a baseline estradiol level greater than 4,500 pg/mL were excluded from participation as a precautionary measure.

Dr. Lamb said the next step planned by the researchers is a dose-finding study to learn whether a smaller dose of FSH would be equally effective, or if perhaps a larger dose would bring a better response.

She disclosed having received a research grant from Ferring Pharmaceuticals.

A larger trial will be required to determine whether the FSH bolus truly does boost pregnancy rates.

Source DR. LAMB

DENVER – Daily self-administered vaginal danazol effectively decreased pain symptoms caused by rectovaginal endometriosis that persisted despite insertion of a levonorgestrel-releasing IUD, a small, prospective, self-controlled pilot study has shown.

The levonorgestrel-releasing IUD (Mirena) is indicated as a contraceptive, and also to treat heavy periods in women who choose to have an IUD. However, the device is also seeing expanding off-label use as a treatment for endometriosis. Several studies indicate the hormone-releasing IUD is effective at improving endometriosis-related pain symptoms in many women who don't want to resort to oral or injectable medications (Contraception 2010; 81:117-22). But for the one-quarter to one-third of patients who request device removal after 6 months because of inadequate pain relief, what's the next option? That was the question Dr. Simone Ferrero and his colleagues set out to answer. He reported on 15 women with rectovaginal endometriosis and chronic pelvic pain, deep dyspareunia, dysmenorrhea, and difficulty in defecating who remained symptomatic despite insertion of Mirena. At the time of study enrollment, they had been on the levonorgestrel-releasing IUD for a mean of 8.2 months and indicated they were either “dissatisfied” or “very dissatisfied” with it. They were then placed on vaginal danazol (Danocrine) at 100 mg/day.

After 3 months of dual therapy, patients reported a significant progressive decrease in mean pain scores on a visual analog scale for chronic pelvic pain, dysmenorrhea, and dyspareunia compared with baseline, according to Dr. Ferrero of San Martino Hospital and the University of Genoa (Italy).

After 6 months, the intensity of all of these symptoms was further diminished, and the reduction in difficulty in defecation had achieved significance. The volume of rectovaginal nodules was significantly reduced compared with baseline.

The most common treatment-related adverse events were seborrhea, acne, and/or oily hair in four patients, headache in three, weight gain in excess of 3 kg in two women, and vaginal irritation in two. No adverse effects were noted in lipid profiles, liver function, or clotting factors.

Twelve of the 15 subjects pronounced themselves satisfied with the dual therapy and opted to continue with it after completing the 6-month study. The major remaining question unanswered by this or other studies is whether the improvement in pain symptoms will continue for the entire 5-year life of the coil, he noted.

He said he had no relevant financial conflicts of interest.

DENVER – Daily self-administered vaginal danazol effectively decreased pain symptoms caused by rectovaginal endometriosis that persisted despite insertion of a levonorgestrel-releasing IUD, a small, prospective, self-controlled pilot study has shown.

The levonorgestrel-releasing IUD (Mirena) is indicated as a contraceptive, and also to treat heavy periods in women who choose to have an IUD. However, the device is also seeing expanding off-label use as a treatment for endometriosis. Several studies indicate the hormone-releasing IUD is effective at improving endometriosis-related pain symptoms in many women who don't want to resort to oral or injectable medications (Contraception 2010; 81:117-22). But for the one-quarter to one-third of patients who request device removal after 6 months because of inadequate pain relief, what's the next option? That was the question Dr. Simone Ferrero and his colleagues set out to answer. He reported on 15 women with rectovaginal endometriosis and chronic pelvic pain, deep dyspareunia, dysmenorrhea, and difficulty in defecating who remained symptomatic despite insertion of Mirena. At the time of study enrollment, they had been on the levonorgestrel-releasing IUD for a mean of 8.2 months and indicated they were either “dissatisfied” or “very dissatisfied” with it. They were then placed on vaginal danazol (Danocrine) at 100 mg/day.

After 3 months of dual therapy, patients reported a significant progressive decrease in mean pain scores on a visual analog scale for chronic pelvic pain, dysmenorrhea, and dyspareunia compared with baseline, according to Dr. Ferrero of San Martino Hospital and the University of Genoa (Italy).

After 6 months, the intensity of all of these symptoms was further diminished, and the reduction in difficulty in defecation had achieved significance. The volume of rectovaginal nodules was significantly reduced compared with baseline.

The most common treatment-related adverse events were seborrhea, acne, and/or oily hair in four patients, headache in three, weight gain in excess of 3 kg in two women, and vaginal irritation in two. No adverse effects were noted in lipid profiles, liver function, or clotting factors.

Twelve of the 15 subjects pronounced themselves satisfied with the dual therapy and opted to continue with it after completing the 6-month study. The major remaining question unanswered by this or other studies is whether the improvement in pain symptoms will continue for the entire 5-year life of the coil, he noted.

He said he had no relevant financial conflicts of interest.

DENVER – Daily self-administered vaginal danazol effectively decreased pain symptoms caused by rectovaginal endometriosis that persisted despite insertion of a levonorgestrel-releasing IUD, a small, prospective, self-controlled pilot study has shown.

The levonorgestrel-releasing IUD (Mirena) is indicated as a contraceptive, and also to treat heavy periods in women who choose to have an IUD. However, the device is also seeing expanding off-label use as a treatment for endometriosis. Several studies indicate the hormone-releasing IUD is effective at improving endometriosis-related pain symptoms in many women who don't want to resort to oral or injectable medications (Contraception 2010; 81:117-22). But for the one-quarter to one-third of patients who request device removal after 6 months because of inadequate pain relief, what's the next option? That was the question Dr. Simone Ferrero and his colleagues set out to answer. He reported on 15 women with rectovaginal endometriosis and chronic pelvic pain, deep dyspareunia, dysmenorrhea, and difficulty in defecating who remained symptomatic despite insertion of Mirena. At the time of study enrollment, they had been on the levonorgestrel-releasing IUD for a mean of 8.2 months and indicated they were either “dissatisfied” or “very dissatisfied” with it. They were then placed on vaginal danazol (Danocrine) at 100 mg/day.

After 3 months of dual therapy, patients reported a significant progressive decrease in mean pain scores on a visual analog scale for chronic pelvic pain, dysmenorrhea, and dyspareunia compared with baseline, according to Dr. Ferrero of San Martino Hospital and the University of Genoa (Italy).

After 6 months, the intensity of all of these symptoms was further diminished, and the reduction in difficulty in defecation had achieved significance. The volume of rectovaginal nodules was significantly reduced compared with baseline.

The most common treatment-related adverse events were seborrhea, acne, and/or oily hair in four patients, headache in three, weight gain in excess of 3 kg in two women, and vaginal irritation in two. No adverse effects were noted in lipid profiles, liver function, or clotting factors.

Twelve of the 15 subjects pronounced themselves satisfied with the dual therapy and opted to continue with it after completing the 6-month study. The major remaining question unanswered by this or other studies is whether the improvement in pain symptoms will continue for the entire 5-year life of the coil, he noted.

He said he had no relevant financial conflicts of interest.

DENVER – Infertile women with blood type O have an increased prevalence of diminished ovarian reserve, according to Dr. Edward J. Nejat.

In contrast, the A blood group antigen, comprised of blood types A and AB, appears to be protective against diminished ovarian reserve. These are novel findings whose clinical implications must await further study, said Dr. Nejat of Albert Einstein College of Medicine, New York.

He presented a cross-sectional observational study involving 563 women under age 45 years seeking treatment for infertility at Montefiore Medical Center in New York or at the Yale University in vitro fertilization program in New Haven, Conn. Diminished ovarian reserve, defined by a baseline serum follicle-stimulating hormone level greater than 10 mIU/mL, was present in 70 subjects.

Ovarian reserve reflects the quantity of gametes available for procreation. Dr. Nejat and his coworkers decided to look for a possible association between blood type and ovarian reserve because other than advancing age, the determinants of ovarian reserve are unclear. Other investigators have previously described a link between blood type A and ovarian hyperstimulation syndrome.

A total of 61% of women with diminished ovarian reserve were blood type O, as were 43% of those with a baseline follicle-stimulation hormone level of 10 mIU/mL. After adjusting the results for age and site, women with blood type O were at twofold greater risk of having diminished ovarian reserve than were women with other blood types.

The A blood group antigen was present in 26% of women with diminished ovarian reserve and 41% of those with adequate ovarian reserve. The adjusted risk of diminished ovarian reserve in women possessing the A blood group antigen was half that in women with blood types O or B. The relationship between blood type and diminished ovarian reserve was independent of age.

Dr. Nejat said he had no relevant financial conflicts.

DENVER – Infertile women with blood type O have an increased prevalence of diminished ovarian reserve, according to Dr. Edward J. Nejat.

In contrast, the A blood group antigen, comprised of blood types A and AB, appears to be protective against diminished ovarian reserve. These are novel findings whose clinical implications must await further study, said Dr. Nejat of Albert Einstein College of Medicine, New York.

He presented a cross-sectional observational study involving 563 women under age 45 years seeking treatment for infertility at Montefiore Medical Center in New York or at the Yale University in vitro fertilization program in New Haven, Conn. Diminished ovarian reserve, defined by a baseline serum follicle-stimulating hormone level greater than 10 mIU/mL, was present in 70 subjects.

Ovarian reserve reflects the quantity of gametes available for procreation. Dr. Nejat and his coworkers decided to look for a possible association between blood type and ovarian reserve because other than advancing age, the determinants of ovarian reserve are unclear. Other investigators have previously described a link between blood type A and ovarian hyperstimulation syndrome.

A total of 61% of women with diminished ovarian reserve were blood type O, as were 43% of those with a baseline follicle-stimulation hormone level of 10 mIU/mL. After adjusting the results for age and site, women with blood type O were at twofold greater risk of having diminished ovarian reserve than were women with other blood types.

The A blood group antigen was present in 26% of women with diminished ovarian reserve and 41% of those with adequate ovarian reserve. The adjusted risk of diminished ovarian reserve in women possessing the A blood group antigen was half that in women with blood types O or B. The relationship between blood type and diminished ovarian reserve was independent of age.

Dr. Nejat said he had no relevant financial conflicts.

DENVER – Infertile women with blood type O have an increased prevalence of diminished ovarian reserve, according to Dr. Edward J. Nejat.

In contrast, the A blood group antigen, comprised of blood types A and AB, appears to be protective against diminished ovarian reserve. These are novel findings whose clinical implications must await further study, said Dr. Nejat of Albert Einstein College of Medicine, New York.

He presented a cross-sectional observational study involving 563 women under age 45 years seeking treatment for infertility at Montefiore Medical Center in New York or at the Yale University in vitro fertilization program in New Haven, Conn. Diminished ovarian reserve, defined by a baseline serum follicle-stimulating hormone level greater than 10 mIU/mL, was present in 70 subjects.

Ovarian reserve reflects the quantity of gametes available for procreation. Dr. Nejat and his coworkers decided to look for a possible association between blood type and ovarian reserve because other than advancing age, the determinants of ovarian reserve are unclear. Other investigators have previously described a link between blood type A and ovarian hyperstimulation syndrome.

A total of 61% of women with diminished ovarian reserve were blood type O, as were 43% of those with a baseline follicle-stimulation hormone level of 10 mIU/mL. After adjusting the results for age and site, women with blood type O were at twofold greater risk of having diminished ovarian reserve than were women with other blood types.

The A blood group antigen was present in 26% of women with diminished ovarian reserve and 41% of those with adequate ovarian reserve. The adjusted risk of diminished ovarian reserve in women possessing the A blood group antigen was half that in women with blood types O or B. The relationship between blood type and diminished ovarian reserve was independent of age.

Dr. Nejat said he had no relevant financial conflicts.

DENVER – Women with no history of depression are at sharply increased risk of first-ever, clinically significant depressive symptoms during the menopausal transition, three major prospective longitudinal studies have shown.

It's a situation that requires clinicians to have their depression-detection radar fully powered up, according to Dr. Nanette F. Santoro.

“A very important thing to remember is that this type of depression is new to these women. This is their first episode. They may come into our offices clearly in distress, but they don't have the vocabulary to tell you they're depressed because they don't know what that feels like,” she said in a plenary lecture at the meeting.

Dr. Santoro presented highlights from the ongoing observational Study of Women's Health Across the Nation (SWAN), in which 3,302 African American, white, Hispanic, Japanese, and Chinese women at seven U.S. sites have been evaluated annually since their enrollment during 1996–1997 at age 42–52 years.

“We're now in our 14th year of SWAN, and we're still cranking out data,” noted Dr. Santoro, professor and chair of the department of obstetrics and gynecology at the University of Colorado, Denver.

At baseline, when the women were premenopausal, 23% had clinically relevant depressive symptoms, as defined by a score of 16 or more on the Center for Epidemiologic Studies Depression Scale (CES-D).

The other 77% of women, those with low baseline CES-D scores and no lifetime history of depression, were hit particularly hard by depressed mood symptoms in the menopausal transition. In a multivariate analysis, a woman with a CES-D of less than 16 at baseline had a 30% higher odds of having a CES-D score of 16 or greater when she was in the early perimenopausal period, which is marked by increased menstrual irregularity but at least one menses within the past 3 months.

Women in the late perimenopausal period, as defined by 3–11 months of amenorrhea, had an adjusted 73% increased odds of significant depressive symptoms, compared with those who were still premenopausal.

The risk was elevated even more in women with significant vasomotor symptoms (J. Affect. Disord. 2007;103:267–72).

“That late perimenopause is just a bummer. It almost doubles the risk,” Dr. Santoro observed.

The risk declines slightly to a 63% increased odds of significant depressive symptoms during the postmenopausal period.

Hormone therapy, which was used by 20% of the SWAN women, may have conferred modest relief from depressive symptoms, as HT users had a peak 64% increase in the odds of a CES-D of 16 or more during the menopausal transition.

The risk of new-onset depressive symptoms during menopause was independent of demographic, psychosocial, and behavioral factors, as well as comorbid conditions, all of which were factored into the multivariate regression analysis.

Chinese women had half the risk of depressive symptoms compared with white women, but the risk in the other ethnic groups didn't vary significantly from that in the white women.

Similar results have been reported from the Harvard Study of Moods and Cycles, in which Dr. Lee S. Cohen and his coworkers studied a cohort of premenopausal women with no lifetime history of major depression. The investigators found that for these women, who were less racially diverse than the SWAN women, entry into perimenopause was associated with a doubled likelihood of developing significant depressive symptoms compared with similar-age women who remained premenopausal.

As in SWAN, the risk of depression was even greater in women with self-reported significant hot flashes and night sweats.

In the Harvard longitudinal study, the use of HT didn't affect the risk of developing depressive symptoms; there was a suggestion that it might have lessened the risk of severe depression arising during the menopausal transition, although the patient numbers were too small to draw firm conclusions (Arch. Gen. Psychiatry 2006;63:385-90).

Investigators at the University of Pennsylvania, Philadelphia, reported that women with no history of depression at enrollment in their longitudinal study were 4.3-fold more likely to post high CES-D scores during the menopausal transition than when they were premenopausal. Formal diagnosis of a depressive disorder was 2.5 times more likely to occur in the menopausal transition (Arch. Gen. Psychiatry 2006;63:375-82).

The Harvard group speculated that the increased risk for developing a first episode of depression when entering the perimenopause could be due in part to the marked sleep disruption caused by hot flashes, and/or to sensitivity to abrupt changes in the reproductive hormone milieu.

In line with that hypothesis, the SWAN investigators recently reported that higher testosterone levels appear to contribute to depressive symptoms arising during the menopausal transition.

No other hormones were associated with a CES-D score of 16 or more (Arch. Gen. Psychiatry 2010;67:598-607).

The SWAN study is funded by the National Institutes of Health. Dr. Santoro said she had no relevant financial conflicts of interest.

'They may come into our offices clearly in distress, but they don't have the vocabulary to tell you they're depressed.'

Source DR. SANTORO

DENVER – Women with no history of depression are at sharply increased risk of first-ever, clinically significant depressive symptoms during the menopausal transition, three major prospective longitudinal studies have shown.

It's a situation that requires clinicians to have their depression-detection radar fully powered up, according to Dr. Nanette F. Santoro.

“A very important thing to remember is that this type of depression is new to these women. This is their first episode. They may come into our offices clearly in distress, but they don't have the vocabulary to tell you they're depressed because they don't know what that feels like,” she said in a plenary lecture at the meeting.

Dr. Santoro presented highlights from the ongoing observational Study of Women's Health Across the Nation (SWAN), in which 3,302 African American, white, Hispanic, Japanese, and Chinese women at seven U.S. sites have been evaluated annually since their enrollment during 1996–1997 at age 42–52 years.

“We're now in our 14th year of SWAN, and we're still cranking out data,” noted Dr. Santoro, professor and chair of the department of obstetrics and gynecology at the University of Colorado, Denver.

At baseline, when the women were premenopausal, 23% had clinically relevant depressive symptoms, as defined by a score of 16 or more on the Center for Epidemiologic Studies Depression Scale (CES-D).

The other 77% of women, those with low baseline CES-D scores and no lifetime history of depression, were hit particularly hard by depressed mood symptoms in the menopausal transition. In a multivariate analysis, a woman with a CES-D of less than 16 at baseline had a 30% higher odds of having a CES-D score of 16 or greater when she was in the early perimenopausal period, which is marked by increased menstrual irregularity but at least one menses within the past 3 months.

Women in the late perimenopausal period, as defined by 3–11 months of amenorrhea, had an adjusted 73% increased odds of significant depressive symptoms, compared with those who were still premenopausal.

The risk was elevated even more in women with significant vasomotor symptoms (J. Affect. Disord. 2007;103:267–72).

“That late perimenopause is just a bummer. It almost doubles the risk,” Dr. Santoro observed.

The risk declines slightly to a 63% increased odds of significant depressive symptoms during the postmenopausal period.

Hormone therapy, which was used by 20% of the SWAN women, may have conferred modest relief from depressive symptoms, as HT users had a peak 64% increase in the odds of a CES-D of 16 or more during the menopausal transition.

The risk of new-onset depressive symptoms during menopause was independent of demographic, psychosocial, and behavioral factors, as well as comorbid conditions, all of which were factored into the multivariate regression analysis.

Chinese women had half the risk of depressive symptoms compared with white women, but the risk in the other ethnic groups didn't vary significantly from that in the white women.

Similar results have been reported from the Harvard Study of Moods and Cycles, in which Dr. Lee S. Cohen and his coworkers studied a cohort of premenopausal women with no lifetime history of major depression. The investigators found that for these women, who were less racially diverse than the SWAN women, entry into perimenopause was associated with a doubled likelihood of developing significant depressive symptoms compared with similar-age women who remained premenopausal.

As in SWAN, the risk of depression was even greater in women with self-reported significant hot flashes and night sweats.

In the Harvard longitudinal study, the use of HT didn't affect the risk of developing depressive symptoms; there was a suggestion that it might have lessened the risk of severe depression arising during the menopausal transition, although the patient numbers were too small to draw firm conclusions (Arch. Gen. Psychiatry 2006;63:385-90).

Investigators at the University of Pennsylvania, Philadelphia, reported that women with no history of depression at enrollment in their longitudinal study were 4.3-fold more likely to post high CES-D scores during the menopausal transition than when they were premenopausal. Formal diagnosis of a depressive disorder was 2.5 times more likely to occur in the menopausal transition (Arch. Gen. Psychiatry 2006;63:375-82).

The Harvard group speculated that the increased risk for developing a first episode of depression when entering the perimenopause could be due in part to the marked sleep disruption caused by hot flashes, and/or to sensitivity to abrupt changes in the reproductive hormone milieu.

In line with that hypothesis, the SWAN investigators recently reported that higher testosterone levels appear to contribute to depressive symptoms arising during the menopausal transition.

No other hormones were associated with a CES-D score of 16 or more (Arch. Gen. Psychiatry 2010;67:598-607).

The SWAN study is funded by the National Institutes of Health. Dr. Santoro said she had no relevant financial conflicts of interest.

'They may come into our offices clearly in distress, but they don't have the vocabulary to tell you they're depressed.'

Source DR. SANTORO

DENVER – Women with no history of depression are at sharply increased risk of first-ever, clinically significant depressive symptoms during the menopausal transition, three major prospective longitudinal studies have shown.

It's a situation that requires clinicians to have their depression-detection radar fully powered up, according to Dr. Nanette F. Santoro.

“A very important thing to remember is that this type of depression is new to these women. This is their first episode. They may come into our offices clearly in distress, but they don't have the vocabulary to tell you they're depressed because they don't know what that feels like,” she said in a plenary lecture at the meeting.

Dr. Santoro presented highlights from the ongoing observational Study of Women's Health Across the Nation (SWAN), in which 3,302 African American, white, Hispanic, Japanese, and Chinese women at seven U.S. sites have been evaluated annually since their enrollment during 1996–1997 at age 42–52 years.

“We're now in our 14th year of SWAN, and we're still cranking out data,” noted Dr. Santoro, professor and chair of the department of obstetrics and gynecology at the University of Colorado, Denver.

At baseline, when the women were premenopausal, 23% had clinically relevant depressive symptoms, as defined by a score of 16 or more on the Center for Epidemiologic Studies Depression Scale (CES-D).

The other 77% of women, those with low baseline CES-D scores and no lifetime history of depression, were hit particularly hard by depressed mood symptoms in the menopausal transition. In a multivariate analysis, a woman with a CES-D of less than 16 at baseline had a 30% higher odds of having a CES-D score of 16 or greater when she was in the early perimenopausal period, which is marked by increased menstrual irregularity but at least one menses within the past 3 months.

Women in the late perimenopausal period, as defined by 3–11 months of amenorrhea, had an adjusted 73% increased odds of significant depressive symptoms, compared with those who were still premenopausal.

The risk was elevated even more in women with significant vasomotor symptoms (J. Affect. Disord. 2007;103:267–72).

“That late perimenopause is just a bummer. It almost doubles the risk,” Dr. Santoro observed.

The risk declines slightly to a 63% increased odds of significant depressive symptoms during the postmenopausal period.

Hormone therapy, which was used by 20% of the SWAN women, may have conferred modest relief from depressive symptoms, as HT users had a peak 64% increase in the odds of a CES-D of 16 or more during the menopausal transition.

The risk of new-onset depressive symptoms during menopause was independent of demographic, psychosocial, and behavioral factors, as well as comorbid conditions, all of which were factored into the multivariate regression analysis.

Chinese women had half the risk of depressive symptoms compared with white women, but the risk in the other ethnic groups didn't vary significantly from that in the white women.

Similar results have been reported from the Harvard Study of Moods and Cycles, in which Dr. Lee S. Cohen and his coworkers studied a cohort of premenopausal women with no lifetime history of major depression. The investigators found that for these women, who were less racially diverse than the SWAN women, entry into perimenopause was associated with a doubled likelihood of developing significant depressive symptoms compared with similar-age women who remained premenopausal.

As in SWAN, the risk of depression was even greater in women with self-reported significant hot flashes and night sweats.

In the Harvard longitudinal study, the use of HT didn't affect the risk of developing depressive symptoms; there was a suggestion that it might have lessened the risk of severe depression arising during the menopausal transition, although the patient numbers were too small to draw firm conclusions (Arch. Gen. Psychiatry 2006;63:385-90).

Investigators at the University of Pennsylvania, Philadelphia, reported that women with no history of depression at enrollment in their longitudinal study were 4.3-fold more likely to post high CES-D scores during the menopausal transition than when they were premenopausal. Formal diagnosis of a depressive disorder was 2.5 times more likely to occur in the menopausal transition (Arch. Gen. Psychiatry 2006;63:375-82).

The Harvard group speculated that the increased risk for developing a first episode of depression when entering the perimenopause could be due in part to the marked sleep disruption caused by hot flashes, and/or to sensitivity to abrupt changes in the reproductive hormone milieu.

In line with that hypothesis, the SWAN investigators recently reported that higher testosterone levels appear to contribute to depressive symptoms arising during the menopausal transition.

No other hormones were associated with a CES-D score of 16 or more (Arch. Gen. Psychiatry 2010;67:598-607).

The SWAN study is funded by the National Institutes of Health. Dr. Santoro said she had no relevant financial conflicts of interest.

'They may come into our offices clearly in distress, but they don't have the vocabulary to tell you they're depressed.'

Source DR. SANTORO

Major Finding: The annual rate of bone loss during the late perimenopausal and early postmenopausal years is 1.8%–2.3% in the lumbar spine and 1.0%–1.4% in the hip. At those rates, 5 years of bone loss would translate to a 7%–10% drop in BMD at the spine in the average woman, along with a 5%–7% decline at the hip.

Data Source: SWAN, a long-term, longitudinal, observational study of 3,302 women from five ethnic groups at seven U.S. sites who were pre- or early perimenopausal at enrollment.

Disclosures: Dr. Santoro declared having no financial interests relevant to the National Institutes of Health–funded study.

DENVER – The Study of Women's Health Across the Nation has filled important knowledge gaps regarding bone loss rates at various stages of the menopausal transition, enabling physicians for the first time to make informed decisions about the appropriate time to screen for osteoporosis.

“Hypoestrogenic bone loss does not occur until the late transition. Duration of amenorrhea is the best predictor of when this process begins. There's no rationale to measure bone mineral density prior to 90 days of amenorrhea if postmenopausal osteoporosis is the clinical issue,” Dr. Nanette F. Santoro explained.

“Bone mineral density at the lumbar spine and total hip starts dropping like a stone as soon as the women get to late menopause, so 3–11 months of amenorrhea is the tipping point for bone density. There is no point in assessing it sooner if you think they may have bone loss related to the menopause transition, because it's not going to be estrogen-related prior to this point,” said Dr. Santoro, a long-time SWAN (Study of Women's Health Across the Nation) investigator and chair of obstetrics and gynecology at the University of Colorado at Denver.

The SWAN findings have important clinical implications because most guidelines don't recommend routine screening of women for osteoporosis until age 65. That's too late. Since the rate of BMD loss accelerates markedly in late menopause, accompanied by an attendant increase in fracture risk, it makes sense to measure BMD after a woman has experienced 3 months of amenorrhea, and to intervene if she is beginning to lose bone rapidly, she continued.

SWAN showed that the annual rate of bone loss during the late perimenopausal and early postmenopausal years is 1.8%–2.3% in the lumbar spine and 1.0%–1.4% in the hip.

At those rates, 5 years of bone loss would translate to a 7%–10% drop in BMD at the spine in the average woman, along with a 5%–7% decline at the hip. And that in turn foretells a 50%–100% higher fracture rate.

Another key SWAN finding regarding BMD changes during the menopausal transition is that rates of bone loss are markedly greater in women who are in the lowest tertile of body weight.

Indeed, women in the top tertile for body weight had a 33%–55% slower rate of bone loss than did those in the lightest tertile.

The apparent large ethnic differences in bone loss rates observed in SWAN turned out on closer inspection to be explained chiefly by ethnic differences in body weight.

SWAN is a long-term, longitudinal, observational study involving 3,302 women who were pre- or early perimenopausal at enrollment. Participants were recruited from five ethnic groups – white, black, Hispanic, Japanese, and Chinese – at seven U.S. sites.

The BMD substudy included 1,902 SWAN participants with BMD measurements obtained at up to six annual visits. The key findings of the BMD substudy have already been published (J. Clin. Endocrinol. Metab. 2008;93:861-8). Dr. Santoro, in her plenary lecture at the meeting, sought to spread the word.

Major Finding: The annual rate of bone loss during the late perimenopausal and early postmenopausal years is 1.8%–2.3% in the lumbar spine and 1.0%–1.4% in the hip. At those rates, 5 years of bone loss would translate to a 7%–10% drop in BMD at the spine in the average woman, along with a 5%–7% decline at the hip.

Data Source: SWAN, a long-term, longitudinal, observational study of 3,302 women from five ethnic groups at seven U.S. sites who were pre- or early perimenopausal at enrollment.

Disclosures: Dr. Santoro declared having no financial interests relevant to the National Institutes of Health–funded study.

DENVER – The Study of Women's Health Across the Nation has filled important knowledge gaps regarding bone loss rates at various stages of the menopausal transition, enabling physicians for the first time to make informed decisions about the appropriate time to screen for osteoporosis.

“Hypoestrogenic bone loss does not occur until the late transition. Duration of amenorrhea is the best predictor of when this process begins. There's no rationale to measure bone mineral density prior to 90 days of amenorrhea if postmenopausal osteoporosis is the clinical issue,” Dr. Nanette F. Santoro explained.

“Bone mineral density at the lumbar spine and total hip starts dropping like a stone as soon as the women get to late menopause, so 3–11 months of amenorrhea is the tipping point for bone density. There is no point in assessing it sooner if you think they may have bone loss related to the menopause transition, because it's not going to be estrogen-related prior to this point,” said Dr. Santoro, a long-time SWAN (Study of Women's Health Across the Nation) investigator and chair of obstetrics and gynecology at the University of Colorado at Denver.

The SWAN findings have important clinical implications because most guidelines don't recommend routine screening of women for osteoporosis until age 65. That's too late. Since the rate of BMD loss accelerates markedly in late menopause, accompanied by an attendant increase in fracture risk, it makes sense to measure BMD after a woman has experienced 3 months of amenorrhea, and to intervene if she is beginning to lose bone rapidly, she continued.

SWAN showed that the annual rate of bone loss during the late perimenopausal and early postmenopausal years is 1.8%–2.3% in the lumbar spine and 1.0%–1.4% in the hip.

At those rates, 5 years of bone loss would translate to a 7%–10% drop in BMD at the spine in the average woman, along with a 5%–7% decline at the hip. And that in turn foretells a 50%–100% higher fracture rate.

Another key SWAN finding regarding BMD changes during the menopausal transition is that rates of bone loss are markedly greater in women who are in the lowest tertile of body weight.

Indeed, women in the top tertile for body weight had a 33%–55% slower rate of bone loss than did those in the lightest tertile.

The apparent large ethnic differences in bone loss rates observed in SWAN turned out on closer inspection to be explained chiefly by ethnic differences in body weight.

SWAN is a long-term, longitudinal, observational study involving 3,302 women who were pre- or early perimenopausal at enrollment. Participants were recruited from five ethnic groups – white, black, Hispanic, Japanese, and Chinese – at seven U.S. sites.

The BMD substudy included 1,902 SWAN participants with BMD measurements obtained at up to six annual visits. The key findings of the BMD substudy have already been published (J. Clin. Endocrinol. Metab. 2008;93:861-8). Dr. Santoro, in her plenary lecture at the meeting, sought to spread the word.

Major Finding: The annual rate of bone loss during the late perimenopausal and early postmenopausal years is 1.8%–2.3% in the lumbar spine and 1.0%–1.4% in the hip. At those rates, 5 years of bone loss would translate to a 7%–10% drop in BMD at the spine in the average woman, along with a 5%–7% decline at the hip.

Data Source: SWAN, a long-term, longitudinal, observational study of 3,302 women from five ethnic groups at seven U.S. sites who were pre- or early perimenopausal at enrollment.

Disclosures: Dr. Santoro declared having no financial interests relevant to the National Institutes of Health–funded study.

DENVER – The Study of Women's Health Across the Nation has filled important knowledge gaps regarding bone loss rates at various stages of the menopausal transition, enabling physicians for the first time to make informed decisions about the appropriate time to screen for osteoporosis.

“Hypoestrogenic bone loss does not occur until the late transition. Duration of amenorrhea is the best predictor of when this process begins. There's no rationale to measure bone mineral density prior to 90 days of amenorrhea if postmenopausal osteoporosis is the clinical issue,” Dr. Nanette F. Santoro explained.

“Bone mineral density at the lumbar spine and total hip starts dropping like a stone as soon as the women get to late menopause, so 3–11 months of amenorrhea is the tipping point for bone density. There is no point in assessing it sooner if you think they may have bone loss related to the menopause transition, because it's not going to be estrogen-related prior to this point,” said Dr. Santoro, a long-time SWAN (Study of Women's Health Across the Nation) investigator and chair of obstetrics and gynecology at the University of Colorado at Denver.

The SWAN findings have important clinical implications because most guidelines don't recommend routine screening of women for osteoporosis until age 65. That's too late. Since the rate of BMD loss accelerates markedly in late menopause, accompanied by an attendant increase in fracture risk, it makes sense to measure BMD after a woman has experienced 3 months of amenorrhea, and to intervene if she is beginning to lose bone rapidly, she continued.

SWAN showed that the annual rate of bone loss during the late perimenopausal and early postmenopausal years is 1.8%–2.3% in the lumbar spine and 1.0%–1.4% in the hip.

At those rates, 5 years of bone loss would translate to a 7%–10% drop in BMD at the spine in the average woman, along with a 5%–7% decline at the hip. And that in turn foretells a 50%–100% higher fracture rate.

Another key SWAN finding regarding BMD changes during the menopausal transition is that rates of bone loss are markedly greater in women who are in the lowest tertile of body weight.

Indeed, women in the top tertile for body weight had a 33%–55% slower rate of bone loss than did those in the lightest tertile.

The apparent large ethnic differences in bone loss rates observed in SWAN turned out on closer inspection to be explained chiefly by ethnic differences in body weight.

SWAN is a long-term, longitudinal, observational study involving 3,302 women who were pre- or early perimenopausal at enrollment. Participants were recruited from five ethnic groups – white, black, Hispanic, Japanese, and Chinese – at seven U.S. sites.

The BMD substudy included 1,902 SWAN participants with BMD measurements obtained at up to six annual visits. The key findings of the BMD substudy have already been published (J. Clin. Endocrinol. Metab. 2008;93:861-8). Dr. Santoro, in her plenary lecture at the meeting, sought to spread the word.

Major Finding: After 11 years of follow-up, the incidence of breast cancer is up by 25% in the dual-hormone therapy group relative to placebo. Yet the relative increase in mortality is 96%.

Data Source: An updated analysis of the Women's Health Initiative randomized trials.

Disclosures: Dr. Chlebowski disclosed that he receives grant support from Amgen and is on the speakers bureaus for AstraZeneca and Novartis. Dr. Coates reported having no relevant financial disclosures.

SAN ANTONIO – Menopausal hormone therapy with estrogen plus progestin doubles a woman's risk of death from breast cancer, nearly doubles the risk of death from non–small cell lung cancer, and increases the risk of death from colorectal cancer by 54%, according to an updated analysis of the Women's Health Initiative randomized trials.

Because breast and lung cancer are the top two causes of cancer mortality in women, these are sobering findings with important clinical implications, observed Dr. Rowan T. Chlebowski, professor of medicine at the University of California, Los Angeles.

The 54% increased risk of death after diagnosis of colorectal cancer in Women's Health Initiative (WHI) participants who were randomized to combined-hormone therapy rather than placebo was a trend that didn't achieve statistical significance. But it's nonetheless a finding that crushes the enthusiasm that greeted an earlier WHI report of a 44% reduction in the incidence of colorectal cancer in combined-hormone therapy users after 5.6 years of follow-up (N. Engl. J. Med. 2004;350:991–1004).

Given the initial observation of fewer colorectal cancers being diagnosed in the combined-therapy arm of the WHI, investigators were quite surprised by the tumor characteristics of these cancers at time of diagnosis: The colorectal cancers arising in the combined-therapy group – although fewer in number – were much higher risk. In all, 76% of them were pathologically staged as regional or metastatic disease, compared with 48% of colorectal cancers in women on placebo, and 59% percent of the colorectal cancers detected in combined-hormone therapy users were lymph node positive, compared with just 29% in placebo-treated controls.

The WHI consisted of two separate National Institutes of Health–funded, randomized trials that profoundly altered the management of menopausal symptoms. In the early 1990s, more than 40% of all postmenopausal women were on hormonal therapy with estrogen alone or in combination with progestin. Following the initial WHI report of multiple adverse effects of estrogen plus progestin, the popularity of hormone therapy dropped off the table.

One WHI study involved 16,608 postmenopausal women aged 50–79 years with an intact uterus who were randomized to estrogen plus progestin or to placebo for a median of 5.6 years. The other study included 10,739 postmenopausal women with prior hysterectomy who were randomized to conjugated equine estrogens alone or placebo for an average of 7.1 years.

In the examination of WHI trends for the big-three (breast, lung, and colorectal) cancers in women, there is a consistent disparity between their relatively modestly increased incidence in dual-hormone therapy users, relative to placebo, and the far larger death rates resulting from these cancers. For example, after 11 years of follow-up, the incidence of breast cancer is up by 25% in the dual-hormone therapy group, relative to placebo. Yet the relative increase in mortality is 96%. Similarly, the incidence of non–small cell lung cancer (NSCLC) was 23% greater in women on combined-hormone therapy than in those on placebo, but the risk of death from NSCLC was 87% greater.

“The greater effect of estrogen and progestin on deaths from breast, lung, and colorectal cancer – [compared with] the effect on incidence – [suggests that] combined-hormone therapy facilitates growth and metastatic spread of established cancers, perhaps mediated by angiogenesis stimulation,” the oncologist said, adding that “in a variety of preclinical models, estrogen and progestin are potent angiogenesis stimulators.”

The investigators' initial hypothesis was that nearly all the increase in breast cancers associated with combined-hormone therapy would involve estrogen receptor–positive tumors. Not so. In fact, the new analysis – based upon 11 years of follow-up and 678 cases of breast cancer – shows that all breast cancer subtypes appear to be increased, relative to rates in the placebo arm.

For example, combined-hormone therapy was indeed associated with an adjusted 27% greater increase in estrogen receptor–positive breast cancers than with placebo in a multivariate analysis, but it was also associated with a 40% increase in estrogen receptor–negative tumors, compared with controls. Also noteworthy were the combined-therapy group's adjusted 78% increase in triple-negative cancers, the twofold increase in HER2-overexpressing tumors, and the 37% increase in HER2-negative tumors.

Nearly all the increase in lung cancer deaths associated with dual-hormone therapy resulted from NSCLC. Hormone therapy had no effect upon small cell lung cancer rates.

Among current smokers, the cumulative risk of death from lung cancer was 3.42% in those who used dual-hormone therapy for 5-plus years and 2.39% in placebo-treated controls. In other words, 1 in 100 current smokers who used estrogen plus progestin for 5-plus years experienced an otherwise-avoidable death from NSCLC. Among past smokers, the rate was 1 in 200. These numbers are worth keeping in mind, given that today roughly 15% of U.S. women are current smokers, and 35% are past smokers, he noted.

Turning to the results of the estrogen-alone WHI trial, he pointed out that the therapy had no impact on incidence or death rates from lung or colorectal cancer, relative to placebo, but there was a nonsignificant 20% reduction in the relative risk of breast cancer in the hormone therapy group. This trend for a breast cancer–reduction benefit achieved significance in the nearly 4,500 study participants who were randomized to estrogen alone or placebo 5 years or more following the last menstrual period, where the hormonal therapy group enjoyed a 37% relative risk reduction. Of course, that's not how hormone therapy is ordinarily employed in clinical practice, the physician pointed out.

One audience member rose to say that the oft-quoted sharply increased risk of uterine cancer in women with an intact uterus on estrogen alone dates back to older studies using doses that were considerably higher than those available in contemporary practice, as well as older methods of patient monitoring. What about the possibility of exploring ways to provide estrogen alone to menopausal women with an intact uterus without exposing them to increased uterine cancer risk? she asked.

Dr. Chlebowski said he thinks it's certainly an appropriate research project, but he'd advise against trying it in clinical practice, given the product labeling and the malpractice lawsuit climate.

His take-home message from the expanded WHI analysis: “Even short-term use of combined-hormone therapy should be reserved for women with limiting climacteric symptoms [that are] not manageable by other means.”

In a conference-closing review of the past year's top developments in early breast cancer, Dr. Alan Coates singled out Dr. Chlebowski's presentation on the WHI results as hands-down the most important study of the year in the field of cancer epidemiology. “As we've known before, there's a small but real increase in the incidence of breast cancer with combined-hormone replacement. The new finding is that there's a massive increase – nearly a doubling – in mortality from breast cancer. And the mortality increase isn't confined to breast cancer. … This disparate increase in mortality over incidence in several tumor types suggests that the estrogen and progestin [combination] is doing something to the behavior of existing tumors,” said Dr. Coates of the University of Sydney.

The incidence of breast cancer is up 25% with dual-hormone therapy, but the relative increase in mortality is 96%.

Source DR. CHLEBOWSKI

Major Finding: After 11 years of follow-up, the incidence of breast cancer is up by 25% in the dual-hormone therapy group relative to placebo. Yet the relative increase in mortality is 96%.

Data Source: An updated analysis of the Women's Health Initiative randomized trials.

Disclosures: Dr. Chlebowski disclosed that he receives grant support from Amgen and is on the speakers bureaus for AstraZeneca and Novartis. Dr. Coates reported having no relevant financial disclosures.

SAN ANTONIO – Menopausal hormone therapy with estrogen plus progestin doubles a woman's risk of death from breast cancer, nearly doubles the risk of death from non–small cell lung cancer, and increases the risk of death from colorectal cancer by 54%, according to an updated analysis of the Women's Health Initiative randomized trials.

Because breast and lung cancer are the top two causes of cancer mortality in women, these are sobering findings with important clinical implications, observed Dr. Rowan T. Chlebowski, professor of medicine at the University of California, Los Angeles.

The 54% increased risk of death after diagnosis of colorectal cancer in Women's Health Initiative (WHI) participants who were randomized to combined-hormone therapy rather than placebo was a trend that didn't achieve statistical significance. But it's nonetheless a finding that crushes the enthusiasm that greeted an earlier WHI report of a 44% reduction in the incidence of colorectal cancer in combined-hormone therapy users after 5.6 years of follow-up (N. Engl. J. Med. 2004;350:991–1004).

Given the initial observation of fewer colorectal cancers being diagnosed in the combined-therapy arm of the WHI, investigators were quite surprised by the tumor characteristics of these cancers at time of diagnosis: The colorectal cancers arising in the combined-therapy group – although fewer in number – were much higher risk. In all, 76% of them were pathologically staged as regional or metastatic disease, compared with 48% of colorectal cancers in women on placebo, and 59% percent of the colorectal cancers detected in combined-hormone therapy users were lymph node positive, compared with just 29% in placebo-treated controls.

The WHI consisted of two separate National Institutes of Health–funded, randomized trials that profoundly altered the management of menopausal symptoms. In the early 1990s, more than 40% of all postmenopausal women were on hormonal therapy with estrogen alone or in combination with progestin. Following the initial WHI report of multiple adverse effects of estrogen plus progestin, the popularity of hormone therapy dropped off the table.

One WHI study involved 16,608 postmenopausal women aged 50–79 years with an intact uterus who were randomized to estrogen plus progestin or to placebo for a median of 5.6 years. The other study included 10,739 postmenopausal women with prior hysterectomy who were randomized to conjugated equine estrogens alone or placebo for an average of 7.1 years.

In the examination of WHI trends for the big-three (breast, lung, and colorectal) cancers in women, there is a consistent disparity between their relatively modestly increased incidence in dual-hormone therapy users, relative to placebo, and the far larger death rates resulting from these cancers. For example, after 11 years of follow-up, the incidence of breast cancer is up by 25% in the dual-hormone therapy group, relative to placebo. Yet the relative increase in mortality is 96%. Similarly, the incidence of non–small cell lung cancer (NSCLC) was 23% greater in women on combined-hormone therapy than in those on placebo, but the risk of death from NSCLC was 87% greater.

“The greater effect of estrogen and progestin on deaths from breast, lung, and colorectal cancer – [compared with] the effect on incidence – [suggests that] combined-hormone therapy facilitates growth and metastatic spread of established cancers, perhaps mediated by angiogenesis stimulation,” the oncologist said, adding that “in a variety of preclinical models, estrogen and progestin are potent angiogenesis stimulators.”

The investigators' initial hypothesis was that nearly all the increase in breast cancers associated with combined-hormone therapy would involve estrogen receptor–positive tumors. Not so. In fact, the new analysis – based upon 11 years of follow-up and 678 cases of breast cancer – shows that all breast cancer subtypes appear to be increased, relative to rates in the placebo arm.

For example, combined-hormone therapy was indeed associated with an adjusted 27% greater increase in estrogen receptor–positive breast cancers than with placebo in a multivariate analysis, but it was also associated with a 40% increase in estrogen receptor–negative tumors, compared with controls. Also noteworthy were the combined-therapy group's adjusted 78% increase in triple-negative cancers, the twofold increase in HER2-overexpressing tumors, and the 37% increase in HER2-negative tumors.

Nearly all the increase in lung cancer deaths associated with dual-hormone therapy resulted from NSCLC. Hormone therapy had no effect upon small cell lung cancer rates.

Among current smokers, the cumulative risk of death from lung cancer was 3.42% in those who used dual-hormone therapy for 5-plus years and 2.39% in placebo-treated controls. In other words, 1 in 100 current smokers who used estrogen plus progestin for 5-plus years experienced an otherwise-avoidable death from NSCLC. Among past smokers, the rate was 1 in 200. These numbers are worth keeping in mind, given that today roughly 15% of U.S. women are current smokers, and 35% are past smokers, he noted.

Turning to the results of the estrogen-alone WHI trial, he pointed out that the therapy had no impact on incidence or death rates from lung or colorectal cancer, relative to placebo, but there was a nonsignificant 20% reduction in the relative risk of breast cancer in the hormone therapy group. This trend for a breast cancer–reduction benefit achieved significance in the nearly 4,500 study participants who were randomized to estrogen alone or placebo 5 years or more following the last menstrual period, where the hormonal therapy group enjoyed a 37% relative risk reduction. Of course, that's not how hormone therapy is ordinarily employed in clinical practice, the physician pointed out.

One audience member rose to say that the oft-quoted sharply increased risk of uterine cancer in women with an intact uterus on estrogen alone dates back to older studies using doses that were considerably higher than those available in contemporary practice, as well as older methods of patient monitoring. What about the possibility of exploring ways to provide estrogen alone to menopausal women with an intact uterus without exposing them to increased uterine cancer risk? she asked.

Dr. Chlebowski said he thinks it's certainly an appropriate research project, but he'd advise against trying it in clinical practice, given the product labeling and the malpractice lawsuit climate.

His take-home message from the expanded WHI analysis: “Even short-term use of combined-hormone therapy should be reserved for women with limiting climacteric symptoms [that are] not manageable by other means.”

In a conference-closing review of the past year's top developments in early breast cancer, Dr. Alan Coates singled out Dr. Chlebowski's presentation on the WHI results as hands-down the most important study of the year in the field of cancer epidemiology. “As we've known before, there's a small but real increase in the incidence of breast cancer with combined-hormone replacement. The new finding is that there's a massive increase – nearly a doubling – in mortality from breast cancer. And the mortality increase isn't confined to breast cancer. … This disparate increase in mortality over incidence in several tumor types suggests that the estrogen and progestin [combination] is doing something to the behavior of existing tumors,” said Dr. Coates of the University of Sydney.

The incidence of breast cancer is up 25% with dual-hormone therapy, but the relative increase in mortality is 96%.

Source DR. CHLEBOWSKI

Major Finding: After 11 years of follow-up, the incidence of breast cancer is up by 25% in the dual-hormone therapy group relative to placebo. Yet the relative increase in mortality is 96%.

Data Source: An updated analysis of the Women's Health Initiative randomized trials.

Disclosures: Dr. Chlebowski disclosed that he receives grant support from Amgen and is on the speakers bureaus for AstraZeneca and Novartis. Dr. Coates reported having no relevant financial disclosures.

SAN ANTONIO – Menopausal hormone therapy with estrogen plus progestin doubles a woman's risk of death from breast cancer, nearly doubles the risk of death from non–small cell lung cancer, and increases the risk of death from colorectal cancer by 54%, according to an updated analysis of the Women's Health Initiative randomized trials.

Because breast and lung cancer are the top two causes of cancer mortality in women, these are sobering findings with important clinical implications, observed Dr. Rowan T. Chlebowski, professor of medicine at the University of California, Los Angeles.

The 54% increased risk of death after diagnosis of colorectal cancer in Women's Health Initiative (WHI) participants who were randomized to combined-hormone therapy rather than placebo was a trend that didn't achieve statistical significance. But it's nonetheless a finding that crushes the enthusiasm that greeted an earlier WHI report of a 44% reduction in the incidence of colorectal cancer in combined-hormone therapy users after 5.6 years of follow-up (N. Engl. J. Med. 2004;350:991–1004).

Given the initial observation of fewer colorectal cancers being diagnosed in the combined-therapy arm of the WHI, investigators were quite surprised by the tumor characteristics of these cancers at time of diagnosis: The colorectal cancers arising in the combined-therapy group – although fewer in number – were much higher risk. In all, 76% of them were pathologically staged as regional or metastatic disease, compared with 48% of colorectal cancers in women on placebo, and 59% percent of the colorectal cancers detected in combined-hormone therapy users were lymph node positive, compared with just 29% in placebo-treated controls.

The WHI consisted of two separate National Institutes of Health–funded, randomized trials that profoundly altered the management of menopausal symptoms. In the early 1990s, more than 40% of all postmenopausal women were on hormonal therapy with estrogen alone or in combination with progestin. Following the initial WHI report of multiple adverse effects of estrogen plus progestin, the popularity of hormone therapy dropped off the table.

One WHI study involved 16,608 postmenopausal women aged 50–79 years with an intact uterus who were randomized to estrogen plus progestin or to placebo for a median of 5.6 years. The other study included 10,739 postmenopausal women with prior hysterectomy who were randomized to conjugated equine estrogens alone or placebo for an average of 7.1 years.

In the examination of WHI trends for the big-three (breast, lung, and colorectal) cancers in women, there is a consistent disparity between their relatively modestly increased incidence in dual-hormone therapy users, relative to placebo, and the far larger death rates resulting from these cancers. For example, after 11 years of follow-up, the incidence of breast cancer is up by 25% in the dual-hormone therapy group, relative to placebo. Yet the relative increase in mortality is 96%. Similarly, the incidence of non–small cell lung cancer (NSCLC) was 23% greater in women on combined-hormone therapy than in those on placebo, but the risk of death from NSCLC was 87% greater.

“The greater effect of estrogen and progestin on deaths from breast, lung, and colorectal cancer – [compared with] the effect on incidence – [suggests that] combined-hormone therapy facilitates growth and metastatic spread of established cancers, perhaps mediated by angiogenesis stimulation,” the oncologist said, adding that “in a variety of preclinical models, estrogen and progestin are potent angiogenesis stimulators.”

The investigators' initial hypothesis was that nearly all the increase in breast cancers associated with combined-hormone therapy would involve estrogen receptor–positive tumors. Not so. In fact, the new analysis – based upon 11 years of follow-up and 678 cases of breast cancer – shows that all breast cancer subtypes appear to be increased, relative to rates in the placebo arm.

For example, combined-hormone therapy was indeed associated with an adjusted 27% greater increase in estrogen receptor–positive breast cancers than with placebo in a multivariate analysis, but it was also associated with a 40% increase in estrogen receptor–negative tumors, compared with controls. Also noteworthy were the combined-therapy group's adjusted 78% increase in triple-negative cancers, the twofold increase in HER2-overexpressing tumors, and the 37% increase in HER2-negative tumors.

Nearly all the increase in lung cancer deaths associated with dual-hormone therapy resulted from NSCLC. Hormone therapy had no effect upon small cell lung cancer rates.

Among current smokers, the cumulative risk of death from lung cancer was 3.42% in those who used dual-hormone therapy for 5-plus years and 2.39% in placebo-treated controls. In other words, 1 in 100 current smokers who used estrogen plus progestin for 5-plus years experienced an otherwise-avoidable death from NSCLC. Among past smokers, the rate was 1 in 200. These numbers are worth keeping in mind, given that today roughly 15% of U.S. women are current smokers, and 35% are past smokers, he noted.

Turning to the results of the estrogen-alone WHI trial, he pointed out that the therapy had no impact on incidence or death rates from lung or colorectal cancer, relative to placebo, but there was a nonsignificant 20% reduction in the relative risk of breast cancer in the hormone therapy group. This trend for a breast cancer–reduction benefit achieved significance in the nearly 4,500 study participants who were randomized to estrogen alone or placebo 5 years or more following the last menstrual period, where the hormonal therapy group enjoyed a 37% relative risk reduction. Of course, that's not how hormone therapy is ordinarily employed in clinical practice, the physician pointed out.

One audience member rose to say that the oft-quoted sharply increased risk of uterine cancer in women with an intact uterus on estrogen alone dates back to older studies using doses that were considerably higher than those available in contemporary practice, as well as older methods of patient monitoring. What about the possibility of exploring ways to provide estrogen alone to menopausal women with an intact uterus without exposing them to increased uterine cancer risk? she asked.

Dr. Chlebowski said he thinks it's certainly an appropriate research project, but he'd advise against trying it in clinical practice, given the product labeling and the malpractice lawsuit climate.

His take-home message from the expanded WHI analysis: “Even short-term use of combined-hormone therapy should be reserved for women with limiting climacteric symptoms [that are] not manageable by other means.”

In a conference-closing review of the past year's top developments in early breast cancer, Dr. Alan Coates singled out Dr. Chlebowski's presentation on the WHI results as hands-down the most important study of the year in the field of cancer epidemiology. “As we've known before, there's a small but real increase in the incidence of breast cancer with combined-hormone replacement. The new finding is that there's a massive increase – nearly a doubling – in mortality from breast cancer. And the mortality increase isn't confined to breast cancer. … This disparate increase in mortality over incidence in several tumor types suggests that the estrogen and progestin [combination] is doing something to the behavior of existing tumors,” said Dr. Coates of the University of Sydney.

The incidence of breast cancer is up 25% with dual-hormone therapy, but the relative increase in mortality is 96%.

Source DR. CHLEBOWSKI

Major Finding: A total of 90% of patients with cryopyrin-associated periodic syndrome remained in remission continuously for the full 2 years on subcutaneous canakinumab injected once every 8 weeks.

Data Source: A 2-year, open-label study of 166 CAPS patients aged 3 years or older, of whom 109 were canakinumab-naive.

Disclosures: The canakinumab study was sponsored by Novartis, which provided Dr. Leslie with grant support.

GOTHENBURG, SWEDEN — Interleukin-1 blockade with canakinumab provided rapid and sustained clinical remission in the great majority of treated children and adults with cryopyrin-associated periodic syndrome who participated in a large 2-year study.

Most participants experienced significant improvement within a day or two after their first injection and were complete clinical responders with normalized inflammatory markers by day 8. said Dr. Kieron S. Leslie.

In all, 90% of patients remained in remission continuously for the full 2 years on subcutaneous canakinumab (Ilaris) injected once every 8 weeks, added Dr. Leslie, a dermatologist at the University of California, San Francisco.

The new study confirms canakinumab's safety and efficacy over a far longer treatment period. It also provides important new prescribing information: namely, that children with cryopyrin-associated periodic syndrome (CAPS) – as well as adults with the most severe form of the syndrome, known as neonatal-onset multisystem inflammatory disease (NOMID) – often require an upward dosing adjustment to obtain complete response.

CAPS is the latest term for a three-part autoinflammatory disease spectrum caused by mutations in the NLRP3 gene. At the mildest end is familial cold autoinflammatory syndrome (FCAS), an autosomal dominant condition marked by arthralgia, cold-induced rash, and conjunctivitis. In the middle is Muckle-Wells syndrome, also autosomal dominant, and characterized by sensorineural deafness and, in one-quarter of cases, by amyloid A amyloidosis. At the most severe end of the CAPS spectrum is NOMID, which includes the other disease manifestations plus a destructive arthritis and progressive meningitis resulting in visual impairment, deafness, and intellectual impairment.

Canakinumab is a fully human monoclonal antibody directed against IgG1 and interleukin-1 beta. It has a half-life of about 25 days. It was licensed last year in both the United States and Europe for treatment of CAPS. The standard weight-based dosing regimen is subcutaneous injection of 150 mg once every 8 weeks in adults, or 2 mg/kg in patients weighing 40 kg or less.

The 2-year, open-label study involved 166 CAPS patients aged 3 years or older, of whom 109 were canakinumab naive, including 38 children. The other 57 patients were rolled over from earlier studies. In all, 91% of subjects completed the 2-year study.

All 57 patients with prior exposure to canakinumab had a complete response to the biologic in this study, as did 85 of 109 treatment-naive patients.

Of the 85 treatment-naive complete responders, 79 achieved their complete response within 8 days; the rest did so during days 10-21.

All 24 canakinumab-naive patients who didn't attain a complete response nonetheless showed lesser clinical improvement. A complete response required a rating of minimal or no disease on the physician's global assessment of disease activity, plus normalization of both C-reactive protein and serum amyloid A levels, inflammatory markers that were typically elevated to 70-100 mg/L before treatment.

A dose increase was required in 36% of the 47 pediatric patients in the study, compared with 19% of the adults.

Children with Muckle-Wells syndrome or NOMID required a mean 5.5 and 5.8 mg/kg, respectively, of canakinumab per injection, compared with the standard 2.0 mg/kg. Of the 32 participants with NOMID, 47% required a dose increase; adults with NOMID required a mean dose of 229 mg rather than the 150 mg listed in the product labeling, the dermatologist continued.

In all, 92% of patients had no injection site reactions. The injection site reactions in the 8% of affected patients were mild to moderate.

Patients on canakinumab reported an increase in mild upper respiratory tract infections. Severe adverse events (mainly urosepsis, other major infections, or vertigo) occurred in 10%. However, only three patients withdrew from the study because of adverse events over the course of 2 years.

Dr. Leslie was asked how canakinumab compares in terms of efficacy and cost to anakinra (Kineret), an interleukin-1 antagonist that has also shown efficacy in CAPS.

He replied that there are no comparative trials, but anecdotally the results are quite comparable. Both drugs bring almost complete remission.

The difference is that anakinra has a half-life of 6 hours and must be administered daily rather than every 8 weeks. And moderate to severe injection site reactions are a problematic issue with anakinra.

Major Finding: A total of 90% of patients with cryopyrin-associated periodic syndrome remained in remission continuously for the full 2 years on subcutaneous canakinumab injected once every 8 weeks.

Data Source: A 2-year, open-label study of 166 CAPS patients aged 3 years or older, of whom 109 were canakinumab-naive.

Disclosures: The canakinumab study was sponsored by Novartis, which provided Dr. Leslie with grant support.

GOTHENBURG, SWEDEN — Interleukin-1 blockade with canakinumab provided rapid and sustained clinical remission in the great majority of treated children and adults with cryopyrin-associated periodic syndrome who participated in a large 2-year study.

Most participants experienced significant improvement within a day or two after their first injection and were complete clinical responders with normalized inflammatory markers by day 8. said Dr. Kieron S. Leslie.

In all, 90% of patients remained in remission continuously for the full 2 years on subcutaneous canakinumab (Ilaris) injected once every 8 weeks, added Dr. Leslie, a dermatologist at the University of California, San Francisco.

The new study confirms canakinumab's safety and efficacy over a far longer treatment period. It also provides important new prescribing information: namely, that children with cryopyrin-associated periodic syndrome (CAPS) – as well as adults with the most severe form of the syndrome, known as neonatal-onset multisystem inflammatory disease (NOMID) – often require an upward dosing adjustment to obtain complete response.

CAPS is the latest term for a three-part autoinflammatory disease spectrum caused by mutations in the NLRP3 gene. At the mildest end is familial cold autoinflammatory syndrome (FCAS), an autosomal dominant condition marked by arthralgia, cold-induced rash, and conjunctivitis. In the middle is Muckle-Wells syndrome, also autosomal dominant, and characterized by sensorineural deafness and, in one-quarter of cases, by amyloid A amyloidosis. At the most severe end of the CAPS spectrum is NOMID, which includes the other disease manifestations plus a destructive arthritis and progressive meningitis resulting in visual impairment, deafness, and intellectual impairment.

Canakinumab is a fully human monoclonal antibody directed against IgG1 and interleukin-1 beta. It has a half-life of about 25 days. It was licensed last year in both the United States and Europe for treatment of CAPS. The standard weight-based dosing regimen is subcutaneous injection of 150 mg once every 8 weeks in adults, or 2 mg/kg in patients weighing 40 kg or less.

The 2-year, open-label study involved 166 CAPS patients aged 3 years or older, of whom 109 were canakinumab naive, including 38 children. The other 57 patients were rolled over from earlier studies. In all, 91% of subjects completed the 2-year study.

All 57 patients with prior exposure to canakinumab had a complete response to the biologic in this study, as did 85 of 109 treatment-naive patients.

Of the 85 treatment-naive complete responders, 79 achieved their complete response within 8 days; the rest did so during days 10-21.

All 24 canakinumab-naive patients who didn't attain a complete response nonetheless showed lesser clinical improvement. A complete response required a rating of minimal or no disease on the physician's global assessment of disease activity, plus normalization of both C-reactive protein and serum amyloid A levels, inflammatory markers that were typically elevated to 70-100 mg/L before treatment.

A dose increase was required in 36% of the 47 pediatric patients in the study, compared with 19% of the adults.

Children with Muckle-Wells syndrome or NOMID required a mean 5.5 and 5.8 mg/kg, respectively, of canakinumab per injection, compared with the standard 2.0 mg/kg. Of the 32 participants with NOMID, 47% required a dose increase; adults with NOMID required a mean dose of 229 mg rather than the 150 mg listed in the product labeling, the dermatologist continued.

In all, 92% of patients had no injection site reactions. The injection site reactions in the 8% of affected patients were mild to moderate.

Patients on canakinumab reported an increase in mild upper respiratory tract infections. Severe adverse events (mainly urosepsis, other major infections, or vertigo) occurred in 10%. However, only three patients withdrew from the study because of adverse events over the course of 2 years.

Dr. Leslie was asked how canakinumab compares in terms of efficacy and cost to anakinra (Kineret), an interleukin-1 antagonist that has also shown efficacy in CAPS.

He replied that there are no comparative trials, but anecdotally the results are quite comparable. Both drugs bring almost complete remission.

The difference is that anakinra has a half-life of 6 hours and must be administered daily rather than every 8 weeks. And moderate to severe injection site reactions are a problematic issue with anakinra.

Major Finding: A total of 90% of patients with cryopyrin-associated periodic syndrome remained in remission continuously for the full 2 years on subcutaneous canakinumab injected once every 8 weeks.

Data Source: A 2-year, open-label study of 166 CAPS patients aged 3 years or older, of whom 109 were canakinumab-naive.

Disclosures: The canakinumab study was sponsored by Novartis, which provided Dr. Leslie with grant support.

GOTHENBURG, SWEDEN — Interleukin-1 blockade with canakinumab provided rapid and sustained clinical remission in the great majority of treated children and adults with cryopyrin-associated periodic syndrome who participated in a large 2-year study.

Most participants experienced significant improvement within a day or two after their first injection and were complete clinical responders with normalized inflammatory markers by day 8. said Dr. Kieron S. Leslie.

In all, 90% of patients remained in remission continuously for the full 2 years on subcutaneous canakinumab (Ilaris) injected once every 8 weeks, added Dr. Leslie, a dermatologist at the University of California, San Francisco.

The new study confirms canakinumab's safety and efficacy over a far longer treatment period. It also provides important new prescribing information: namely, that children with cryopyrin-associated periodic syndrome (CAPS) – as well as adults with the most severe form of the syndrome, known as neonatal-onset multisystem inflammatory disease (NOMID) – often require an upward dosing adjustment to obtain complete response.

CAPS is the latest term for a three-part autoinflammatory disease spectrum caused by mutations in the NLRP3 gene. At the mildest end is familial cold autoinflammatory syndrome (FCAS), an autosomal dominant condition marked by arthralgia, cold-induced rash, and conjunctivitis. In the middle is Muckle-Wells syndrome, also autosomal dominant, and characterized by sensorineural deafness and, in one-quarter of cases, by amyloid A amyloidosis. At the most severe end of the CAPS spectrum is NOMID, which includes the other disease manifestations plus a destructive arthritis and progressive meningitis resulting in visual impairment, deafness, and intellectual impairment.

Canakinumab is a fully human monoclonal antibody directed against IgG1 and interleukin-1 beta. It has a half-life of about 25 days. It was licensed last year in both the United States and Europe for treatment of CAPS. The standard weight-based dosing regimen is subcutaneous injection of 150 mg once every 8 weeks in adults, or 2 mg/kg in patients weighing 40 kg or less.

The 2-year, open-label study involved 166 CAPS patients aged 3 years or older, of whom 109 were canakinumab naive, including 38 children. The other 57 patients were rolled over from earlier studies. In all, 91% of subjects completed the 2-year study.

All 57 patients with prior exposure to canakinumab had a complete response to the biologic in this study, as did 85 of 109 treatment-naive patients.

Of the 85 treatment-naive complete responders, 79 achieved their complete response within 8 days; the rest did so during days 10-21.

All 24 canakinumab-naive patients who didn't attain a complete response nonetheless showed lesser clinical improvement. A complete response required a rating of minimal or no disease on the physician's global assessment of disease activity, plus normalization of both C-reactive protein and serum amyloid A levels, inflammatory markers that were typically elevated to 70-100 mg/L before treatment.

A dose increase was required in 36% of the 47 pediatric patients in the study, compared with 19% of the adults.

Children with Muckle-Wells syndrome or NOMID required a mean 5.5 and 5.8 mg/kg, respectively, of canakinumab per injection, compared with the standard 2.0 mg/kg. Of the 32 participants with NOMID, 47% required a dose increase; adults with NOMID required a mean dose of 229 mg rather than the 150 mg listed in the product labeling, the dermatologist continued.

In all, 92% of patients had no injection site reactions. The injection site reactions in the 8% of affected patients were mild to moderate.

Patients on canakinumab reported an increase in mild upper respiratory tract infections. Severe adverse events (mainly urosepsis, other major infections, or vertigo) occurred in 10%. However, only three patients withdrew from the study because of adverse events over the course of 2 years.

Dr. Leslie was asked how canakinumab compares in terms of efficacy and cost to anakinra (Kineret), an interleukin-1 antagonist that has also shown efficacy in CAPS.

He replied that there are no comparative trials, but anecdotally the results are quite comparable. Both drugs bring almost complete remission.

The difference is that anakinra has a half-life of 6 hours and must be administered daily rather than every 8 weeks. And moderate to severe injection site reactions are a problematic issue with anakinra.