Bruce K. Dixon

CHICAGO — Magnetic resonance imaging done prior to treatment for breast cancer can reveal cancer missed by mammography and ultrasonography, yielding more accurate information about the extent of disease, according to a poster presented at the annual meeting of the Radiological Society of North America.

“We found almost 29% more cancer by doing the magnetic resonance imaging before surgery or radiation therapy than we thought we had diagnosed with standard mammography, ultrasound, and clinical examination,” said Dr. Gillian Newstead of the University of Chicago in an interview. Identifying more cancer up front will influence the course of treatment and ideally produce a more positive long-term outcome, she said.

The researchers classified newly diagnosed breast cancers in 140 women (mean age 56.5 years), of which 53.5% were invasive ductal carcinoma (IDC) with extensive intraductal component (EIC). Additional lesions identified by MRI in 40 women included 26 in the same quadrant, 11 in a different quadrant, and 3 in the contralateral breast. Specifically, 23 of the lesions were identified as IDC with EIC, 6 as IDC, 6 as ductal carcinoma in situ, and 5 as invasive lobular cancer. Clinical management was changed in 31 of the 40 women: 20 underwent more extensive surgery, 8 were converted from breast conservation to mastectomy, and 3 were given additional neoadjuvant chemotherapy.

Although mammography and ultrasonography are still the primary imaging methods for breast cancer screening and diagnosis, the higher soft tissue contrast and gadolinium-enhanced images obtained by MRI improve the sensitivity of detection and allow more accurate evaluation of the cancer. Most breast cancers enhance rapidly after IV injection of contrast agents because of higher vascularity and the angiogenic factors that produce an increase in capillary permeability.

“The MR is looking at the new blood vessel growth, or angiogenesis, in tumors and it's a functional test in that sense, so we see lesions that may not show up on mammograms, especially in dense breasts. And there are some tumors that grow in such a way that makes them more difficult to perceive on a mammogram,” she added.

“Patients underwent imaging in the prone position with the breasts gently immobilized within lateral compression plates. Contrast injection was made with IV administration of 0.1 mmol/kg gadodiamide followed by a 20-mL saline flush at the rate of 2.0 mL per second. MR images were acquired using a 1.5-T scanner with use of a dedicated breast coil,” the investigators said. The resolution on the MRI machine was 1.6 mm.

Hospitals have been slow to assimilate MRI into clinical practice because there have been a lot of different techniques proposed by academic centers, Dr. Newstead said. “That's becoming less of an issue as our magnets are getting faster and we don't have to make as many compromises; so I would say that any person with a fairly modern magnet and a modern breast coil should be able to achieve satisfactory resolution both spatially and temporally,” she said.

MRI has found a home at the University of Chicago's breast imaging section, not only for pretreatment assessment but also to detect cancer recurrence post treatment and to screen high-risk women. “Early detection of local recurrence improves long-term survival, but postoperative mammographic and ultrasound evaluation often is limited, especially in patients with dense, fibroglandular tissue and postsurgical or postradiation fibrosis,” the authors wrote, noting that recurrent tumor exhibits early enhancement.

“MR is a sensitive modality for detection of early recurrent tumor, and breast cancer recurrence must be differentiated from acute and subacute posttreatment changes. Most recurrent tumor, unlike unrecognized residual tumor, usually presents at least 2 years following breast conservation treatment. Normal parenchymal enhancement usually is diminished after breast irradiation. Recurrent tumor may therefore be readily visible in the postradiation breast,” they said.

False-positive findings are not a problem with high-resolution MRI and correct procedure, Dr. Newstead said. “When we find something on MR that wasn't seen before on mammography or ultrasound, typically we'll bring the patient back for a repeat ultrasound and mammogram. If we see something, we'll do a biopsy right then. But if we can't find anything [with conventional imaging]—which happens in about 40% of our cases—and MR is the only finding, then we'll bring the patient back and repeat the MRI study. If it still looks worrisome, we'll go ahead and biopsy at the same time, so she only has to come back once,” Dr. Newstead explained.

'We found almost 29% more cancer by doing the magnetic resonance imaging.' DR. NEWSTEAD

CHICAGO — Magnetic resonance imaging done prior to treatment for breast cancer can reveal cancer missed by mammography and ultrasonography, yielding more accurate information about the extent of disease, according to a poster presented at the annual meeting of the Radiological Society of North America.

“We found almost 29% more cancer by doing the magnetic resonance imaging before surgery or radiation therapy than we thought we had diagnosed with standard mammography, ultrasound, and clinical examination,” said Dr. Gillian Newstead of the University of Chicago in an interview. Identifying more cancer up front will influence the course of treatment and ideally produce a more positive long-term outcome, she said.

The researchers classified newly diagnosed breast cancers in 140 women (mean age 56.5 years), of which 53.5% were invasive ductal carcinoma (IDC) with extensive intraductal component (EIC). Additional lesions identified by MRI in 40 women included 26 in the same quadrant, 11 in a different quadrant, and 3 in the contralateral breast. Specifically, 23 of the lesions were identified as IDC with EIC, 6 as IDC, 6 as ductal carcinoma in situ, and 5 as invasive lobular cancer. Clinical management was changed in 31 of the 40 women: 20 underwent more extensive surgery, 8 were converted from breast conservation to mastectomy, and 3 were given additional neoadjuvant chemotherapy.

Although mammography and ultrasonography are still the primary imaging methods for breast cancer screening and diagnosis, the higher soft tissue contrast and gadolinium-enhanced images obtained by MRI improve the sensitivity of detection and allow more accurate evaluation of the cancer. Most breast cancers enhance rapidly after IV injection of contrast agents because of higher vascularity and the angiogenic factors that produce an increase in capillary permeability.

“The MR is looking at the new blood vessel growth, or angiogenesis, in tumors and it's a functional test in that sense, so we see lesions that may not show up on mammograms, especially in dense breasts. And there are some tumors that grow in such a way that makes them more difficult to perceive on a mammogram,” she added.

“Patients underwent imaging in the prone position with the breasts gently immobilized within lateral compression plates. Contrast injection was made with IV administration of 0.1 mmol/kg gadodiamide followed by a 20-mL saline flush at the rate of 2.0 mL per second. MR images were acquired using a 1.5-T scanner with use of a dedicated breast coil,” the investigators said. The resolution on the MRI machine was 1.6 mm.

Hospitals have been slow to assimilate MRI into clinical practice because there have been a lot of different techniques proposed by academic centers, Dr. Newstead said. “That's becoming less of an issue as our magnets are getting faster and we don't have to make as many compromises; so I would say that any person with a fairly modern magnet and a modern breast coil should be able to achieve satisfactory resolution both spatially and temporally,” she said.

MRI has found a home at the University of Chicago's breast imaging section, not only for pretreatment assessment but also to detect cancer recurrence post treatment and to screen high-risk women. “Early detection of local recurrence improves long-term survival, but postoperative mammographic and ultrasound evaluation often is limited, especially in patients with dense, fibroglandular tissue and postsurgical or postradiation fibrosis,” the authors wrote, noting that recurrent tumor exhibits early enhancement.

“MR is a sensitive modality for detection of early recurrent tumor, and breast cancer recurrence must be differentiated from acute and subacute posttreatment changes. Most recurrent tumor, unlike unrecognized residual tumor, usually presents at least 2 years following breast conservation treatment. Normal parenchymal enhancement usually is diminished after breast irradiation. Recurrent tumor may therefore be readily visible in the postradiation breast,” they said.

False-positive findings are not a problem with high-resolution MRI and correct procedure, Dr. Newstead said. “When we find something on MR that wasn't seen before on mammography or ultrasound, typically we'll bring the patient back for a repeat ultrasound and mammogram. If we see something, we'll do a biopsy right then. But if we can't find anything [with conventional imaging]—which happens in about 40% of our cases—and MR is the only finding, then we'll bring the patient back and repeat the MRI study. If it still looks worrisome, we'll go ahead and biopsy at the same time, so she only has to come back once,” Dr. Newstead explained.

'We found almost 29% more cancer by doing the magnetic resonance imaging.' DR. NEWSTEAD

CHICAGO — Magnetic resonance imaging done prior to treatment for breast cancer can reveal cancer missed by mammography and ultrasonography, yielding more accurate information about the extent of disease, according to a poster presented at the annual meeting of the Radiological Society of North America.

“We found almost 29% more cancer by doing the magnetic resonance imaging before surgery or radiation therapy than we thought we had diagnosed with standard mammography, ultrasound, and clinical examination,” said Dr. Gillian Newstead of the University of Chicago in an interview. Identifying more cancer up front will influence the course of treatment and ideally produce a more positive long-term outcome, she said.

The researchers classified newly diagnosed breast cancers in 140 women (mean age 56.5 years), of which 53.5% were invasive ductal carcinoma (IDC) with extensive intraductal component (EIC). Additional lesions identified by MRI in 40 women included 26 in the same quadrant, 11 in a different quadrant, and 3 in the contralateral breast. Specifically, 23 of the lesions were identified as IDC with EIC, 6 as IDC, 6 as ductal carcinoma in situ, and 5 as invasive lobular cancer. Clinical management was changed in 31 of the 40 women: 20 underwent more extensive surgery, 8 were converted from breast conservation to mastectomy, and 3 were given additional neoadjuvant chemotherapy.

Although mammography and ultrasonography are still the primary imaging methods for breast cancer screening and diagnosis, the higher soft tissue contrast and gadolinium-enhanced images obtained by MRI improve the sensitivity of detection and allow more accurate evaluation of the cancer. Most breast cancers enhance rapidly after IV injection of contrast agents because of higher vascularity and the angiogenic factors that produce an increase in capillary permeability.

“The MR is looking at the new blood vessel growth, or angiogenesis, in tumors and it's a functional test in that sense, so we see lesions that may not show up on mammograms, especially in dense breasts. And there are some tumors that grow in such a way that makes them more difficult to perceive on a mammogram,” she added.

“Patients underwent imaging in the prone position with the breasts gently immobilized within lateral compression plates. Contrast injection was made with IV administration of 0.1 mmol/kg gadodiamide followed by a 20-mL saline flush at the rate of 2.0 mL per second. MR images were acquired using a 1.5-T scanner with use of a dedicated breast coil,” the investigators said. The resolution on the MRI machine was 1.6 mm.

Hospitals have been slow to assimilate MRI into clinical practice because there have been a lot of different techniques proposed by academic centers, Dr. Newstead said. “That's becoming less of an issue as our magnets are getting faster and we don't have to make as many compromises; so I would say that any person with a fairly modern magnet and a modern breast coil should be able to achieve satisfactory resolution both spatially and temporally,” she said.

MRI has found a home at the University of Chicago's breast imaging section, not only for pretreatment assessment but also to detect cancer recurrence post treatment and to screen high-risk women. “Early detection of local recurrence improves long-term survival, but postoperative mammographic and ultrasound evaluation often is limited, especially in patients with dense, fibroglandular tissue and postsurgical or postradiation fibrosis,” the authors wrote, noting that recurrent tumor exhibits early enhancement.

“MR is a sensitive modality for detection of early recurrent tumor, and breast cancer recurrence must be differentiated from acute and subacute posttreatment changes. Most recurrent tumor, unlike unrecognized residual tumor, usually presents at least 2 years following breast conservation treatment. Normal parenchymal enhancement usually is diminished after breast irradiation. Recurrent tumor may therefore be readily visible in the postradiation breast,” they said.

False-positive findings are not a problem with high-resolution MRI and correct procedure, Dr. Newstead said. “When we find something on MR that wasn't seen before on mammography or ultrasound, typically we'll bring the patient back for a repeat ultrasound and mammogram. If we see something, we'll do a biopsy right then. But if we can't find anything [with conventional imaging]—which happens in about 40% of our cases—and MR is the only finding, then we'll bring the patient back and repeat the MRI study. If it still looks worrisome, we'll go ahead and biopsy at the same time, so she only has to come back once,” Dr. Newstead explained.

'We found almost 29% more cancer by doing the magnetic resonance imaging.' DR. NEWSTEAD

Kate Johnson of the Montreal Bureau contributed to this report.

MONTREAL – A total of 35% of those with polycystic ovary syndrome also had depression in a case-control study of 206 women.

“We recommend that women with PCOS should be routinely screened and adequately treated for depression,” study investigator Elizabeth M. Hollinrake said at the joint annual meeting of the American Society for Reproductive Medicine and the Canadian Fertility and Andrology Society.

Among women with PCOS, the odds ratio was 5.11 for newly diagnosed depression and 4.23 for depression overall (newly diagnosed and previously diagnosed depression), compared with controls who did not have polycystic ovary syndrome, said Ms. Hollinrake, a third-year medical student at the University of Iowa in Iowa City.

In an interview, the study's lead author, Dr. Anuja Dokras, noted that the results also show for the first time that depression in PCOS patients is significantly associated with both high body mass index (BMI) and insulin resistance.

“Between 50% and 70% of women who are treated for depression recover completely, so this is an important target population that we should be both screening and treating,” added Dr. Dokras, who is with the University of Iowa Hospitals and Clinics, Iowa City.

The study, which earned a first-place award among the General Program Prize Papers presented at the meeting, compared 103 women who had PCOS with 103 controls. Women with PCOS diagnosed by the Rotterdam criteria were recruited from a reproductive endocrinology clinic; women without PCOS who attend the gynecology clinic for an annual exam were used as controls.

Dr. Dokras and Ms. Hollinrake used the Primary Care Evaluation of Mental Disorders Patient Health Questionnaire to diagnose major depressive disorder and other depressive syndromes.

The Beck Depression Inventory was used to score the severity of depression. Chi-square and t-testing were used to compare differences between women with PCOS and controls, and PCOS women with and without depression.

In the PCOS group, 35% (36 women) were classified as depressed, compared with 10.7% (11 women) of those in the control group, which represents a statistically significant difference. Of these 47 women with depression, 22 were already on antidepressants when they entered the clinic.

When these 22 women were not considered, the rate of newly diagnosed depression was 21% in the group with polycystic ovary syndrome and 3% in the control group.

Women with PCOS had a significantly higher mean BMI than did controls (34.9 versus 25.4), as did the subset of PCOS women who were depressed compared with those who had screened negative.

“Although increased BMI among the depressed women is in keeping with the literature, ours is the first study to show this correlation in depressed women with PCOS,” Dr. Dokras said.

Among the women with PCOS, 11% of those with depression also had diabetes, compared with none of the women without depression; the depressed women also had significantly higher glucose, insulin, and QUICKI scores.

“Importantly, women with PCOS have higher androgen levels, so one would have expected that if that was the basis, we would find some correlation with depression. On the contrary, these data showed no association with androgens … only with BMI and insulin resistance,” Dr. Dokras said.

Kate Johnson of the Montreal Bureau contributed to this report.

MONTREAL – A total of 35% of those with polycystic ovary syndrome also had depression in a case-control study of 206 women.

“We recommend that women with PCOS should be routinely screened and adequately treated for depression,” study investigator Elizabeth M. Hollinrake said at the joint annual meeting of the American Society for Reproductive Medicine and the Canadian Fertility and Andrology Society.

Among women with PCOS, the odds ratio was 5.11 for newly diagnosed depression and 4.23 for depression overall (newly diagnosed and previously diagnosed depression), compared with controls who did not have polycystic ovary syndrome, said Ms. Hollinrake, a third-year medical student at the University of Iowa in Iowa City.

In an interview, the study's lead author, Dr. Anuja Dokras, noted that the results also show for the first time that depression in PCOS patients is significantly associated with both high body mass index (BMI) and insulin resistance.

“Between 50% and 70% of women who are treated for depression recover completely, so this is an important target population that we should be both screening and treating,” added Dr. Dokras, who is with the University of Iowa Hospitals and Clinics, Iowa City.

The study, which earned a first-place award among the General Program Prize Papers presented at the meeting, compared 103 women who had PCOS with 103 controls. Women with PCOS diagnosed by the Rotterdam criteria were recruited from a reproductive endocrinology clinic; women without PCOS who attend the gynecology clinic for an annual exam were used as controls.

Dr. Dokras and Ms. Hollinrake used the Primary Care Evaluation of Mental Disorders Patient Health Questionnaire to diagnose major depressive disorder and other depressive syndromes.

The Beck Depression Inventory was used to score the severity of depression. Chi-square and t-testing were used to compare differences between women with PCOS and controls, and PCOS women with and without depression.

In the PCOS group, 35% (36 women) were classified as depressed, compared with 10.7% (11 women) of those in the control group, which represents a statistically significant difference. Of these 47 women with depression, 22 were already on antidepressants when they entered the clinic.

When these 22 women were not considered, the rate of newly diagnosed depression was 21% in the group with polycystic ovary syndrome and 3% in the control group.

Women with PCOS had a significantly higher mean BMI than did controls (34.9 versus 25.4), as did the subset of PCOS women who were depressed compared with those who had screened negative.

“Although increased BMI among the depressed women is in keeping with the literature, ours is the first study to show this correlation in depressed women with PCOS,” Dr. Dokras said.

Among the women with PCOS, 11% of those with depression also had diabetes, compared with none of the women without depression; the depressed women also had significantly higher glucose, insulin, and QUICKI scores.

“Importantly, women with PCOS have higher androgen levels, so one would have expected that if that was the basis, we would find some correlation with depression. On the contrary, these data showed no association with androgens … only with BMI and insulin resistance,” Dr. Dokras said.

Kate Johnson of the Montreal Bureau contributed to this report.

MONTREAL – A total of 35% of those with polycystic ovary syndrome also had depression in a case-control study of 206 women.

“We recommend that women with PCOS should be routinely screened and adequately treated for depression,” study investigator Elizabeth M. Hollinrake said at the joint annual meeting of the American Society for Reproductive Medicine and the Canadian Fertility and Andrology Society.

Among women with PCOS, the odds ratio was 5.11 for newly diagnosed depression and 4.23 for depression overall (newly diagnosed and previously diagnosed depression), compared with controls who did not have polycystic ovary syndrome, said Ms. Hollinrake, a third-year medical student at the University of Iowa in Iowa City.

In an interview, the study's lead author, Dr. Anuja Dokras, noted that the results also show for the first time that depression in PCOS patients is significantly associated with both high body mass index (BMI) and insulin resistance.

“Between 50% and 70% of women who are treated for depression recover completely, so this is an important target population that we should be both screening and treating,” added Dr. Dokras, who is with the University of Iowa Hospitals and Clinics, Iowa City.

The study, which earned a first-place award among the General Program Prize Papers presented at the meeting, compared 103 women who had PCOS with 103 controls. Women with PCOS diagnosed by the Rotterdam criteria were recruited from a reproductive endocrinology clinic; women without PCOS who attend the gynecology clinic for an annual exam were used as controls.

Dr. Dokras and Ms. Hollinrake used the Primary Care Evaluation of Mental Disorders Patient Health Questionnaire to diagnose major depressive disorder and other depressive syndromes.

The Beck Depression Inventory was used to score the severity of depression. Chi-square and t-testing were used to compare differences between women with PCOS and controls, and PCOS women with and without depression.

In the PCOS group, 35% (36 women) were classified as depressed, compared with 10.7% (11 women) of those in the control group, which represents a statistically significant difference. Of these 47 women with depression, 22 were already on antidepressants when they entered the clinic.

When these 22 women were not considered, the rate of newly diagnosed depression was 21% in the group with polycystic ovary syndrome and 3% in the control group.

Women with PCOS had a significantly higher mean BMI than did controls (34.9 versus 25.4), as did the subset of PCOS women who were depressed compared with those who had screened negative.

“Although increased BMI among the depressed women is in keeping with the literature, ours is the first study to show this correlation in depressed women with PCOS,” Dr. Dokras said.

Among the women with PCOS, 11% of those with depression also had diabetes, compared with none of the women without depression; the depressed women also had significantly higher glucose, insulin, and QUICKI scores.

“Importantly, women with PCOS have higher androgen levels, so one would have expected that if that was the basis, we would find some correlation with depression. On the contrary, these data showed no association with androgens … only with BMI and insulin resistance,” Dr. Dokras said.

MONTREAL — The addition of simvastatin to an oral contraceptive regimen significantly reduces hirsutism and elevated levels of total testosterone in women with polycystic ovary syndrome, according to a study conducted by Dr. Antoni J. Duleba of Yale University, New Haven, Conn., and associates.

“This is the first report that simvastatin improves a clinical end point of polycystic ovary syndrome/hirsutism,” Dr. Duleba, the lead investigator, said in an interview.

The data were presented by another investigator in the study, Dr. Beata Banaszewska, at the conjoint annual meeting of the American Society for Reproductive Medicine and the Canadian Fertility and Andrology Society.

Oral contraceptives “do reduce testosterone levels, but in this crossover study, we can appreciate that statins have a greater power to this effect,” said Dr. Banaszewska, of Poznan University of Medical Sciences in Poland.

PCOS affects 5%–10% of women of childbearing age, according to Dr. Duleba. Estimates of the annual cost of evaluation and care in the United States are about $4 billion. “Symptomatic treatments partly improve the situation, and long term, these patients are at increased risk of cardiovascular problems.”

The study randomized 48 PCOS patients (mean age 24 years) into two groups. One received oral contraceptives (OC) (20-mcg ethinyl estradiol and 150-mcg desogestrel) for 12 weeks. Then 20-mg simvastatin was added to their regimen daily for 12 more weeks.

The other group received the combined regimen for 12 weeks then was given OCs alone for 12 weeks. Clinical, endocrine, and metabolic evaluations were performed at baseline, at crossover (12 weeks), and at 24 weeks.

“Simvastatin decreased total testosterone by 18% below the effect of OCs,” Dr. Duleba said. “This effect was paralleled by a 16% decrease of free testosterone below the effect of OCs. We also found that the hirsutism declined, and there was a strong trend toward an improvement in acne, which did not reach statistical significance.”

A simvastatin-attributable decline of hirsutism was modestly but significantly greater than with OC alone; this 4% difference was statistically significant. “Patients were happy. … They did not want to stop therapy,” Dr. Duleba said.

“In PCOS, there is an abnormal hypothalamic-pituitary function characterized by elevated LH. It's usually measured by the ratio of LH to FSH, and we observed that statins also improved this ratio,” he added. Simvastatin, in comparison with OCs, decreased LH by 24% and the LH-FSH ratio by 22%.

Furthermore, simvastatin (as compared with OCs) decreased total cholesterol by 12%, LDL cholesterol by 21%, and triglycerides by 18%—preventing the OC-induced rise in triglycerides.

“So the statin not only normalized androgens, it also normalized hypothalamic-pituitary function. And of course, the statin improved lipid profiles,” Dr. Duleba said.

BMI was not significantly affected.

Kate Johnson contributed to this report.

'The statin not only normalized androgens, it also normalized hypothalamic-pituitary function.' DR. DULEBA

MONTREAL — The addition of simvastatin to an oral contraceptive regimen significantly reduces hirsutism and elevated levels of total testosterone in women with polycystic ovary syndrome, according to a study conducted by Dr. Antoni J. Duleba of Yale University, New Haven, Conn., and associates.

“This is the first report that simvastatin improves a clinical end point of polycystic ovary syndrome/hirsutism,” Dr. Duleba, the lead investigator, said in an interview.

The data were presented by another investigator in the study, Dr. Beata Banaszewska, at the conjoint annual meeting of the American Society for Reproductive Medicine and the Canadian Fertility and Andrology Society.

Oral contraceptives “do reduce testosterone levels, but in this crossover study, we can appreciate that statins have a greater power to this effect,” said Dr. Banaszewska, of Poznan University of Medical Sciences in Poland.

PCOS affects 5%–10% of women of childbearing age, according to Dr. Duleba. Estimates of the annual cost of evaluation and care in the United States are about $4 billion. “Symptomatic treatments partly improve the situation, and long term, these patients are at increased risk of cardiovascular problems.”

The study randomized 48 PCOS patients (mean age 24 years) into two groups. One received oral contraceptives (OC) (20-mcg ethinyl estradiol and 150-mcg desogestrel) for 12 weeks. Then 20-mg simvastatin was added to their regimen daily for 12 more weeks.

The other group received the combined regimen for 12 weeks then was given OCs alone for 12 weeks. Clinical, endocrine, and metabolic evaluations were performed at baseline, at crossover (12 weeks), and at 24 weeks.

“Simvastatin decreased total testosterone by 18% below the effect of OCs,” Dr. Duleba said. “This effect was paralleled by a 16% decrease of free testosterone below the effect of OCs. We also found that the hirsutism declined, and there was a strong trend toward an improvement in acne, which did not reach statistical significance.”

A simvastatin-attributable decline of hirsutism was modestly but significantly greater than with OC alone; this 4% difference was statistically significant. “Patients were happy. … They did not want to stop therapy,” Dr. Duleba said.

“In PCOS, there is an abnormal hypothalamic-pituitary function characterized by elevated LH. It's usually measured by the ratio of LH to FSH, and we observed that statins also improved this ratio,” he added. Simvastatin, in comparison with OCs, decreased LH by 24% and the LH-FSH ratio by 22%.

Furthermore, simvastatin (as compared with OCs) decreased total cholesterol by 12%, LDL cholesterol by 21%, and triglycerides by 18%—preventing the OC-induced rise in triglycerides.

“So the statin not only normalized androgens, it also normalized hypothalamic-pituitary function. And of course, the statin improved lipid profiles,” Dr. Duleba said.

BMI was not significantly affected.

Kate Johnson contributed to this report.

'The statin not only normalized androgens, it also normalized hypothalamic-pituitary function.' DR. DULEBA

MONTREAL — The addition of simvastatin to an oral contraceptive regimen significantly reduces hirsutism and elevated levels of total testosterone in women with polycystic ovary syndrome, according to a study conducted by Dr. Antoni J. Duleba of Yale University, New Haven, Conn., and associates.

“This is the first report that simvastatin improves a clinical end point of polycystic ovary syndrome/hirsutism,” Dr. Duleba, the lead investigator, said in an interview.

The data were presented by another investigator in the study, Dr. Beata Banaszewska, at the conjoint annual meeting of the American Society for Reproductive Medicine and the Canadian Fertility and Andrology Society.

Oral contraceptives “do reduce testosterone levels, but in this crossover study, we can appreciate that statins have a greater power to this effect,” said Dr. Banaszewska, of Poznan University of Medical Sciences in Poland.

PCOS affects 5%–10% of women of childbearing age, according to Dr. Duleba. Estimates of the annual cost of evaluation and care in the United States are about $4 billion. “Symptomatic treatments partly improve the situation, and long term, these patients are at increased risk of cardiovascular problems.”

The study randomized 48 PCOS patients (mean age 24 years) into two groups. One received oral contraceptives (OC) (20-mcg ethinyl estradiol and 150-mcg desogestrel) for 12 weeks. Then 20-mg simvastatin was added to their regimen daily for 12 more weeks.

The other group received the combined regimen for 12 weeks then was given OCs alone for 12 weeks. Clinical, endocrine, and metabolic evaluations were performed at baseline, at crossover (12 weeks), and at 24 weeks.

“Simvastatin decreased total testosterone by 18% below the effect of OCs,” Dr. Duleba said. “This effect was paralleled by a 16% decrease of free testosterone below the effect of OCs. We also found that the hirsutism declined, and there was a strong trend toward an improvement in acne, which did not reach statistical significance.”

A simvastatin-attributable decline of hirsutism was modestly but significantly greater than with OC alone; this 4% difference was statistically significant. “Patients were happy. … They did not want to stop therapy,” Dr. Duleba said.

“In PCOS, there is an abnormal hypothalamic-pituitary function characterized by elevated LH. It's usually measured by the ratio of LH to FSH, and we observed that statins also improved this ratio,” he added. Simvastatin, in comparison with OCs, decreased LH by 24% and the LH-FSH ratio by 22%.

Furthermore, simvastatin (as compared with OCs) decreased total cholesterol by 12%, LDL cholesterol by 21%, and triglycerides by 18%—preventing the OC-induced rise in triglycerides.

“So the statin not only normalized androgens, it also normalized hypothalamic-pituitary function. And of course, the statin improved lipid profiles,” Dr. Duleba said.

BMI was not significantly affected.

Kate Johnson contributed to this report.

'The statin not only normalized androgens, it also normalized hypothalamic-pituitary function.' DR. DULEBA

ATLANTA — Computed tomographic angiography with a 16-channel detector can be used to accurately screen patients for blunt cervical vascular and cerebrovascular injuries, according to two studies presented at the annual meeting of the American Association for the Surgery of Trauma.

“Though ours was a relatively small study population and future studies are needed to focus on the accuracy of grading by CTA, this technology should be considered the screening standard for patients at risk of blunt cervical vascular injury,” said chief author Alexander L. Eastman, M.D., of the University of Texas Southwestern Medical Center in Dallas. “The severe and unforgiving nature of an undiagnosed blunt cervical vascular injury presents a real problem. Given the large differences in treated and untreated stroke rates, the principle of screening and early detection is vital. Despite this, the definition of an ideal screening test remains controversial, [though] catheter arteriography remains the 'gold standard.'”

In previous head-to-head studies using less powerful scanners, CTA failed to match the performances of catheter arteriography (CA). When a new 16-channel machine arrived at Parkland Hospital, the Dallas researchers decided to put it to the test.

Data from all patients presenting to their level I trauma center at risk for blunt cervical vascular injury were collected prospectively. During an 8-month period, each patient was evaluated with CTA and the findings confirmed with standard CA of the head, neck, and aortic arch.

Of more than 3,000 trauma admissions during 8 months, 148 patients were deemed at risk for blunt cervical vascular injury. A total of 135 patients received both CTA and CA, and 13 received CTA only, due primarily to patient rejection of CA and discharge prior to CA. Among 41 patients, 43 blunt cervical vascular injuries were identified, yielding an overall incidence of 1.4% and an incidence within the screened population of more than 30%. Results of the two procedures were concordant in 42 of 43 cases with blunt cervical vascular injuries.

The remaining patients had normal CTAs confirmed by a normal CA, the investigators wrote.

The overall incidence of carotid artery injury (CAI) was 0.6% and vertebral artery injury (VAI) was 96%. Of the VAIs, 96% were associated with at least one cervical spine fracture. In the patients who underwent both CTA and CA, the detection sensitivity of CTA was 100% for CAI and 96% for VAI.

The overall sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of CTA for blunt cervical vascular injury were 97.1%, 100%, 100%, 98.9%, and 99.3%, respectively, they said.

An additional enhancement offered by CTA is the ability to subtract other anatomic structures and focus on the vascular system exclusively, Dr. Eastman said. Vertebral artery injuries also are impressive when viewed at the CT workstation, he added.

When patients with negative CTA who did not have an angiogram were followed up at 3–12 months, none were found to have an injury or neurologic sequelae.

Following Dr. Eastman's presentation, discussant David A. Spain, M.D., agreed that 16-slice CTA is ready for prime time. However, “Is it ready for non-prime time?” asked Dr. Spain, who is with the Stanford University Medical Center, Stanford, Calif. “Who reads these studies at 2 a.m.? Three-dimensional reconstructions are very important to accurate interpretations, and if no one is available to read the exam, how long before you have a definitive answer as to whether these patients have an injury?” he added.

“I think obviously there's going to be some house staff reading at first,” replied Dr. Eastman. “We're lucky at our institution that our neuroradiologists are exquisitely helpful … so you get a reading almost immediately.”

CTA vs. ART

The second study, conducted at Rhode Island Hospital and Brown Medical School in Providence, compared 16-slice CTA with 4-vessel cerebral arteriography (ART) in screening for blunt cerebrovascular injuries.

Screening detects many asymptomatic cerebrovascular injuries. “However, it has not been proven to prevent strokes, and thus many centers have been reluctant to implement screening protocols,” they wrote. “It is particularly difficult to justify because ART, the gold-standard diagnostic test, is invasive and resource intensive.”

“We developed our screening protocol using arteriography for symptomatic patients because … we need a gold standard test when a patient is having symptoms or signs consistent with an injury,” said lead author Walter L. Biffl, M.D. The investigators settled on 16-slice CTA for patients with high-risk mechanisms and injury patterns. To further capture any group that may be at risk, they enlarged the study group to include any patient with cranial or cervical trauma who was undergoing a CT scan.

The protocol called for CTA in all trauma patients with cranial or cervical trauma undergoing CT scanning. Any abnormality was further investigated with ART, and patients were followed for neurologic changes. The investigators reviewed records to determine if clinical injuries were missed by CTA, and then compared ART and CTA images.

Between June 2004 and February 2005, the team did 225 CTAs. A total of 17 patients (7.5%) were diagnosed with blunt cerebrovascular injuries, including 11 carotid and 6 vertebral injuries. CTA did not miss any clinically important blunt cerebrovascular injury, the researchers said.

“Importantly, nobody during the study period who had had a normal CTA developed signs or symptoms of a vascular injury, and that was what we set out to explore,” Dr. Biffl said. “The disconcerting thing in this study is that two patients who didn't meet the screening criteria presented with symptoms related to a vascular injury.”

One of those patients was an elderly man who had been in a minor auto accident. He was evaluated and sent home from the emergency department, but returned with persistent headache and Horner Syndrome. He was found to have dissection of the carotid artery. The other patient was a young woman who had fractures of the femur and clavicle who, because she didn't have cranial or cervical trauma, didn't undergo a CTA. She woke up the next day in the orthopedic service with a stroke.

“We've concluded from this study that CTA is a reliable, noninvasive screening test for clinically significant blunt cervical vascular injuries,” Dr. Biffl said. “We need multicenter prospective trials to clarify the risk factors and to assess the accuracy of noninvasive screening tests and to evaluate the efficacy of treatment strategies,” he added.

ATLANTA — Computed tomographic angiography with a 16-channel detector can be used to accurately screen patients for blunt cervical vascular and cerebrovascular injuries, according to two studies presented at the annual meeting of the American Association for the Surgery of Trauma.

“Though ours was a relatively small study population and future studies are needed to focus on the accuracy of grading by CTA, this technology should be considered the screening standard for patients at risk of blunt cervical vascular injury,” said chief author Alexander L. Eastman, M.D., of the University of Texas Southwestern Medical Center in Dallas. “The severe and unforgiving nature of an undiagnosed blunt cervical vascular injury presents a real problem. Given the large differences in treated and untreated stroke rates, the principle of screening and early detection is vital. Despite this, the definition of an ideal screening test remains controversial, [though] catheter arteriography remains the 'gold standard.'”

In previous head-to-head studies using less powerful scanners, CTA failed to match the performances of catheter arteriography (CA). When a new 16-channel machine arrived at Parkland Hospital, the Dallas researchers decided to put it to the test.

Data from all patients presenting to their level I trauma center at risk for blunt cervical vascular injury were collected prospectively. During an 8-month period, each patient was evaluated with CTA and the findings confirmed with standard CA of the head, neck, and aortic arch.

Of more than 3,000 trauma admissions during 8 months, 148 patients were deemed at risk for blunt cervical vascular injury. A total of 135 patients received both CTA and CA, and 13 received CTA only, due primarily to patient rejection of CA and discharge prior to CA. Among 41 patients, 43 blunt cervical vascular injuries were identified, yielding an overall incidence of 1.4% and an incidence within the screened population of more than 30%. Results of the two procedures were concordant in 42 of 43 cases with blunt cervical vascular injuries.

The remaining patients had normal CTAs confirmed by a normal CA, the investigators wrote.

The overall incidence of carotid artery injury (CAI) was 0.6% and vertebral artery injury (VAI) was 96%. Of the VAIs, 96% were associated with at least one cervical spine fracture. In the patients who underwent both CTA and CA, the detection sensitivity of CTA was 100% for CAI and 96% for VAI.

The overall sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of CTA for blunt cervical vascular injury were 97.1%, 100%, 100%, 98.9%, and 99.3%, respectively, they said.

An additional enhancement offered by CTA is the ability to subtract other anatomic structures and focus on the vascular system exclusively, Dr. Eastman said. Vertebral artery injuries also are impressive when viewed at the CT workstation, he added.

When patients with negative CTA who did not have an angiogram were followed up at 3–12 months, none were found to have an injury or neurologic sequelae.

Following Dr. Eastman's presentation, discussant David A. Spain, M.D., agreed that 16-slice CTA is ready for prime time. However, “Is it ready for non-prime time?” asked Dr. Spain, who is with the Stanford University Medical Center, Stanford, Calif. “Who reads these studies at 2 a.m.? Three-dimensional reconstructions are very important to accurate interpretations, and if no one is available to read the exam, how long before you have a definitive answer as to whether these patients have an injury?” he added.

“I think obviously there's going to be some house staff reading at first,” replied Dr. Eastman. “We're lucky at our institution that our neuroradiologists are exquisitely helpful … so you get a reading almost immediately.”

CTA vs. ART

The second study, conducted at Rhode Island Hospital and Brown Medical School in Providence, compared 16-slice CTA with 4-vessel cerebral arteriography (ART) in screening for blunt cerebrovascular injuries.

Screening detects many asymptomatic cerebrovascular injuries. “However, it has not been proven to prevent strokes, and thus many centers have been reluctant to implement screening protocols,” they wrote. “It is particularly difficult to justify because ART, the gold-standard diagnostic test, is invasive and resource intensive.”

“We developed our screening protocol using arteriography for symptomatic patients because … we need a gold standard test when a patient is having symptoms or signs consistent with an injury,” said lead author Walter L. Biffl, M.D. The investigators settled on 16-slice CTA for patients with high-risk mechanisms and injury patterns. To further capture any group that may be at risk, they enlarged the study group to include any patient with cranial or cervical trauma who was undergoing a CT scan.

The protocol called for CTA in all trauma patients with cranial or cervical trauma undergoing CT scanning. Any abnormality was further investigated with ART, and patients were followed for neurologic changes. The investigators reviewed records to determine if clinical injuries were missed by CTA, and then compared ART and CTA images.

Between June 2004 and February 2005, the team did 225 CTAs. A total of 17 patients (7.5%) were diagnosed with blunt cerebrovascular injuries, including 11 carotid and 6 vertebral injuries. CTA did not miss any clinically important blunt cerebrovascular injury, the researchers said.

“Importantly, nobody during the study period who had had a normal CTA developed signs or symptoms of a vascular injury, and that was what we set out to explore,” Dr. Biffl said. “The disconcerting thing in this study is that two patients who didn't meet the screening criteria presented with symptoms related to a vascular injury.”

One of those patients was an elderly man who had been in a minor auto accident. He was evaluated and sent home from the emergency department, but returned with persistent headache and Horner Syndrome. He was found to have dissection of the carotid artery. The other patient was a young woman who had fractures of the femur and clavicle who, because she didn't have cranial or cervical trauma, didn't undergo a CTA. She woke up the next day in the orthopedic service with a stroke.

“We've concluded from this study that CTA is a reliable, noninvasive screening test for clinically significant blunt cervical vascular injuries,” Dr. Biffl said. “We need multicenter prospective trials to clarify the risk factors and to assess the accuracy of noninvasive screening tests and to evaluate the efficacy of treatment strategies,” he added.

ATLANTA — Computed tomographic angiography with a 16-channel detector can be used to accurately screen patients for blunt cervical vascular and cerebrovascular injuries, according to two studies presented at the annual meeting of the American Association for the Surgery of Trauma.

“Though ours was a relatively small study population and future studies are needed to focus on the accuracy of grading by CTA, this technology should be considered the screening standard for patients at risk of blunt cervical vascular injury,” said chief author Alexander L. Eastman, M.D., of the University of Texas Southwestern Medical Center in Dallas. “The severe and unforgiving nature of an undiagnosed blunt cervical vascular injury presents a real problem. Given the large differences in treated and untreated stroke rates, the principle of screening and early detection is vital. Despite this, the definition of an ideal screening test remains controversial, [though] catheter arteriography remains the 'gold standard.'”

In previous head-to-head studies using less powerful scanners, CTA failed to match the performances of catheter arteriography (CA). When a new 16-channel machine arrived at Parkland Hospital, the Dallas researchers decided to put it to the test.

Data from all patients presenting to their level I trauma center at risk for blunt cervical vascular injury were collected prospectively. During an 8-month period, each patient was evaluated with CTA and the findings confirmed with standard CA of the head, neck, and aortic arch.

Of more than 3,000 trauma admissions during 8 months, 148 patients were deemed at risk for blunt cervical vascular injury. A total of 135 patients received both CTA and CA, and 13 received CTA only, due primarily to patient rejection of CA and discharge prior to CA. Among 41 patients, 43 blunt cervical vascular injuries were identified, yielding an overall incidence of 1.4% and an incidence within the screened population of more than 30%. Results of the two procedures were concordant in 42 of 43 cases with blunt cervical vascular injuries.

The remaining patients had normal CTAs confirmed by a normal CA, the investigators wrote.

The overall incidence of carotid artery injury (CAI) was 0.6% and vertebral artery injury (VAI) was 96%. Of the VAIs, 96% were associated with at least one cervical spine fracture. In the patients who underwent both CTA and CA, the detection sensitivity of CTA was 100% for CAI and 96% for VAI.

The overall sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of CTA for blunt cervical vascular injury were 97.1%, 100%, 100%, 98.9%, and 99.3%, respectively, they said.

An additional enhancement offered by CTA is the ability to subtract other anatomic structures and focus on the vascular system exclusively, Dr. Eastman said. Vertebral artery injuries also are impressive when viewed at the CT workstation, he added.

When patients with negative CTA who did not have an angiogram were followed up at 3–12 months, none were found to have an injury or neurologic sequelae.

Following Dr. Eastman's presentation, discussant David A. Spain, M.D., agreed that 16-slice CTA is ready for prime time. However, “Is it ready for non-prime time?” asked Dr. Spain, who is with the Stanford University Medical Center, Stanford, Calif. “Who reads these studies at 2 a.m.? Three-dimensional reconstructions are very important to accurate interpretations, and if no one is available to read the exam, how long before you have a definitive answer as to whether these patients have an injury?” he added.

“I think obviously there's going to be some house staff reading at first,” replied Dr. Eastman. “We're lucky at our institution that our neuroradiologists are exquisitely helpful … so you get a reading almost immediately.”

CTA vs. ART

The second study, conducted at Rhode Island Hospital and Brown Medical School in Providence, compared 16-slice CTA with 4-vessel cerebral arteriography (ART) in screening for blunt cerebrovascular injuries.

Screening detects many asymptomatic cerebrovascular injuries. “However, it has not been proven to prevent strokes, and thus many centers have been reluctant to implement screening protocols,” they wrote. “It is particularly difficult to justify because ART, the gold-standard diagnostic test, is invasive and resource intensive.”

“We developed our screening protocol using arteriography for symptomatic patients because … we need a gold standard test when a patient is having symptoms or signs consistent with an injury,” said lead author Walter L. Biffl, M.D. The investigators settled on 16-slice CTA for patients with high-risk mechanisms and injury patterns. To further capture any group that may be at risk, they enlarged the study group to include any patient with cranial or cervical trauma who was undergoing a CT scan.

The protocol called for CTA in all trauma patients with cranial or cervical trauma undergoing CT scanning. Any abnormality was further investigated with ART, and patients were followed for neurologic changes. The investigators reviewed records to determine if clinical injuries were missed by CTA, and then compared ART and CTA images.

Between June 2004 and February 2005, the team did 225 CTAs. A total of 17 patients (7.5%) were diagnosed with blunt cerebrovascular injuries, including 11 carotid and 6 vertebral injuries. CTA did not miss any clinically important blunt cerebrovascular injury, the researchers said.

“Importantly, nobody during the study period who had had a normal CTA developed signs or symptoms of a vascular injury, and that was what we set out to explore,” Dr. Biffl said. “The disconcerting thing in this study is that two patients who didn't meet the screening criteria presented with symptoms related to a vascular injury.”

One of those patients was an elderly man who had been in a minor auto accident. He was evaluated and sent home from the emergency department, but returned with persistent headache and Horner Syndrome. He was found to have dissection of the carotid artery. The other patient was a young woman who had fractures of the femur and clavicle who, because she didn't have cranial or cervical trauma, didn't undergo a CTA. She woke up the next day in the orthopedic service with a stroke.

“We've concluded from this study that CTA is a reliable, noninvasive screening test for clinically significant blunt cervical vascular injuries,” Dr. Biffl said. “We need multicenter prospective trials to clarify the risk factors and to assess the accuracy of noninvasive screening tests and to evaluate the efficacy of treatment strategies,” he added.

A third tumor necrosis factor inhibitor has been added to the arsenal of drugs approved for treating psoriatic arthritis.

Adalimumab, a fully human, anti-TNF monoclonal antibody, significantly improved joint and skin manifestations, inhibited structural changes on radiographs, lessened disability due to joint damage, and improved quality of life in patients with moderately to severely active psoriatic arthritis, according to the findings of multicenter study.

Adalimumab and infliximab have been approved by the Food and Drug Administration for the treatment of psoriatic arthritis (PsA), but not for the dermatologic treatment of psoriasis in the absence of joint involvement. A third TNF inhibitor, etanercept, is approved for both PsA and the severe plaque of psoriasis.

In the study that served as the basis for the FDA approval of adalimumab for PsA, patients were stratified according to methotrexate use (yes or no) and degree of psoriatic involvement, and then randomized in a 1:1 ratio by site to receive either drug or placebo.

Of the 315 patients randomized to receive treatment, 162 were assigned to the placebo group and 153 were assigned to self-injected adalimumab 40 mg every other week. All patients who completed the 24-week protocol were eligible for long-term treatment in an open-label extension study.

The trial, which was conducted at 50 sites in the United States, Canada, and Europe, showed that patients treated with adalimumab achieved significantly higher American College of Rheumatology (ACR) response rates than those treated with placebo at all time points.

“At week 12, the ACR20 response rate was 58% for the adalimumab treatment group and 14% for the placebo-treated group,” study leader Philip J. Mease, M.D., of the Swedish Medical Center in Seattle, and his colleagues reported (Arthritis Rheum. 2005;52:3279–89).

“At week 24, the ACR 20 response rates were 57% and 15%, respectively. At 12 and 24 weeks, the ACR50 response rates were significantly higher in the adalimumab arm than in the placebo arm, and a significant difference in ACR 70 responses was also evident,” they said, adding that ACR responses developed rapidly, “with statistically significant between-group differences in the ACR20 and ACR50 responses observed at week 2”; 27% vs. 6% achieving ACR20 and 11% vs. 0% achieving ACR50. At week 4, 7% vs. 1% achieved ACR70.

Across the board, response rates did not differ between patients taking adalimumab in combination with methotrexate and those taking the TNF inhibitor alone.

The mean change in the modified total Sharp score in patients who had both baseline and week 24 radiographs was −0.2 for those on adalimumab compared with 1.0 for those receiving placebo injections (P less than .001), “implying that protection against progressive structural damage was achieved,” Dr. Mease said.

“Improvements seen in the skin manifestations of the disease were significant and occurred rapidly, results that were as good as or in some cases superior to results seen with other biologics,” Dr. Mease told this newspaper. “At week 24, PASI [psoriasis area and severity index] showed a 75% improvement in 16% of adalimumab-treated patients, compared with only 3% of placebo patients (P less than .001).

Similarly, the physician's global assessment of psoriasis resulted in ratings of the lesions as “clear” or “almost clear” in 67% of the 70 adalimumab-treated patients evaluated, compared with only 10% of the 70 placebo-treated patients evaluated for psoriasis (P less than .001).

“It appears that the response was a little faster in the skin with adalimumab, as has also been seen with infliximab, than with other biologics. When it comes to joint symptoms and important aspects such as quality of life, physical function, and inhibition of progressive joint damage, the three anti-TNF drugs are similar; but if you have a patient with really severe skin disease, there may be a slight advantage to using either infliximab or adalimumab,” Dr. Mease said.

The ink had hardly dried on this study when, in October, the FDA approved adalimumab for the treatment of PsA. “With etanercept, the PsA indication came ahead of the psoriasis indication, and the same is going to be true of adalimumab; that indication will likely follow once the pure psoriasis trials are fully considered by the FDA,” said Dr. Mease.

The cost of etanercept and adalimumab, when used for RA or PsA in the standard dose of 50 mg per week and 40 mg every other week, respectively, is similar, he said. “The comparative costs of these agents in psoriasis have yet to be fully understood, and ultimately will depend upon the dosages used to achieve optimal effects in the skin.”

Adalimumab was generally well tolerated during the 24-week trial. Common side effects “were similar to those seen in clinical trials involving patients with RA or were thought to be related to underlying disease,” according to the authors.

Serious adverse events were experienced by 12 patients, including 7 in the placebo group and 5 in the adalimumab group. In the latter, events included nasal septum disorder, toe arthrodesis, aggravation of convulsions, viral meningitis (attributed to West Nile virus) and renal calculus; most of these were considered unrelated to the study medication.

The authors stress that longer-term follow-up from the open-label extension study is needed to confirm these results. The study was supported by Abbott Laboratories.

Dr. Mease has received consulting fees or honoraria of less than $10,000/year from Abbott.

A third tumor necrosis factor inhibitor has been added to the arsenal of drugs approved for treating psoriatic arthritis.

Adalimumab, a fully human, anti-TNF monoclonal antibody, significantly improved joint and skin manifestations, inhibited structural changes on radiographs, lessened disability due to joint damage, and improved quality of life in patients with moderately to severely active psoriatic arthritis, according to the findings of multicenter study.

Adalimumab and infliximab have been approved by the Food and Drug Administration for the treatment of psoriatic arthritis (PsA), but not for the dermatologic treatment of psoriasis in the absence of joint involvement. A third TNF inhibitor, etanercept, is approved for both PsA and the severe plaque of psoriasis.

In the study that served as the basis for the FDA approval of adalimumab for PsA, patients were stratified according to methotrexate use (yes or no) and degree of psoriatic involvement, and then randomized in a 1:1 ratio by site to receive either drug or placebo.

Of the 315 patients randomized to receive treatment, 162 were assigned to the placebo group and 153 were assigned to self-injected adalimumab 40 mg every other week. All patients who completed the 24-week protocol were eligible for long-term treatment in an open-label extension study.

The trial, which was conducted at 50 sites in the United States, Canada, and Europe, showed that patients treated with adalimumab achieved significantly higher American College of Rheumatology (ACR) response rates than those treated with placebo at all time points.

“At week 12, the ACR20 response rate was 58% for the adalimumab treatment group and 14% for the placebo-treated group,” study leader Philip J. Mease, M.D., of the Swedish Medical Center in Seattle, and his colleagues reported (Arthritis Rheum. 2005;52:3279–89).

“At week 24, the ACR 20 response rates were 57% and 15%, respectively. At 12 and 24 weeks, the ACR50 response rates were significantly higher in the adalimumab arm than in the placebo arm, and a significant difference in ACR 70 responses was also evident,” they said, adding that ACR responses developed rapidly, “with statistically significant between-group differences in the ACR20 and ACR50 responses observed at week 2”; 27% vs. 6% achieving ACR20 and 11% vs. 0% achieving ACR50. At week 4, 7% vs. 1% achieved ACR70.

Across the board, response rates did not differ between patients taking adalimumab in combination with methotrexate and those taking the TNF inhibitor alone.

The mean change in the modified total Sharp score in patients who had both baseline and week 24 radiographs was −0.2 for those on adalimumab compared with 1.0 for those receiving placebo injections (P less than .001), “implying that protection against progressive structural damage was achieved,” Dr. Mease said.

“Improvements seen in the skin manifestations of the disease were significant and occurred rapidly, results that were as good as or in some cases superior to results seen with other biologics,” Dr. Mease told this newspaper. “At week 24, PASI [psoriasis area and severity index] showed a 75% improvement in 16% of adalimumab-treated patients, compared with only 3% of placebo patients (P less than .001).

Similarly, the physician's global assessment of psoriasis resulted in ratings of the lesions as “clear” or “almost clear” in 67% of the 70 adalimumab-treated patients evaluated, compared with only 10% of the 70 placebo-treated patients evaluated for psoriasis (P less than .001).

“It appears that the response was a little faster in the skin with adalimumab, as has also been seen with infliximab, than with other biologics. When it comes to joint symptoms and important aspects such as quality of life, physical function, and inhibition of progressive joint damage, the three anti-TNF drugs are similar; but if you have a patient with really severe skin disease, there may be a slight advantage to using either infliximab or adalimumab,” Dr. Mease said.

The ink had hardly dried on this study when, in October, the FDA approved adalimumab for the treatment of PsA. “With etanercept, the PsA indication came ahead of the psoriasis indication, and the same is going to be true of adalimumab; that indication will likely follow once the pure psoriasis trials are fully considered by the FDA,” said Dr. Mease.

The cost of etanercept and adalimumab, when used for RA or PsA in the standard dose of 50 mg per week and 40 mg every other week, respectively, is similar, he said. “The comparative costs of these agents in psoriasis have yet to be fully understood, and ultimately will depend upon the dosages used to achieve optimal effects in the skin.”

Adalimumab was generally well tolerated during the 24-week trial. Common side effects “were similar to those seen in clinical trials involving patients with RA or were thought to be related to underlying disease,” according to the authors.

Serious adverse events were experienced by 12 patients, including 7 in the placebo group and 5 in the adalimumab group. In the latter, events included nasal septum disorder, toe arthrodesis, aggravation of convulsions, viral meningitis (attributed to West Nile virus) and renal calculus; most of these were considered unrelated to the study medication.

The authors stress that longer-term follow-up from the open-label extension study is needed to confirm these results. The study was supported by Abbott Laboratories.

Dr. Mease has received consulting fees or honoraria of less than $10,000/year from Abbott.

A third tumor necrosis factor inhibitor has been added to the arsenal of drugs approved for treating psoriatic arthritis.

Adalimumab, a fully human, anti-TNF monoclonal antibody, significantly improved joint and skin manifestations, inhibited structural changes on radiographs, lessened disability due to joint damage, and improved quality of life in patients with moderately to severely active psoriatic arthritis, according to the findings of multicenter study.

Adalimumab and infliximab have been approved by the Food and Drug Administration for the treatment of psoriatic arthritis (PsA), but not for the dermatologic treatment of psoriasis in the absence of joint involvement. A third TNF inhibitor, etanercept, is approved for both PsA and the severe plaque of psoriasis.

In the study that served as the basis for the FDA approval of adalimumab for PsA, patients were stratified according to methotrexate use (yes or no) and degree of psoriatic involvement, and then randomized in a 1:1 ratio by site to receive either drug or placebo.

Of the 315 patients randomized to receive treatment, 162 were assigned to the placebo group and 153 were assigned to self-injected adalimumab 40 mg every other week. All patients who completed the 24-week protocol were eligible for long-term treatment in an open-label extension study.

The trial, which was conducted at 50 sites in the United States, Canada, and Europe, showed that patients treated with adalimumab achieved significantly higher American College of Rheumatology (ACR) response rates than those treated with placebo at all time points.

“At week 12, the ACR20 response rate was 58% for the adalimumab treatment group and 14% for the placebo-treated group,” study leader Philip J. Mease, M.D., of the Swedish Medical Center in Seattle, and his colleagues reported (Arthritis Rheum. 2005;52:3279–89).

“At week 24, the ACR 20 response rates were 57% and 15%, respectively. At 12 and 24 weeks, the ACR50 response rates were significantly higher in the adalimumab arm than in the placebo arm, and a significant difference in ACR 70 responses was also evident,” they said, adding that ACR responses developed rapidly, “with statistically significant between-group differences in the ACR20 and ACR50 responses observed at week 2”; 27% vs. 6% achieving ACR20 and 11% vs. 0% achieving ACR50. At week 4, 7% vs. 1% achieved ACR70.

Across the board, response rates did not differ between patients taking adalimumab in combination with methotrexate and those taking the TNF inhibitor alone.

The mean change in the modified total Sharp score in patients who had both baseline and week 24 radiographs was −0.2 for those on adalimumab compared with 1.0 for those receiving placebo injections (P less than .001), “implying that protection against progressive structural damage was achieved,” Dr. Mease said.

“Improvements seen in the skin manifestations of the disease were significant and occurred rapidly, results that were as good as or in some cases superior to results seen with other biologics,” Dr. Mease told this newspaper. “At week 24, PASI [psoriasis area and severity index] showed a 75% improvement in 16% of adalimumab-treated patients, compared with only 3% of placebo patients (P less than .001).

Similarly, the physician's global assessment of psoriasis resulted in ratings of the lesions as “clear” or “almost clear” in 67% of the 70 adalimumab-treated patients evaluated, compared with only 10% of the 70 placebo-treated patients evaluated for psoriasis (P less than .001).

“It appears that the response was a little faster in the skin with adalimumab, as has also been seen with infliximab, than with other biologics. When it comes to joint symptoms and important aspects such as quality of life, physical function, and inhibition of progressive joint damage, the three anti-TNF drugs are similar; but if you have a patient with really severe skin disease, there may be a slight advantage to using either infliximab or adalimumab,” Dr. Mease said.

The ink had hardly dried on this study when, in October, the FDA approved adalimumab for the treatment of PsA. “With etanercept, the PsA indication came ahead of the psoriasis indication, and the same is going to be true of adalimumab; that indication will likely follow once the pure psoriasis trials are fully considered by the FDA,” said Dr. Mease.

The cost of etanercept and adalimumab, when used for RA or PsA in the standard dose of 50 mg per week and 40 mg every other week, respectively, is similar, he said. “The comparative costs of these agents in psoriasis have yet to be fully understood, and ultimately will depend upon the dosages used to achieve optimal effects in the skin.”

Adalimumab was generally well tolerated during the 24-week trial. Common side effects “were similar to those seen in clinical trials involving patients with RA or were thought to be related to underlying disease,” according to the authors.

Serious adverse events were experienced by 12 patients, including 7 in the placebo group and 5 in the adalimumab group. In the latter, events included nasal septum disorder, toe arthrodesis, aggravation of convulsions, viral meningitis (attributed to West Nile virus) and renal calculus; most of these were considered unrelated to the study medication.

The authors stress that longer-term follow-up from the open-label extension study is needed to confirm these results. The study was supported by Abbott Laboratories.

Dr. Mease has received consulting fees or honoraria of less than $10,000/year from Abbott.

CLEVELAND — Tumor necrosis factor-α blockade should not be instituted in patients with known multiple sclerosis and should be used with caution in patients with family histories or other risk factors for MS, according to Jeffrey A. Cohen, M.D., a neurologist at the Cleveland Clinic.

In addition, physicians should be alert to uncommon central nervous system manifestations in patients receiving tumor necrosis factor (TNF) blockade for their inflammatory diseases, he said at a meeting on the treatment of autoimmune and inflammatory disorders.

TNF inhibitors currently approved by the Food and Drug Administration include the monoclonal antibodies infliximab (Remicade) and adalimumab (Humira) and the fusion protein etanercept (Enbrel).

TNF blockade both prevents and abrogates demyelinating disease in vitro and in animal studies. However, in humans, TNF blockade actually increased MS activity, said Dr. Cohen, citing data from two studies of infliximab and the discontinued lenercept. “In addition, treatment of other diseases for which TNF inhibitors are highly effective, including rheumatoid arthritis, Crohn's disease, and psoriasis, on rare occasions leads to CNS inflammatory demyelinating syndromes,” said Dr. Cohen at a summit sponsored by the Cleveland Clinic.

Failure of a TNF antagonist therapy in MS may be due to pleiotropic aspects of TNF actions, he noted. “In the CNS, TNF mediates cellular apoptosis and tissue damage, has important immunoregulatory functions, and is involved in tissue repair and regeneration. This experience reminds us that in the development of novel therapeutics, one must be cautious in extrapolating from animal models to human disease and from the results in one human disease to another,” he said.

Discussion of restarting therapy in patients who have been taken off a TNF inhibition because they developed a CNS manifestation involved a hypothetical case representing a composite of patients created for teaching purposes: a 32-year-old woman with a 5-year history of active Crohn's disease unresponsive to 6-mercaptopurine, mesalamine (Pentasa), and budesonide. She was started on infliximab and responded after the third infusion with complete resolution of abdominal pain and cramping and with a marked reduction in the frequency of bowel movements.

“After 12 months of therapy, she developed gait imbalance and numbness and tingling of the hands and feet that worsened over several weeks, making it difficult for her to walk,” Dr. Cohen said. The patient's Crohn's disease remained quiescent. A cranial nerve exam was normal, and the woman had normal strength, mild spasticity in the legs, diffuse hyperreflexia with right Babinski's sign, mild ataxia of the arms and legs, decreased position sense in the hands and feet, and moderate gait ataxia.

The patient's erythrocyte sedimentation rate was 55, she did not have a lupus anticoagulant, her B₁₂ and copper were normal, and an antibody test was negative. An MRI of the cervical spine showed an ovoid lesion in the spinal cord at C3–4 with mild diffuse enhancement. A lumbar puncture showed mild mononuclear cell pleocytosis, normal glucose, mildly elevated protein, normal IgG index, and no oligoclonal bands Dr. Cohen said.

Infliximab therapy was discontinued, and the woman was treated with intravenous methylprednisolone for three days, with the dose tapered over 2 weeks. “Within 12 weeks, the neurologic symptoms had completely resolved,” said Dr. Cohen. “Repeat MRI showed resolution of enhancement of the spinal cord lesion and no other lesions in the brain or spinal cord. Her original Crohn's symptoms recurred, however, and did not respond to MTX [methotrexate] or budesonide. Her symptoms improved on prednisone 60 mg/day but returned when the dose was tapered. She said she had felt much better on infliximab and asked about the possibility of restarting it,” said Dr. Cohen. “The decision to restart infliximab must be based on weighing the risks from Crohn's disease and whether other treatment options exist versus the risk of a recurrent neurologic complication.”

“The differential diagnosis of neurologic manifestations in patients with immune mediated inflammatory disorders treated with TNF inhibitors is broad and includes neurologic complications of the underlying disease, neoplastic or infectious complications of TNF inhibitors, and direct neurologic complications of TNF inhibitors. Reported neurologic complications of TNF inhibitors include CNS demyelinating syndromes, aseptic meningitis, seizures, ischemic optic neuropathy, and demyelinating peripheral neuropathies,” according to Dr. Cohen.

“CNS demyelination can occur anytime after an anti-TNF agent is started, and clinical manifestations reflect the anatomic site of involvement. Demyelination has been reported with all TNF antagonists and thus appears to be a class effect.”

In terms of the nervous system, Dr. Cohen recommends avoiding TNF blockade for patients who are known to have MS or who might be at risk of MS; nor should TNF inhibitor infusions be given to patients who have had a previous clinically isolated CNS syndrome without the formal diagnosis of MS or to patients who have cranial MRIs that look suggestive of MS but do not yet have clinical manifestations, advised Dr. Cohen.

“If you're forced to use TNF blockade because your patient has inflammatory bowel disease, RA [rheumatoid arthritis], or psoriasis that is not responding well to other [treatments], you need to watch closely for potential CNS demyelination, and that should include both clinical monitoring and periodic MRI. If a patient develops a CNS complication, TNF blockade should be interrupted and the investigation should include neurologic assessment to clarify the nature of the complication. That evaluation should include lumbar puncture, and treatment should include a corticosteroid. If the patient continues to have CNS demyelinating events following discontinuation of TNF blockade, you've probably unmasked incipient MS, in which case I would consider disease-modifying therapy for MS,” Dr. Cohen said.

The neurologist advised against looking for MS in every patient prior to starting a TNF inhibitor for treatment of inflammatory bowel disease, rheumatoid arthritis, or psoriasis. “In particular, I would not obtain an MRI unless there was some clinical suggestion of potential [for MS].” However, uveitis is a different story: “Uveitis is a manifestation that can occur in MS, so I would look very carefully for any indication of MS involvement” before beginning TNF blockade.

CLEVELAND — Tumor necrosis factor-α blockade should not be instituted in patients with known multiple sclerosis and should be used with caution in patients with family histories or other risk factors for MS, according to Jeffrey A. Cohen, M.D., a neurologist at the Cleveland Clinic.

In addition, physicians should be alert to uncommon central nervous system manifestations in patients receiving tumor necrosis factor (TNF) blockade for their inflammatory diseases, he said at a meeting on the treatment of autoimmune and inflammatory disorders.

TNF inhibitors currently approved by the Food and Drug Administration include the monoclonal antibodies infliximab (Remicade) and adalimumab (Humira) and the fusion protein etanercept (Enbrel).

TNF blockade both prevents and abrogates demyelinating disease in vitro and in animal studies. However, in humans, TNF blockade actually increased MS activity, said Dr. Cohen, citing data from two studies of infliximab and the discontinued lenercept. “In addition, treatment of other diseases for which TNF inhibitors are highly effective, including rheumatoid arthritis, Crohn's disease, and psoriasis, on rare occasions leads to CNS inflammatory demyelinating syndromes,” said Dr. Cohen at a summit sponsored by the Cleveland Clinic.

Failure of a TNF antagonist therapy in MS may be due to pleiotropic aspects of TNF actions, he noted. “In the CNS, TNF mediates cellular apoptosis and tissue damage, has important immunoregulatory functions, and is involved in tissue repair and regeneration. This experience reminds us that in the development of novel therapeutics, one must be cautious in extrapolating from animal models to human disease and from the results in one human disease to another,” he said.

Discussion of restarting therapy in patients who have been taken off a TNF inhibition because they developed a CNS manifestation involved a hypothetical case representing a composite of patients created for teaching purposes: a 32-year-old woman with a 5-year history of active Crohn's disease unresponsive to 6-mercaptopurine, mesalamine (Pentasa), and budesonide. She was started on infliximab and responded after the third infusion with complete resolution of abdominal pain and cramping and with a marked reduction in the frequency of bowel movements.

“After 12 months of therapy, she developed gait imbalance and numbness and tingling of the hands and feet that worsened over several weeks, making it difficult for her to walk,” Dr. Cohen said. The patient's Crohn's disease remained quiescent. A cranial nerve exam was normal, and the woman had normal strength, mild spasticity in the legs, diffuse hyperreflexia with right Babinski's sign, mild ataxia of the arms and legs, decreased position sense in the hands and feet, and moderate gait ataxia.

The patient's erythrocyte sedimentation rate was 55, she did not have a lupus anticoagulant, her B₁₂ and copper were normal, and an antibody test was negative. An MRI of the cervical spine showed an ovoid lesion in the spinal cord at C3–4 with mild diffuse enhancement. A lumbar puncture showed mild mononuclear cell pleocytosis, normal glucose, mildly elevated protein, normal IgG index, and no oligoclonal bands Dr. Cohen said.

Infliximab therapy was discontinued, and the woman was treated with intravenous methylprednisolone for three days, with the dose tapered over 2 weeks. “Within 12 weeks, the neurologic symptoms had completely resolved,” said Dr. Cohen. “Repeat MRI showed resolution of enhancement of the spinal cord lesion and no other lesions in the brain or spinal cord. Her original Crohn's symptoms recurred, however, and did not respond to MTX [methotrexate] or budesonide. Her symptoms improved on prednisone 60 mg/day but returned when the dose was tapered. She said she had felt much better on infliximab and asked about the possibility of restarting it,” said Dr. Cohen. “The decision to restart infliximab must be based on weighing the risks from Crohn's disease and whether other treatment options exist versus the risk of a recurrent neurologic complication.”

“The differential diagnosis of neurologic manifestations in patients with immune mediated inflammatory disorders treated with TNF inhibitors is broad and includes neurologic complications of the underlying disease, neoplastic or infectious complications of TNF inhibitors, and direct neurologic complications of TNF inhibitors. Reported neurologic complications of TNF inhibitors include CNS demyelinating syndromes, aseptic meningitis, seizures, ischemic optic neuropathy, and demyelinating peripheral neuropathies,” according to Dr. Cohen.

“CNS demyelination can occur anytime after an anti-TNF agent is started, and clinical manifestations reflect the anatomic site of involvement. Demyelination has been reported with all TNF antagonists and thus appears to be a class effect.”

In terms of the nervous system, Dr. Cohen recommends avoiding TNF blockade for patients who are known to have MS or who might be at risk of MS; nor should TNF inhibitor infusions be given to patients who have had a previous clinically isolated CNS syndrome without the formal diagnosis of MS or to patients who have cranial MRIs that look suggestive of MS but do not yet have clinical manifestations, advised Dr. Cohen.

“If you're forced to use TNF blockade because your patient has inflammatory bowel disease, RA [rheumatoid arthritis], or psoriasis that is not responding well to other [treatments], you need to watch closely for potential CNS demyelination, and that should include both clinical monitoring and periodic MRI. If a patient develops a CNS complication, TNF blockade should be interrupted and the investigation should include neurologic assessment to clarify the nature of the complication. That evaluation should include lumbar puncture, and treatment should include a corticosteroid. If the patient continues to have CNS demyelinating events following discontinuation of TNF blockade, you've probably unmasked incipient MS, in which case I would consider disease-modifying therapy for MS,” Dr. Cohen said.

The neurologist advised against looking for MS in every patient prior to starting a TNF inhibitor for treatment of inflammatory bowel disease, rheumatoid arthritis, or psoriasis. “In particular, I would not obtain an MRI unless there was some clinical suggestion of potential [for MS].” However, uveitis is a different story: “Uveitis is a manifestation that can occur in MS, so I would look very carefully for any indication of MS involvement” before beginning TNF blockade.

CLEVELAND — Tumor necrosis factor-α blockade should not be instituted in patients with known multiple sclerosis and should be used with caution in patients with family histories or other risk factors for MS, according to Jeffrey A. Cohen, M.D., a neurologist at the Cleveland Clinic.

In addition, physicians should be alert to uncommon central nervous system manifestations in patients receiving tumor necrosis factor (TNF) blockade for their inflammatory diseases, he said at a meeting on the treatment of autoimmune and inflammatory disorders.

TNF inhibitors currently approved by the Food and Drug Administration include the monoclonal antibodies infliximab (Remicade) and adalimumab (Humira) and the fusion protein etanercept (Enbrel).

TNF blockade both prevents and abrogates demyelinating disease in vitro and in animal studies. However, in humans, TNF blockade actually increased MS activity, said Dr. Cohen, citing data from two studies of infliximab and the discontinued lenercept. “In addition, treatment of other diseases for which TNF inhibitors are highly effective, including rheumatoid arthritis, Crohn's disease, and psoriasis, on rare occasions leads to CNS inflammatory demyelinating syndromes,” said Dr. Cohen at a summit sponsored by the Cleveland Clinic.

Failure of a TNF antagonist therapy in MS may be due to pleiotropic aspects of TNF actions, he noted. “In the CNS, TNF mediates cellular apoptosis and tissue damage, has important immunoregulatory functions, and is involved in tissue repair and regeneration. This experience reminds us that in the development of novel therapeutics, one must be cautious in extrapolating from animal models to human disease and from the results in one human disease to another,” he said.

Discussion of restarting therapy in patients who have been taken off a TNF inhibition because they developed a CNS manifestation involved a hypothetical case representing a composite of patients created for teaching purposes: a 32-year-old woman with a 5-year history of active Crohn's disease unresponsive to 6-mercaptopurine, mesalamine (Pentasa), and budesonide. She was started on infliximab and responded after the third infusion with complete resolution of abdominal pain and cramping and with a marked reduction in the frequency of bowel movements.

“After 12 months of therapy, she developed gait imbalance and numbness and tingling of the hands and feet that worsened over several weeks, making it difficult for her to walk,” Dr. Cohen said. The patient's Crohn's disease remained quiescent. A cranial nerve exam was normal, and the woman had normal strength, mild spasticity in the legs, diffuse hyperreflexia with right Babinski's sign, mild ataxia of the arms and legs, decreased position sense in the hands and feet, and moderate gait ataxia.

The patient's erythrocyte sedimentation rate was 55, she did not have a lupus anticoagulant, her B₁₂ and copper were normal, and an antibody test was negative. An MRI of the cervical spine showed an ovoid lesion in the spinal cord at C3–4 with mild diffuse enhancement. A lumbar puncture showed mild mononuclear cell pleocytosis, normal glucose, mildly elevated protein, normal IgG index, and no oligoclonal bands Dr. Cohen said.

Infliximab therapy was discontinued, and the woman was treated with intravenous methylprednisolone for three days, with the dose tapered over 2 weeks. “Within 12 weeks, the neurologic symptoms had completely resolved,” said Dr. Cohen. “Repeat MRI showed resolution of enhancement of the spinal cord lesion and no other lesions in the brain or spinal cord. Her original Crohn's symptoms recurred, however, and did not respond to MTX [methotrexate] or budesonide. Her symptoms improved on prednisone 60 mg/day but returned when the dose was tapered. She said she had felt much better on infliximab and asked about the possibility of restarting it,” said Dr. Cohen. “The decision to restart infliximab must be based on weighing the risks from Crohn's disease and whether other treatment options exist versus the risk of a recurrent neurologic complication.”

“The differential diagnosis of neurologic manifestations in patients with immune mediated inflammatory disorders treated with TNF inhibitors is broad and includes neurologic complications of the underlying disease, neoplastic or infectious complications of TNF inhibitors, and direct neurologic complications of TNF inhibitors. Reported neurologic complications of TNF inhibitors include CNS demyelinating syndromes, aseptic meningitis, seizures, ischemic optic neuropathy, and demyelinating peripheral neuropathies,” according to Dr. Cohen.

“CNS demyelination can occur anytime after an anti-TNF agent is started, and clinical manifestations reflect the anatomic site of involvement. Demyelination has been reported with all TNF antagonists and thus appears to be a class effect.”

In terms of the nervous system, Dr. Cohen recommends avoiding TNF blockade for patients who are known to have MS or who might be at risk of MS; nor should TNF inhibitor infusions be given to patients who have had a previous clinically isolated CNS syndrome without the formal diagnosis of MS or to patients who have cranial MRIs that look suggestive of MS but do not yet have clinical manifestations, advised Dr. Cohen.

“If you're forced to use TNF blockade because your patient has inflammatory bowel disease, RA [rheumatoid arthritis], or psoriasis that is not responding well to other [treatments], you need to watch closely for potential CNS demyelination, and that should include both clinical monitoring and periodic MRI. If a patient develops a CNS complication, TNF blockade should be interrupted and the investigation should include neurologic assessment to clarify the nature of the complication. That evaluation should include lumbar puncture, and treatment should include a corticosteroid. If the patient continues to have CNS demyelinating events following discontinuation of TNF blockade, you've probably unmasked incipient MS, in which case I would consider disease-modifying therapy for MS,” Dr. Cohen said.

The neurologist advised against looking for MS in every patient prior to starting a TNF inhibitor for treatment of inflammatory bowel disease, rheumatoid arthritis, or psoriasis. “In particular, I would not obtain an MRI unless there was some clinical suggestion of potential [for MS].” However, uveitis is a different story: “Uveitis is a manifestation that can occur in MS, so I would look very carefully for any indication of MS involvement” before beginning TNF blockade.

CLEVELAND — Treatment with a tumor necrosis factor-α inhibitor may trigger a demyelinating polyneuropathy with Guillain-Barré-like symptoms, according to MaryAnn Mays, M.D., of the Cleveland Clinic Foundation.

The case in point, presented in a poster at a symposium on the treatment of autoimmune and inflammatory disorders sponsored by the clinic, was that of a 56-year-old man with seropositive rheumatoid arthritis who became severely disabled after infliximab infusions were added to his methotrexate therapy.

Dr. Mays, a neurologist, reported in an interview that the patient's rheumatoid arthritis symptoms lessened markedly following his first anti-TNF treatment in 2002, but following an infusion in late 2003, he experienced dizziness and hearing loss that lasted for a week. The symptoms recurred and lasted longer following a third infusion 2 months later.

The next infliximab infusion in April 2004 produced worsening neurologic symptoms, including blurred vision, headaches, dysarthria, hearing loss, ataxia, dysphagia requiring percutaneous endoscopic gastrostomy for nutrition, and progressive weakness, Dr. Mays said.

“Initial evaluation included cerebrospinal fluid WBC of 123, protein 79, and electromyograph consistent with demyelinating polyneuropathy. But the overall pattern was not typical of Guillain-Barré syndrome [GBS],” Dr. Mays said. “He had high white count and normal protein. Auditory evoked potentials showed a right central conduction disturbance. His detrusor urinae muscle did not respond to stimuli, which is typical of GBS. His right Babinski sign was atypical of GBS.”

Feyrouz Al-Ashkar, M.D., the lead investigator and a rheumatologist, noted in an interview that by the time the patient was brought to the clinic, he “could not walk, use his hands, lift his head, or feed himself, although he could still breathe on his own.”

“He received intravenous immunoglobulin and steroids before we saw him. When he got here, he again received intravenous steroids and another course of intravenous immunoglobulin, and slowly, but surely, he recovered completely,” Dr. Al-Ashkar said.

Dr. Mays noted that “the fact that the patient responded well to a second course of intravenous immunoglobulin was further evidence that what he had was a demyelinating polyneuropathy other than GBS.”

According to Dr. Al-Ashkar, the message to clinicians “is that if you start noticing neurologic deficits or other adverse events, especially demyelinating diseases, in patients who are receiving infliximab, this should alert you to stop it and look for another treatment.”

Dr. Al-Ashkar wrote that “if neurologic symptoms occur following [TNF] infusion, then evaluation for demyelinating disease, including chronic inflammatory demyelinating polyneuropathy, multiple sclerosis, and GBS, should be pursued.

“In such cases, our experience would suggest that there is potential for worsening of neurologic deficits with each infliximab treatment, and that continuing treatments after onset of neurologic symptoms would be relatively contraindicated,” she wrote.

CLEVELAND — Treatment with a tumor necrosis factor-α inhibitor may trigger a demyelinating polyneuropathy with Guillain-Barré-like symptoms, according to MaryAnn Mays, M.D., of the Cleveland Clinic Foundation.

The case in point, presented in a poster at a symposium on the treatment of autoimmune and inflammatory disorders sponsored by the clinic, was that of a 56-year-old man with seropositive rheumatoid arthritis who became severely disabled after infliximab infusions were added to his methotrexate therapy.

Dr. Mays, a neurologist, reported in an interview that the patient's rheumatoid arthritis symptoms lessened markedly following his first anti-TNF treatment in 2002, but following an infusion in late 2003, he experienced dizziness and hearing loss that lasted for a week. The symptoms recurred and lasted longer following a third infusion 2 months later.

The next infliximab infusion in April 2004 produced worsening neurologic symptoms, including blurred vision, headaches, dysarthria, hearing loss, ataxia, dysphagia requiring percutaneous endoscopic gastrostomy for nutrition, and progressive weakness, Dr. Mays said.

“Initial evaluation included cerebrospinal fluid WBC of 123, protein 79, and electromyograph consistent with demyelinating polyneuropathy. But the overall pattern was not typical of Guillain-Barré syndrome [GBS],” Dr. Mays said. “He had high white count and normal protein. Auditory evoked potentials showed a right central conduction disturbance. His detrusor urinae muscle did not respond to stimuli, which is typical of GBS. His right Babinski sign was atypical of GBS.”

Feyrouz Al-Ashkar, M.D., the lead investigator and a rheumatologist, noted in an interview that by the time the patient was brought to the clinic, he “could not walk, use his hands, lift his head, or feed himself, although he could still breathe on his own.”

“He received intravenous immunoglobulin and steroids before we saw him. When he got here, he again received intravenous steroids and another course of intravenous immunoglobulin, and slowly, but surely, he recovered completely,” Dr. Al-Ashkar said.

Dr. Mays noted that “the fact that the patient responded well to a second course of intravenous immunoglobulin was further evidence that what he had was a demyelinating polyneuropathy other than GBS.”

According to Dr. Al-Ashkar, the message to clinicians “is that if you start noticing neurologic deficits or other adverse events, especially demyelinating diseases, in patients who are receiving infliximab, this should alert you to stop it and look for another treatment.”

Dr. Al-Ashkar wrote that “if neurologic symptoms occur following [TNF] infusion, then evaluation for demyelinating disease, including chronic inflammatory demyelinating polyneuropathy, multiple sclerosis, and GBS, should be pursued.

“In such cases, our experience would suggest that there is potential for worsening of neurologic deficits with each infliximab treatment, and that continuing treatments after onset of neurologic symptoms would be relatively contraindicated,” she wrote.

CLEVELAND — Treatment with a tumor necrosis factor-α inhibitor may trigger a demyelinating polyneuropathy with Guillain-Barré-like symptoms, according to MaryAnn Mays, M.D., of the Cleveland Clinic Foundation.

The case in point, presented in a poster at a symposium on the treatment of autoimmune and inflammatory disorders sponsored by the clinic, was that of a 56-year-old man with seropositive rheumatoid arthritis who became severely disabled after infliximab infusions were added to his methotrexate therapy.

Dr. Mays, a neurologist, reported in an interview that the patient's rheumatoid arthritis symptoms lessened markedly following his first anti-TNF treatment in 2002, but following an infusion in late 2003, he experienced dizziness and hearing loss that lasted for a week. The symptoms recurred and lasted longer following a third infusion 2 months later.

The next infliximab infusion in April 2004 produced worsening neurologic symptoms, including blurred vision, headaches, dysarthria, hearing loss, ataxia, dysphagia requiring percutaneous endoscopic gastrostomy for nutrition, and progressive weakness, Dr. Mays said.

“Initial evaluation included cerebrospinal fluid WBC of 123, protein 79, and electromyograph consistent with demyelinating polyneuropathy. But the overall pattern was not typical of Guillain-Barré syndrome [GBS],” Dr. Mays said. “He had high white count and normal protein. Auditory evoked potentials showed a right central conduction disturbance. His detrusor urinae muscle did not respond to stimuli, which is typical of GBS. His right Babinski sign was atypical of GBS.”

Feyrouz Al-Ashkar, M.D., the lead investigator and a rheumatologist, noted in an interview that by the time the patient was brought to the clinic, he “could not walk, use his hands, lift his head, or feed himself, although he could still breathe on his own.”

“He received intravenous immunoglobulin and steroids before we saw him. When he got here, he again received intravenous steroids and another course of intravenous immunoglobulin, and slowly, but surely, he recovered completely,” Dr. Al-Ashkar said.

Dr. Mays noted that “the fact that the patient responded well to a second course of intravenous immunoglobulin was further evidence that what he had was a demyelinating polyneuropathy other than GBS.”

According to Dr. Al-Ashkar, the message to clinicians “is that if you start noticing neurologic deficits or other adverse events, especially demyelinating diseases, in patients who are receiving infliximab, this should alert you to stop it and look for another treatment.”

Dr. Al-Ashkar wrote that “if neurologic symptoms occur following [TNF] infusion, then evaluation for demyelinating disease, including chronic inflammatory demyelinating polyneuropathy, multiple sclerosis, and GBS, should be pursued.

“In such cases, our experience would suggest that there is potential for worsening of neurologic deficits with each infliximab treatment, and that continuing treatments after onset of neurologic symptoms would be relatively contraindicated,” she wrote.

CLEVELAND — Treatment with a tumor necrosis factor-α inhibitor may trigger a demyelinating polyneuropathy with Guillain-Barré-like symptoms, according to MaryAnn Mays, M.D., of the Cleveland Clinic Foundation.

The case in point, presented in a poster at a symposium on the treatment of autoimmune and inflammatory disorders sponsored by the clinic, was that of a 56-year-old man with seropositive rheumatoid arthritis who became severely disabled after infliximab infusions were added to his methotrexate therapy.

Dr. Mays, a neurologist, said in an interview that following his first anti-TNF treatment in 2002, the patient's rheumatoid arthritis symptoms lessened dramatically, but following an infusion in late 2003, he had dizziness and hearing loss for a week. The symptoms recurred and lasted longer following a third infusion 2 months later.

The next infliximab infusion in April 2004 produced worsening neurologic symptoms, including blurred vision, headaches, dysarthria, hearing loss, ataxia, dysphagia requiring percutaneous endoscopic gastrostomy for nutrition, and progressive weakness, according to Dr. Mays.

“Initial evaluation included cerebrospinal fluid WBC of 123, protein 79, and electromyograph consistent with demyelinating polyneuropathy. But the overall pattern was not typical of Guillain-Barré syndrome [GBS],” Dr. Mays said. “He had high white count and normal protein. Auditory evoked potentials showed a right central conduction disturbance. His detrusor urinae muscle were unresponsive, which is typical of GBS. His right Babinski sign was atypical of GBS.”

Feyrouz Al-Ashkar, M.D., the lead investigator and a rheumatologist, noted in an interview that by the time the patient was brought to the clinic, he “could not walk, use his hands, lift his head, or feed himself, although he could still breathe on his own.”

“He received intravenous immunoglobulin [IVIg] and steroids before we saw him. When he got here, he again received intravenous steroids and another course of intravenous immunoglobulin, and slowly but surely, he recovered completely,” Dr. Al-Ashkar said.

Dr. Mays noted that the patient's response to IVIg supports the diagnosis of a demyelinating polyneuropathy other than GBS.”

Dr. Al-Ashkar said that the onset of neurologic deficits or demyelinating diseases in patients on infliximab is a red flag to stop TNF blockade. “In such cases, our experience would suggest that there is potential for worsening of neurologic deficits with each infliximab treatment, and that continuing treatments after onset of neurologic symptoms would be relatively contraindicated,” according to the poster.

CLEVELAND — Treatment with a tumor necrosis factor-α inhibitor may trigger a demyelinating polyneuropathy with Guillain-Barré-like symptoms, according to MaryAnn Mays, M.D., of the Cleveland Clinic Foundation.

The case in point, presented in a poster at a symposium on the treatment of autoimmune and inflammatory disorders sponsored by the clinic, was that of a 56-year-old man with seropositive rheumatoid arthritis who became severely disabled after infliximab infusions were added to his methotrexate therapy.

Dr. Mays, a neurologist, said in an interview that following his first anti-TNF treatment in 2002, the patient's rheumatoid arthritis symptoms lessened dramatically, but following an infusion in late 2003, he had dizziness and hearing loss for a week. The symptoms recurred and lasted longer following a third infusion 2 months later.

The next infliximab infusion in April 2004 produced worsening neurologic symptoms, including blurred vision, headaches, dysarthria, hearing loss, ataxia, dysphagia requiring percutaneous endoscopic gastrostomy for nutrition, and progressive weakness, according to Dr. Mays.

“Initial evaluation included cerebrospinal fluid WBC of 123, protein 79, and electromyograph consistent with demyelinating polyneuropathy. But the overall pattern was not typical of Guillain-Barré syndrome [GBS],” Dr. Mays said. “He had high white count and normal protein. Auditory evoked potentials showed a right central conduction disturbance. His detrusor urinae muscle were unresponsive, which is typical of GBS. His right Babinski sign was atypical of GBS.”

Feyrouz Al-Ashkar, M.D., the lead investigator and a rheumatologist, noted in an interview that by the time the patient was brought to the clinic, he “could not walk, use his hands, lift his head, or feed himself, although he could still breathe on his own.”

“He received intravenous immunoglobulin [IVIg] and steroids before we saw him. When he got here, he again received intravenous steroids and another course of intravenous immunoglobulin, and slowly but surely, he recovered completely,” Dr. Al-Ashkar said.

Dr. Mays noted that the patient's response to IVIg supports the diagnosis of a demyelinating polyneuropathy other than GBS.”

Dr. Al-Ashkar said that the onset of neurologic deficits or demyelinating diseases in patients on infliximab is a red flag to stop TNF blockade. “In such cases, our experience would suggest that there is potential for worsening of neurologic deficits with each infliximab treatment, and that continuing treatments after onset of neurologic symptoms would be relatively contraindicated,” according to the poster.

CLEVELAND — Treatment with a tumor necrosis factor-α inhibitor may trigger a demyelinating polyneuropathy with Guillain-Barré-like symptoms, according to MaryAnn Mays, M.D., of the Cleveland Clinic Foundation.

The case in point, presented in a poster at a symposium on the treatment of autoimmune and inflammatory disorders sponsored by the clinic, was that of a 56-year-old man with seropositive rheumatoid arthritis who became severely disabled after infliximab infusions were added to his methotrexate therapy.

Dr. Mays, a neurologist, said in an interview that following his first anti-TNF treatment in 2002, the patient's rheumatoid arthritis symptoms lessened dramatically, but following an infusion in late 2003, he had dizziness and hearing loss for a week. The symptoms recurred and lasted longer following a third infusion 2 months later.

The next infliximab infusion in April 2004 produced worsening neurologic symptoms, including blurred vision, headaches, dysarthria, hearing loss, ataxia, dysphagia requiring percutaneous endoscopic gastrostomy for nutrition, and progressive weakness, according to Dr. Mays.

“Initial evaluation included cerebrospinal fluid WBC of 123, protein 79, and electromyograph consistent with demyelinating polyneuropathy. But the overall pattern was not typical of Guillain-Barré syndrome [GBS],” Dr. Mays said. “He had high white count and normal protein. Auditory evoked potentials showed a right central conduction disturbance. His detrusor urinae muscle were unresponsive, which is typical of GBS. His right Babinski sign was atypical of GBS.”

Feyrouz Al-Ashkar, M.D., the lead investigator and a rheumatologist, noted in an interview that by the time the patient was brought to the clinic, he “could not walk, use his hands, lift his head, or feed himself, although he could still breathe on his own.”

“He received intravenous immunoglobulin [IVIg] and steroids before we saw him. When he got here, he again received intravenous steroids and another course of intravenous immunoglobulin, and slowly but surely, he recovered completely,” Dr. Al-Ashkar said.

Dr. Mays noted that the patient's response to IVIg supports the diagnosis of a demyelinating polyneuropathy other than GBS.”

Dr. Al-Ashkar said that the onset of neurologic deficits or demyelinating diseases in patients on infliximab is a red flag to stop TNF blockade. “In such cases, our experience would suggest that there is potential for worsening of neurologic deficits with each infliximab treatment, and that continuing treatments after onset of neurologic symptoms would be relatively contraindicated,” according to the poster.

CLEVELAND — Tumor necrosis factor-α blockade should not be instituted in patients with known multiple sclerosis and should be used with caution in patients with family histories or other risk factors for MS, according to Jeffrey A. Cohen, M.D., a neurologist at the Cleveland Clinic, Ohio.

Physicians should also be alert to uncommon CNS manifestations in patients receiving tumor necrosis factor (TNF) blockade for their inflammatory diseases, he said at a meeting on the treatment of autoimmune and inflammatory disorders.

TNF inhibitors currently approved by the Food and Drug Administration include the monoclonal antibodies infliximab (Remicade) and adalimumab (Humira) and the fusion protein etanercept (Enbrel).

TNF blockade both prevents and abrogates demyelinating disease in vitro and in animal studies. In humans, TNF blockade actually increased MS activity, said Dr. Cohen, citing data from two studies of infliximab and the discontinued lenercept. “In addition, treatment of other diseases for which TNF inhibitors are highly effective, including rheumatoid arthritis, Crohn's disease, and psoriasis, on rare occasions leads to CNS inflammatory demyelinating syndromes,” Dr. Cohen said at a summit sponsored by the Cleveland Clinic.

Failure of anti-TNF therapy in MS may be due to pleiotropic aspects of TNF actions, he noted. “In the CNS, TNF mediates cellular apoptosis and tissue damage, has important immunoregulatory functions, and is involved in tissue repair and regeneration. This experience reminds us that in the development of novel therapeutics, one must be cautious in extrapolating from animal models to human disease and from the results in one human disease to another,” he said. CNS demyelination can occur anytime after an anti-TNF agent is started. Demyelination appears to be a class effect of all TNF antagonists.

Dr. Cohen recommends avoiding TNF blockade for patients with or at risk for MS. Withhold TNF inhibitor infusions from patients who have had a previous clinically isolated CNS syndrome and have cranial MRIs that look suggestive of MS but do not yet have clinical manifestations, advised Dr. Cohen.

Dr. Cohen, a neurologist, advised against looking for MS in every patient prior to starting a TNF inhibitor for treatment of inflammatory bowel disease, rheumatoid arthritis, or psoriasis. “In particular, I would not obtain an MRI unless there was some clinical suggestion of potential (for MS).” However, uveitis is a different story: “Uveitis is a manifestation that can occur in MS, so I would look very carefully for any indication of MS involvement” before beginning TNF blockade.

CLEVELAND — Tumor necrosis factor-α blockade should not be instituted in patients with known multiple sclerosis and should be used with caution in patients with family histories or other risk factors for MS, according to Jeffrey A. Cohen, M.D., a neurologist at the Cleveland Clinic, Ohio.

Physicians should also be alert to uncommon CNS manifestations in patients receiving tumor necrosis factor (TNF) blockade for their inflammatory diseases, he said at a meeting on the treatment of autoimmune and inflammatory disorders.

TNF inhibitors currently approved by the Food and Drug Administration include the monoclonal antibodies infliximab (Remicade) and adalimumab (Humira) and the fusion protein etanercept (Enbrel).

TNF blockade both prevents and abrogates demyelinating disease in vitro and in animal studies. In humans, TNF blockade actually increased MS activity, said Dr. Cohen, citing data from two studies of infliximab and the discontinued lenercept. “In addition, treatment of other diseases for which TNF inhibitors are highly effective, including rheumatoid arthritis, Crohn's disease, and psoriasis, on rare occasions leads to CNS inflammatory demyelinating syndromes,” Dr. Cohen said at a summit sponsored by the Cleveland Clinic.

Failure of anti-TNF therapy in MS may be due to pleiotropic aspects of TNF actions, he noted. “In the CNS, TNF mediates cellular apoptosis and tissue damage, has important immunoregulatory functions, and is involved in tissue repair and regeneration. This experience reminds us that in the development of novel therapeutics, one must be cautious in extrapolating from animal models to human disease and from the results in one human disease to another,” he said. CNS demyelination can occur anytime after an anti-TNF agent is started. Demyelination appears to be a class effect of all TNF antagonists.

Dr. Cohen recommends avoiding TNF blockade for patients with or at risk for MS. Withhold TNF inhibitor infusions from patients who have had a previous clinically isolated CNS syndrome and have cranial MRIs that look suggestive of MS but do not yet have clinical manifestations, advised Dr. Cohen.

Dr. Cohen, a neurologist, advised against looking for MS in every patient prior to starting a TNF inhibitor for treatment of inflammatory bowel disease, rheumatoid arthritis, or psoriasis. “In particular, I would not obtain an MRI unless there was some clinical suggestion of potential (for MS).” However, uveitis is a different story: “Uveitis is a manifestation that can occur in MS, so I would look very carefully for any indication of MS involvement” before beginning TNF blockade.

CLEVELAND — Tumor necrosis factor-α blockade should not be instituted in patients with known multiple sclerosis and should be used with caution in patients with family histories or other risk factors for MS, according to Jeffrey A. Cohen, M.D., a neurologist at the Cleveland Clinic, Ohio.

Physicians should also be alert to uncommon CNS manifestations in patients receiving tumor necrosis factor (TNF) blockade for their inflammatory diseases, he said at a meeting on the treatment of autoimmune and inflammatory disorders.

TNF inhibitors currently approved by the Food and Drug Administration include the monoclonal antibodies infliximab (Remicade) and adalimumab (Humira) and the fusion protein etanercept (Enbrel).

TNF blockade both prevents and abrogates demyelinating disease in vitro and in animal studies. In humans, TNF blockade actually increased MS activity, said Dr. Cohen, citing data from two studies of infliximab and the discontinued lenercept. “In addition, treatment of other diseases for which TNF inhibitors are highly effective, including rheumatoid arthritis, Crohn's disease, and psoriasis, on rare occasions leads to CNS inflammatory demyelinating syndromes,” Dr. Cohen said at a summit sponsored by the Cleveland Clinic.

Failure of anti-TNF therapy in MS may be due to pleiotropic aspects of TNF actions, he noted. “In the CNS, TNF mediates cellular apoptosis and tissue damage, has important immunoregulatory functions, and is involved in tissue repair and regeneration. This experience reminds us that in the development of novel therapeutics, one must be cautious in extrapolating from animal models to human disease and from the results in one human disease to another,” he said. CNS demyelination can occur anytime after an anti-TNF agent is started. Demyelination appears to be a class effect of all TNF antagonists.

Dr. Cohen recommends avoiding TNF blockade for patients with or at risk for MS. Withhold TNF inhibitor infusions from patients who have had a previous clinically isolated CNS syndrome and have cranial MRIs that look suggestive of MS but do not yet have clinical manifestations, advised Dr. Cohen.

Dr. Cohen, a neurologist, advised against looking for MS in every patient prior to starting a TNF inhibitor for treatment of inflammatory bowel disease, rheumatoid arthritis, or psoriasis. “In particular, I would not obtain an MRI unless there was some clinical suggestion of potential (for MS).” However, uveitis is a different story: “Uveitis is a manifestation that can occur in MS, so I would look very carefully for any indication of MS involvement” before beginning TNF blockade.