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Self-Monitoring of Anticoagulant Halves Thromboembolism Risk
Patients who self-monitor their anticoagulation therapy with warfarin reduce their risk of thromboembolic events by half, compared with those in conventional care, U.K. researchers have found.
The researchers, who analyzed individual patient data from 11 randomized controlled trials, saw the benefit as especially marked in patients under age 55, and in those with mechanical heart valves. The types of self-monitoring interventions differed between the studies, and self-management, in which both testing and titration are carried out by the patient, was seen as considerably more helpful than self-testing alone (in which a physician adjusts the dose).
Also, in contrast to findings from a recent meta-analysis (Ann. Intern. Med. 2011;154:472-82), no significant mortality benefit was seen for self-monitoring, compared with conventional care. The risk of major hemorrhage was not significantly reduced in the self-monitoring groups. And while people with atrial fibrillation saw a reduction in thrombosis risk of up to a third, this difference did not reach statistical significance because of the small number of events.
For their research, published online Nov. 30 in the Lancet (doi: 10.1016/S0140- 6736(11)61294-4), Dr. Carl Heneghan, of the department of primary care health sciences at Oxford (U.K.) University, and his colleagues identified 11 randomized controlled trials comparing self-monitoring interventions (8 of which involved self-management) with conventional care for which individual patient data were available. A total of 6,417 patients were included in their analysis, 22% of them women.
Dr. Heneghan and his colleagues looked at time to death, first major hemorrhage, and first thromboembolic event among patients self-monitoring or under conventional care with warfarin and other vitamin K antagonists. Overall, the self-monitoring group saw a significant reduction in thromboembolic events (hazard ratio, 0.51) but not in major hemorrhage or death.
People under age 55 showed a risk reduction of two-thirds for thromboembolic events (HR, 0.33), and in patients with mechanical valves the risk was about halved (0.52).
Patients in the studies evaluating self-management interventions saw greater risk reduction over conventional care (HR, 0.42) than did those in the studies evaluating self-testing alone (0.74).
In subjects aged 85 years and older (n = 99), there were no significant adverse effects of the intervention for all outcomes, which suggested, Dr. Heneghan and his colleagues wrote, that self-monitoring was a "safe option for suitable patients of all ages."
Dr. Heneghan and colleagues’ study was funded by the U.K. National Institute for Health Research. While neither Dr. Heneghan nor his coauthors disclosed conflicts of interest related to their findings, various relationships were disclosed by the investigators of the original trials whose data were used for the meta-analysis.
In an editorial comment accompanying Dr. Heneghan and colleagues’ study, Dr. Paul Alexander Kyrle and Dr. Sabine Eichinger, of the Medical University of Vienna, wrote that the study results do not support the broader use of self-monitoring, but rather support self-monitoring only in patients with mechanical heart valves, particularly those under age 55.
The good results in these patients, they wrote, may be because they are "highly aware of thromboembolic risks and are therefore prepared to manage their medical treatments, including therapy with vitamin K antagonists."
For patients with atrial fibrillation, who were not shown to benefit significantly in Dr. Heneghan and colleagues’ analysis, self-monitoring of vitamin K antagonists could soon become unnecessary with the introduction of newer anticoagulants that do not require monitoring and, in some cases, may be superior in reducing stroke and bleeding in patients with atrial fibrillation, Dr. Kyrle and Dr. Eichinger wrote.
Dr. Kyrle and Dr. Eichinger disclosed that they are consultants for Bayer, the manufacturer of rivaroxaban.
The current meta-analysis confirms the findings from previous reports suggesting that in highly motivated patients, a strategy of self-directed care of anticoagulation improves the quality of anticoagulation, resulting in fewer thromboembolic events without increased risk of a serious bleeding event.
What are the implications for these findings, especially in the United States, where despite the use of home INR monitoring being reimbursed by the Centers for Medicare and Medicaid Services (for chronic oral anticoagulation management in patients with mechanical heart valves, chronic atrial fibrillation, or venous thromboembolism on warfarin), less than 1% of patients undertake self-testing at home?
First, these studies were highly selective in determining eligibility for home INR monitoring and management. About 50% or fewer of the screened patients participated in the self-care strategy; most patients older than 75, who are most likely to benefit from this strategy, were excluded; up to 25% withdrew after enrollment despite demonstrated improvements in quality of life. Thus, the findings only apply to those who are highly motivated, competent, and proficient in self-testing and self-titration.
Second, the populations studied were largely homogeneous, mostly from Europe (where the use of vitamin K antagonists other than warfarin is common), and included mostly white men. Only three studies were from the United States, the largest being THINRS (The Home INR Study) sponsored by the Department of Veteran Affairs and conducted mostly in Caucasian men (N. Engl. J. Med. 2010;363:1608-20). Thus, whether these results can be applied to a wider U.S. population across the spectrum of health care plans and where warfarin is the most commonly used vitamin K antagonist, remains to be determined.
Third, a major issue is cost. Although the present meta-analysis did not investigate cost, in THINRS the cost associated with self-testing was on average $1,249 more per year than usual care.
Finally, the approval and availability of newer anticoagulants such as dabigatran and rivaroxaban that do not require monitoring could potentially alter the landscape of home INR monitoring. However, because dabigatran and rivaroxaban have not been approved for anticoagulation therapy in patients with mechanical heart valves, a self-management strategy using vitamin K antagonists might still be the most desirable option for treating these patients.
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Other considerations that might promote the continued use of warfarin in structured self-care programs for other indications include the expensive cost of the newer agents, familiarity of warfarin use in patients with renal insufficiency, and lack of a readily available antidote for reversal of anticoagulation with dabigatran and rivaroxaban.
Thus, several lingering issues remain about the general applicability of a self-care warfarin anticoagulation program in the United States. Whether this model is cost effective and can be implemented successfully in typical U.S. health care settings warrants further evaluation.
Sanjay Kaul, M.D., M.P.H., is a cardiologist at Cedars-Sinai Medical Center, Los Angeles. He disclosed that he owns stock in Johnson & Johnson.
The current meta-analysis confirms the findings from previous reports suggesting that in highly motivated patients, a strategy of self-directed care of anticoagulation improves the quality of anticoagulation, resulting in fewer thromboembolic events without increased risk of a serious bleeding event.
What are the implications for these findings, especially in the United States, where despite the use of home INR monitoring being reimbursed by the Centers for Medicare and Medicaid Services (for chronic oral anticoagulation management in patients with mechanical heart valves, chronic atrial fibrillation, or venous thromboembolism on warfarin), less than 1% of patients undertake self-testing at home?
First, these studies were highly selective in determining eligibility for home INR monitoring and management. About 50% or fewer of the screened patients participated in the self-care strategy; most patients older than 75, who are most likely to benefit from this strategy, were excluded; up to 25% withdrew after enrollment despite demonstrated improvements in quality of life. Thus, the findings only apply to those who are highly motivated, competent, and proficient in self-testing and self-titration.
Second, the populations studied were largely homogeneous, mostly from Europe (where the use of vitamin K antagonists other than warfarin is common), and included mostly white men. Only three studies were from the United States, the largest being THINRS (The Home INR Study) sponsored by the Department of Veteran Affairs and conducted mostly in Caucasian men (N. Engl. J. Med. 2010;363:1608-20). Thus, whether these results can be applied to a wider U.S. population across the spectrum of health care plans and where warfarin is the most commonly used vitamin K antagonist, remains to be determined.
Third, a major issue is cost. Although the present meta-analysis did not investigate cost, in THINRS the cost associated with self-testing was on average $1,249 more per year than usual care.
Finally, the approval and availability of newer anticoagulants such as dabigatran and rivaroxaban that do not require monitoring could potentially alter the landscape of home INR monitoring. However, because dabigatran and rivaroxaban have not been approved for anticoagulation therapy in patients with mechanical heart valves, a self-management strategy using vitamin K antagonists might still be the most desirable option for treating these patients.
|
Other considerations that might promote the continued use of warfarin in structured self-care programs for other indications include the expensive cost of the newer agents, familiarity of warfarin use in patients with renal insufficiency, and lack of a readily available antidote for reversal of anticoagulation with dabigatran and rivaroxaban.
Thus, several lingering issues remain about the general applicability of a self-care warfarin anticoagulation program in the United States. Whether this model is cost effective and can be implemented successfully in typical U.S. health care settings warrants further evaluation.
Sanjay Kaul, M.D., M.P.H., is a cardiologist at Cedars-Sinai Medical Center, Los Angeles. He disclosed that he owns stock in Johnson & Johnson.
The current meta-analysis confirms the findings from previous reports suggesting that in highly motivated patients, a strategy of self-directed care of anticoagulation improves the quality of anticoagulation, resulting in fewer thromboembolic events without increased risk of a serious bleeding event.
What are the implications for these findings, especially in the United States, where despite the use of home INR monitoring being reimbursed by the Centers for Medicare and Medicaid Services (for chronic oral anticoagulation management in patients with mechanical heart valves, chronic atrial fibrillation, or venous thromboembolism on warfarin), less than 1% of patients undertake self-testing at home?
First, these studies were highly selective in determining eligibility for home INR monitoring and management. About 50% or fewer of the screened patients participated in the self-care strategy; most patients older than 75, who are most likely to benefit from this strategy, were excluded; up to 25% withdrew after enrollment despite demonstrated improvements in quality of life. Thus, the findings only apply to those who are highly motivated, competent, and proficient in self-testing and self-titration.
Second, the populations studied were largely homogeneous, mostly from Europe (where the use of vitamin K antagonists other than warfarin is common), and included mostly white men. Only three studies were from the United States, the largest being THINRS (The Home INR Study) sponsored by the Department of Veteran Affairs and conducted mostly in Caucasian men (N. Engl. J. Med. 2010;363:1608-20). Thus, whether these results can be applied to a wider U.S. population across the spectrum of health care plans and where warfarin is the most commonly used vitamin K antagonist, remains to be determined.
Third, a major issue is cost. Although the present meta-analysis did not investigate cost, in THINRS the cost associated with self-testing was on average $1,249 more per year than usual care.
Finally, the approval and availability of newer anticoagulants such as dabigatran and rivaroxaban that do not require monitoring could potentially alter the landscape of home INR monitoring. However, because dabigatran and rivaroxaban have not been approved for anticoagulation therapy in patients with mechanical heart valves, a self-management strategy using vitamin K antagonists might still be the most desirable option for treating these patients.
|
Other considerations that might promote the continued use of warfarin in structured self-care programs for other indications include the expensive cost of the newer agents, familiarity of warfarin use in patients with renal insufficiency, and lack of a readily available antidote for reversal of anticoagulation with dabigatran and rivaroxaban.
Thus, several lingering issues remain about the general applicability of a self-care warfarin anticoagulation program in the United States. Whether this model is cost effective and can be implemented successfully in typical U.S. health care settings warrants further evaluation.
Sanjay Kaul, M.D., M.P.H., is a cardiologist at Cedars-Sinai Medical Center, Los Angeles. He disclosed that he owns stock in Johnson & Johnson.
Patients who self-monitor their anticoagulation therapy with warfarin reduce their risk of thromboembolic events by half, compared with those in conventional care, U.K. researchers have found.
The researchers, who analyzed individual patient data from 11 randomized controlled trials, saw the benefit as especially marked in patients under age 55, and in those with mechanical heart valves. The types of self-monitoring interventions differed between the studies, and self-management, in which both testing and titration are carried out by the patient, was seen as considerably more helpful than self-testing alone (in which a physician adjusts the dose).
Also, in contrast to findings from a recent meta-analysis (Ann. Intern. Med. 2011;154:472-82), no significant mortality benefit was seen for self-monitoring, compared with conventional care. The risk of major hemorrhage was not significantly reduced in the self-monitoring groups. And while people with atrial fibrillation saw a reduction in thrombosis risk of up to a third, this difference did not reach statistical significance because of the small number of events.
For their research, published online Nov. 30 in the Lancet (doi: 10.1016/S0140- 6736(11)61294-4), Dr. Carl Heneghan, of the department of primary care health sciences at Oxford (U.K.) University, and his colleagues identified 11 randomized controlled trials comparing self-monitoring interventions (8 of which involved self-management) with conventional care for which individual patient data were available. A total of 6,417 patients were included in their analysis, 22% of them women.
Dr. Heneghan and his colleagues looked at time to death, first major hemorrhage, and first thromboembolic event among patients self-monitoring or under conventional care with warfarin and other vitamin K antagonists. Overall, the self-monitoring group saw a significant reduction in thromboembolic events (hazard ratio, 0.51) but not in major hemorrhage or death.
People under age 55 showed a risk reduction of two-thirds for thromboembolic events (HR, 0.33), and in patients with mechanical valves the risk was about halved (0.52).
Patients in the studies evaluating self-management interventions saw greater risk reduction over conventional care (HR, 0.42) than did those in the studies evaluating self-testing alone (0.74).
In subjects aged 85 years and older (n = 99), there were no significant adverse effects of the intervention for all outcomes, which suggested, Dr. Heneghan and his colleagues wrote, that self-monitoring was a "safe option for suitable patients of all ages."
Dr. Heneghan and colleagues’ study was funded by the U.K. National Institute for Health Research. While neither Dr. Heneghan nor his coauthors disclosed conflicts of interest related to their findings, various relationships were disclosed by the investigators of the original trials whose data were used for the meta-analysis.
In an editorial comment accompanying Dr. Heneghan and colleagues’ study, Dr. Paul Alexander Kyrle and Dr. Sabine Eichinger, of the Medical University of Vienna, wrote that the study results do not support the broader use of self-monitoring, but rather support self-monitoring only in patients with mechanical heart valves, particularly those under age 55.
The good results in these patients, they wrote, may be because they are "highly aware of thromboembolic risks and are therefore prepared to manage their medical treatments, including therapy with vitamin K antagonists."
For patients with atrial fibrillation, who were not shown to benefit significantly in Dr. Heneghan and colleagues’ analysis, self-monitoring of vitamin K antagonists could soon become unnecessary with the introduction of newer anticoagulants that do not require monitoring and, in some cases, may be superior in reducing stroke and bleeding in patients with atrial fibrillation, Dr. Kyrle and Dr. Eichinger wrote.
Dr. Kyrle and Dr. Eichinger disclosed that they are consultants for Bayer, the manufacturer of rivaroxaban.
Patients who self-monitor their anticoagulation therapy with warfarin reduce their risk of thromboembolic events by half, compared with those in conventional care, U.K. researchers have found.
The researchers, who analyzed individual patient data from 11 randomized controlled trials, saw the benefit as especially marked in patients under age 55, and in those with mechanical heart valves. The types of self-monitoring interventions differed between the studies, and self-management, in which both testing and titration are carried out by the patient, was seen as considerably more helpful than self-testing alone (in which a physician adjusts the dose).
Also, in contrast to findings from a recent meta-analysis (Ann. Intern. Med. 2011;154:472-82), no significant mortality benefit was seen for self-monitoring, compared with conventional care. The risk of major hemorrhage was not significantly reduced in the self-monitoring groups. And while people with atrial fibrillation saw a reduction in thrombosis risk of up to a third, this difference did not reach statistical significance because of the small number of events.
For their research, published online Nov. 30 in the Lancet (doi: 10.1016/S0140- 6736(11)61294-4), Dr. Carl Heneghan, of the department of primary care health sciences at Oxford (U.K.) University, and his colleagues identified 11 randomized controlled trials comparing self-monitoring interventions (8 of which involved self-management) with conventional care for which individual patient data were available. A total of 6,417 patients were included in their analysis, 22% of them women.
Dr. Heneghan and his colleagues looked at time to death, first major hemorrhage, and first thromboembolic event among patients self-monitoring or under conventional care with warfarin and other vitamin K antagonists. Overall, the self-monitoring group saw a significant reduction in thromboembolic events (hazard ratio, 0.51) but not in major hemorrhage or death.
People under age 55 showed a risk reduction of two-thirds for thromboembolic events (HR, 0.33), and in patients with mechanical valves the risk was about halved (0.52).
Patients in the studies evaluating self-management interventions saw greater risk reduction over conventional care (HR, 0.42) than did those in the studies evaluating self-testing alone (0.74).
In subjects aged 85 years and older (n = 99), there were no significant adverse effects of the intervention for all outcomes, which suggested, Dr. Heneghan and his colleagues wrote, that self-monitoring was a "safe option for suitable patients of all ages."
Dr. Heneghan and colleagues’ study was funded by the U.K. National Institute for Health Research. While neither Dr. Heneghan nor his coauthors disclosed conflicts of interest related to their findings, various relationships were disclosed by the investigators of the original trials whose data were used for the meta-analysis.
In an editorial comment accompanying Dr. Heneghan and colleagues’ study, Dr. Paul Alexander Kyrle and Dr. Sabine Eichinger, of the Medical University of Vienna, wrote that the study results do not support the broader use of self-monitoring, but rather support self-monitoring only in patients with mechanical heart valves, particularly those under age 55.
The good results in these patients, they wrote, may be because they are "highly aware of thromboembolic risks and are therefore prepared to manage their medical treatments, including therapy with vitamin K antagonists."
For patients with atrial fibrillation, who were not shown to benefit significantly in Dr. Heneghan and colleagues’ analysis, self-monitoring of vitamin K antagonists could soon become unnecessary with the introduction of newer anticoagulants that do not require monitoring and, in some cases, may be superior in reducing stroke and bleeding in patients with atrial fibrillation, Dr. Kyrle and Dr. Eichinger wrote.
Dr. Kyrle and Dr. Eichinger disclosed that they are consultants for Bayer, the manufacturer of rivaroxaban.
FROM THE LANCET
Major Finding: Patients self-monitoring while taking vitamin K antagonists saw a 49% reduction in risk of thromboembolic events compared with those under conventional care, with some subgroups seeing further risk reductions.
Data Source: Eleven randomized controlled trials for which individual data from 6,417 patients were available to investigators and could be assessed.
Disclosures: Dr. Kyrle and Dr. Eichinger disclosed that they are consultants for Bayer, the manufacturer of rivaroxaban.
Raised hCG After Molar Pregnancy May Not Mean Malignancy
Women with raised but falling human chorionic gonadotropin concentrations 6 months after a molar pregnancy do not need chemotherapy, as almost all of them will spontaneously remit, the results of a large retrospective cohort study have shown.
The findings, published online Nov. 28 in the Lancet (doi:10.1016/S0140-6736[11]61265-8), challenge current international clinical guidelines (Int. J. Gynecol. Obstet. 2002;77:285-7) that consider chemotherapy to be indicated when hCG concentrations are high for 6 months or more following evacuation of a hydatidiform mole.
The new findings argue that an elevated hCG level at 6 months is not an indicator of malignancy when values are falling, and that instead of initiating chemotherapy, women with raised but falling hCG can undergo surveillance of their hCG levels, with testing until they return to normal. Chemotherapy is needed only if hCG levels are still rising at 6 months, have plateaued, or are greater than 345 IU/L, or if there is radiologic evidence of neoplasia.
If the surveillance approach were to become standard, more women could avoid exposure to toxic chemotherapy drugs and could safely conceive sooner after evacuation of a molar pregnancy, said the authors of the study led by Dr. Roshan Agarwal of Imperial College London. Current U.K. guidelines advise women not to become pregnant until 12 months following chemotherapy, whereas they would have to wait only 6 months after a spontaneous return to normal hCG.
For their research, Dr. Agarwal and colleagues retrospectively identified 13,960 women registered at London’s Charing Cross Hospital between January 1993 and May 2008 who had undergone evacuation of a complete or partial hydatidiform mole. Of these, 974 (7%) required chemotherapy within 6 months, and hCG normalized spontaneously in 12,910 (92%) within 6 months.
The remaining 76 women still had high hCG concentrations (more than 5 IU/L) 6 months after evacuation of the molar pregnancy. Sixty-six patients underwent surveillance, in which blood and urine samples were collected and evaluated every 2 weeks until normal hCG was achieved, followed by monthly urine samples for 6 months. Ten patients underwent chemotherapy.
In the surveillance group, 98% of patients (n = 65) saw hCG values return to normal without chemotherapy (in all but 6 of them within a year), and the remaining patient, who had chronic renal failure, remained healthy despite having elevated hCG, Dr. Agarwal and colleagues reported.
Among the 10 patients who received chemotherapy, 6 had complete responses, and 4 had partial or no responses but remained well, even though hCG concentrations in 2 patients continued to be elevated. There was no significant difference in time to normalization between the groups and no deaths had occurred in either group after a median 2 years’ follow-up.
The investigators acknowledged as a weakness of their study its retrospective design, the use of a single study site, and the small number of patients with raised hCG at 6 months. However, they said, the findings "directly challenge the present clinical dogma" to show that the surveillance model is clinically acceptable. The results "will change international practice and spare women unnecessary exposure to chemotherapy," they wrote in their analysis.
In a case study linked to Dr. Agarwal and colleagues’ article, Rosemary A. Fisher, also of Imperial College London, described a woman who had a miscarriage and three consecutive molar pregnancies, yet was able to achieve a normal pregnancy with use of a donor egg.
"To the best of our knowledge, this report establishes for the first time that oocyte donation can enable women with familial recurrent hydatidiform moles due to NLRP7 mutations to achieve a normal pregnancy," Ms. Fisher and colleagues wrote, adding that this finding offered "hope to other women with this condition." The study also shows "that the major role of NLRP7 in pregnancy is in the developing oocyte."
The study was funded by the National Commissioning Group, the Imperial Experimental Cancer Medicine Center, the Imperial Biomedical Research Center, and Cancer Research UK. The authors of the cohort study and case report declared that they had no relevant financial disclosures.
In an editorial accompanying the study, Dr. Annie N.Y. Cheung and Dr.
Karen K.L. Chan said the data from Dr. Agarwal and colleagues’ study
are reassuring. However, they added, 13% of the cohort received
chemotherapy, and how these individuals would have progressed if no
treatment were given is unknown. Hence, the key question remains: When
and to whom should chemotherapy be given?
The investigators
propose a cutoff hCG concentration of 345 IU/L at 6 months, which was
the median hCG value in patients who responded to chemotherapy in their
cohort. Meanwhile, investigators in an earlier study (Gynecol. Oncol. 2010; 116: 3-9)
proposed that chemotherapy should be started only when total hCG begins
to rise and is greater than 3,000 IU/L, because chemotherapy would
probably be ineffective below this value.
Direct comparison
between the two cohorts is inappropriate because the group in the
earlier study was heterogeneous (patients had been given various
previous treatments), whereas Dr. Agarwal and colleagues’ group was
unique in its homogeneity (all patients had persistently raised but
falling hCG levels after a molar pregnancy). Centers treating this
condition and using a particular protocol should report their findings
so recommendations can be updated for improved treatment of these
patients, Dr. Cheung and Dr. Chan, who are both with the University of
Hong Kong, Queen Mary Hospital, Hong Kong, suggested (Lancet 2011
[doi:10.1016/S0140-6736(11)61518-3]).
They said they had no relevant financial disclosures.In an editorial accompanying the study, Dr. Annie N.Y. Cheung and Dr.
Karen K.L. Chan said the data from Dr. Agarwal and colleagues’ study
are reassuring. However, they added, 13% of the cohort received
chemotherapy, and how these individuals would have progressed if no
treatment were given is unknown. Hence, the key question remains: When
and to whom should chemotherapy be given?
The investigators
propose a cutoff hCG concentration of 345 IU/L at 6 months, which was
the median hCG value in patients who responded to chemotherapy in their
cohort. Meanwhile, investigators in an earlier study (Gynecol. Oncol. 2010; 116: 3-9)
proposed that chemotherapy should be started only when total hCG begins
to rise and is greater than 3,000 IU/L, because chemotherapy would
probably be ineffective below this value.
Direct comparison
between the two cohorts is inappropriate because the group in the
earlier study was heterogeneous (patients had been given various
previous treatments), whereas Dr. Agarwal and colleagues’ group was
unique in its homogeneity (all patients had persistently raised but
falling hCG levels after a molar pregnancy). Centers treating this
condition and using a particular protocol should report their findings
so recommendations can be updated for improved treatment of these
patients, Dr. Cheung and Dr. Chan, who are both with the University of
Hong Kong, Queen Mary Hospital, Hong Kong, suggested (Lancet 2011
[doi:10.1016/S0140-6736(11)61518-3]).
They said they had no relevant financial disclosures.In an editorial accompanying the study, Dr. Annie N.Y. Cheung and Dr.
Karen K.L. Chan said the data from Dr. Agarwal and colleagues’ study
are reassuring. However, they added, 13% of the cohort received
chemotherapy, and how these individuals would have progressed if no
treatment were given is unknown. Hence, the key question remains: When
and to whom should chemotherapy be given?
The investigators
propose a cutoff hCG concentration of 345 IU/L at 6 months, which was
the median hCG value in patients who responded to chemotherapy in their
cohort. Meanwhile, investigators in an earlier study (Gynecol. Oncol. 2010; 116: 3-9)
proposed that chemotherapy should be started only when total hCG begins
to rise and is greater than 3,000 IU/L, because chemotherapy would
probably be ineffective below this value.
Direct comparison
between the two cohorts is inappropriate because the group in the
earlier study was heterogeneous (patients had been given various
previous treatments), whereas Dr. Agarwal and colleagues’ group was
unique in its homogeneity (all patients had persistently raised but
falling hCG levels after a molar pregnancy). Centers treating this
condition and using a particular protocol should report their findings
so recommendations can be updated for improved treatment of these
patients, Dr. Cheung and Dr. Chan, who are both with the University of
Hong Kong, Queen Mary Hospital, Hong Kong, suggested (Lancet 2011
[doi:10.1016/S0140-6736(11)61518-3]).
They said they had no relevant financial disclosures.Women with raised but falling human chorionic gonadotropin concentrations 6 months after a molar pregnancy do not need chemotherapy, as almost all of them will spontaneously remit, the results of a large retrospective cohort study have shown.
The findings, published online Nov. 28 in the Lancet (doi:10.1016/S0140-6736[11]61265-8), challenge current international clinical guidelines (Int. J. Gynecol. Obstet. 2002;77:285-7) that consider chemotherapy to be indicated when hCG concentrations are high for 6 months or more following evacuation of a hydatidiform mole.
The new findings argue that an elevated hCG level at 6 months is not an indicator of malignancy when values are falling, and that instead of initiating chemotherapy, women with raised but falling hCG can undergo surveillance of their hCG levels, with testing until they return to normal. Chemotherapy is needed only if hCG levels are still rising at 6 months, have plateaued, or are greater than 345 IU/L, or if there is radiologic evidence of neoplasia.
If the surveillance approach were to become standard, more women could avoid exposure to toxic chemotherapy drugs and could safely conceive sooner after evacuation of a molar pregnancy, said the authors of the study led by Dr. Roshan Agarwal of Imperial College London. Current U.K. guidelines advise women not to become pregnant until 12 months following chemotherapy, whereas they would have to wait only 6 months after a spontaneous return to normal hCG.
For their research, Dr. Agarwal and colleagues retrospectively identified 13,960 women registered at London’s Charing Cross Hospital between January 1993 and May 2008 who had undergone evacuation of a complete or partial hydatidiform mole. Of these, 974 (7%) required chemotherapy within 6 months, and hCG normalized spontaneously in 12,910 (92%) within 6 months.
The remaining 76 women still had high hCG concentrations (more than 5 IU/L) 6 months after evacuation of the molar pregnancy. Sixty-six patients underwent surveillance, in which blood and urine samples were collected and evaluated every 2 weeks until normal hCG was achieved, followed by monthly urine samples for 6 months. Ten patients underwent chemotherapy.
In the surveillance group, 98% of patients (n = 65) saw hCG values return to normal without chemotherapy (in all but 6 of them within a year), and the remaining patient, who had chronic renal failure, remained healthy despite having elevated hCG, Dr. Agarwal and colleagues reported.
Among the 10 patients who received chemotherapy, 6 had complete responses, and 4 had partial or no responses but remained well, even though hCG concentrations in 2 patients continued to be elevated. There was no significant difference in time to normalization between the groups and no deaths had occurred in either group after a median 2 years’ follow-up.
The investigators acknowledged as a weakness of their study its retrospective design, the use of a single study site, and the small number of patients with raised hCG at 6 months. However, they said, the findings "directly challenge the present clinical dogma" to show that the surveillance model is clinically acceptable. The results "will change international practice and spare women unnecessary exposure to chemotherapy," they wrote in their analysis.
In a case study linked to Dr. Agarwal and colleagues’ article, Rosemary A. Fisher, also of Imperial College London, described a woman who had a miscarriage and three consecutive molar pregnancies, yet was able to achieve a normal pregnancy with use of a donor egg.
"To the best of our knowledge, this report establishes for the first time that oocyte donation can enable women with familial recurrent hydatidiform moles due to NLRP7 mutations to achieve a normal pregnancy," Ms. Fisher and colleagues wrote, adding that this finding offered "hope to other women with this condition." The study also shows "that the major role of NLRP7 in pregnancy is in the developing oocyte."
The study was funded by the National Commissioning Group, the Imperial Experimental Cancer Medicine Center, the Imperial Biomedical Research Center, and Cancer Research UK. The authors of the cohort study and case report declared that they had no relevant financial disclosures.
Women with raised but falling human chorionic gonadotropin concentrations 6 months after a molar pregnancy do not need chemotherapy, as almost all of them will spontaneously remit, the results of a large retrospective cohort study have shown.
The findings, published online Nov. 28 in the Lancet (doi:10.1016/S0140-6736[11]61265-8), challenge current international clinical guidelines (Int. J. Gynecol. Obstet. 2002;77:285-7) that consider chemotherapy to be indicated when hCG concentrations are high for 6 months or more following evacuation of a hydatidiform mole.
The new findings argue that an elevated hCG level at 6 months is not an indicator of malignancy when values are falling, and that instead of initiating chemotherapy, women with raised but falling hCG can undergo surveillance of their hCG levels, with testing until they return to normal. Chemotherapy is needed only if hCG levels are still rising at 6 months, have plateaued, or are greater than 345 IU/L, or if there is radiologic evidence of neoplasia.
If the surveillance approach were to become standard, more women could avoid exposure to toxic chemotherapy drugs and could safely conceive sooner after evacuation of a molar pregnancy, said the authors of the study led by Dr. Roshan Agarwal of Imperial College London. Current U.K. guidelines advise women not to become pregnant until 12 months following chemotherapy, whereas they would have to wait only 6 months after a spontaneous return to normal hCG.
For their research, Dr. Agarwal and colleagues retrospectively identified 13,960 women registered at London’s Charing Cross Hospital between January 1993 and May 2008 who had undergone evacuation of a complete or partial hydatidiform mole. Of these, 974 (7%) required chemotherapy within 6 months, and hCG normalized spontaneously in 12,910 (92%) within 6 months.
The remaining 76 women still had high hCG concentrations (more than 5 IU/L) 6 months after evacuation of the molar pregnancy. Sixty-six patients underwent surveillance, in which blood and urine samples were collected and evaluated every 2 weeks until normal hCG was achieved, followed by monthly urine samples for 6 months. Ten patients underwent chemotherapy.
In the surveillance group, 98% of patients (n = 65) saw hCG values return to normal without chemotherapy (in all but 6 of them within a year), and the remaining patient, who had chronic renal failure, remained healthy despite having elevated hCG, Dr. Agarwal and colleagues reported.
Among the 10 patients who received chemotherapy, 6 had complete responses, and 4 had partial or no responses but remained well, even though hCG concentrations in 2 patients continued to be elevated. There was no significant difference in time to normalization between the groups and no deaths had occurred in either group after a median 2 years’ follow-up.
The investigators acknowledged as a weakness of their study its retrospective design, the use of a single study site, and the small number of patients with raised hCG at 6 months. However, they said, the findings "directly challenge the present clinical dogma" to show that the surveillance model is clinically acceptable. The results "will change international practice and spare women unnecessary exposure to chemotherapy," they wrote in their analysis.
In a case study linked to Dr. Agarwal and colleagues’ article, Rosemary A. Fisher, also of Imperial College London, described a woman who had a miscarriage and three consecutive molar pregnancies, yet was able to achieve a normal pregnancy with use of a donor egg.
"To the best of our knowledge, this report establishes for the first time that oocyte donation can enable women with familial recurrent hydatidiform moles due to NLRP7 mutations to achieve a normal pregnancy," Ms. Fisher and colleagues wrote, adding that this finding offered "hope to other women with this condition." The study also shows "that the major role of NLRP7 in pregnancy is in the developing oocyte."
The study was funded by the National Commissioning Group, the Imperial Experimental Cancer Medicine Center, the Imperial Biomedical Research Center, and Cancer Research UK. The authors of the cohort study and case report declared that they had no relevant financial disclosures.
FROM THE LANCET
Major Finding: Sixty-four of 65 patients saw hCG values return to normal without chemotherapy, and the remaining patient, who had chronic renal failure, remained healthy despite having elevated hCG. Among the 10 patients who received chemotherapy, 6 had complete responses, and 4 had partial or no responses but remained well, even though hCG concentrations in 2 patients continued to be elevated. There was no significant difference in time to normalization between the groups, and no deaths had occurred in either group after a median 2 years’ follow-up.
Data Source: A study of 76 women who still had high hCG concentrations (more than 5 IU/L) 6 months after evacuation of the molar pregnancy.
Disclosures: The study was funded by the National Commissioning Group, the Imperial Experimental Cancer Medicine Center, the Imperial Biomedical Research Center, and Cancer Research UK. The authors of the cohort study and case report said they had no relevant financial disclosures.
Researchers Claim EEG Detects Awareness in Vegetative Patients
Researchers have developed an inexpensive technique that, they say, can detect covert awareness in people diagnosed as vegetative.
The researchers used electroencephalography (EEG), instead of functional MRI (fMRI), a technology previously shown to detect minimal consciousness in people thought to be vegetative based on an evaluation of their behavioral symptoms (N. Engl. J. Med. 2010;362:579-89).
FMRI works by detecting a patient’s ability to modulate a blood oxygen–level dependent (BOLD) response to mental imagery tasks. Barriers to its wider use include its expense; the difficulty of transporting patients to MRI-equipped facilities; imaging problems when patients cannot remain still; and the technology’s inappropriateness for patients with metal implants in their bodies.
EEG, which measures the activity of groups of cortical neurons from scalp electrodes, can be used at the bedside and is inexpensive, widely available, and unaffected by metal.
For their research, published online Nov. 10 in The Lancet (doi:10.1016/S0140-6736(11)61224-5), Damian Cruse, Ph.D., of the University of Western Ontario, London, and his colleagues in the United Kingdom and Belgium recruited 16 patients diagnosed by behavioral indicators as vegetative according to established criteria. The patients varied in age, gender, cause of injury, and time since injury. Of the 16 patients, 5 had traumatic brain injuries, 2 had had a stroke, and the rest had experienced anoxia. The researchers also recruited a group of 12 healthy individuals to serve as controls.
All of the study participants – people diagnosed as vegetative and healthy controls – were repeatedly asked to imagine the action of squeezing their right hands or wiggling all their toes at the prompt of a beep. EEG responses to the commands were measured.
Dr. Cruse and colleagues found that 3 of 16 patients diagnosed as vegetative were able to repeatedly and reliably generate EEG responses to the two different commands. All 3 responding patients were male, between the ages of 29 and 45; 2 had been diagnosed with traumatic brain injuries and 1 with injury caused by anoxia.
Of the controls, nine produced EEG responses that could be classified as significantly above chance; the researchers could not say definitively why three controls did not. However, they noted, the lack of appropriate response underscored the importance of interpreting only positive results in patients, "because this finding shows unequivocally that a null EEG outcome does not necessarily indicate an absence of awareness."
Dr. Cruse and colleagues called it "extremely unlikely" that the response patterns they detected could have been involuntary or automatic, based on the design of the study and the outcomes recorded. "Successful completion of these EEG tasks represents a substantial cognitive feat, not only for patients who were presumed to be vegetative, but also for control participants," they wrote, noting that one patient’s responses were consistent in over 100 repeated trials, better than the vast majority of controls.
While the median age for subjects with traumatic brain injuries was younger than those with non-traumatic injuries (29 years vs. 44 years), the researchers found no significant relationships between the patients’ ages or clinical histories and their ability to respond.
Dr. Cruse and colleagues wrote in their analysis that their study shows that "this EEG method can identify covert awareness in patients diagnosed in the vegetative state with a similar degree of accuracy to other methods of detection."
The Medical Research Council, James S. McDonnell Foundation, Canada Excellence Research Chairs Program, the European Commission, Fonds de la Recherche Scientifique, the Mind Science Foundation, Belgian French-Speaking Community Concerted Research Action, University Hospital of Liège, and University of Liège all contributed funding to the study. Dr. Cruse and his colleagues disclosed no conflicts of interest.
In an editorial comment on Dr. Cruse and colleagues’ study (Lancet
2011 Nov. 10 [doi:10.1016/S0140-6736(11)61591-2]), researchers Morten
Overgaard, Ph.D., of Aalborg University, in Aalborg, Denmark, and Rikke
Overgaard of Aarhus University, in Aarhus, Denmark, wrote that the
findings built on the landmark results from earlier fMRI studies to
present "good evidence that at least some patients in the vegetative
state are conscious."
The authors of the editorial comment did
not challenge the suitability or accuracy of the EEG technology used by
Dr. Cruse and his colleagues. However, they wrote, "the methods in all
these experiments are indirect and investigate a factor other than
consciousness alone."
Command following, they wrote, "might not
be an absolute measure for identification of whether a person is
conscious. Because three (25%) of the 12 healthy controls in this study
could not produce significant EEG records, command following most likely
measures something different than the presence and absence of
consciousness."
A more plausible interpretation of the study’s
findings, they wrote, "is that vegetative and minimally conscious states
distinguish between different levels of cognitive and communicative
abilities, which is a different matter than subjective experience per
se. A new classification system is necessary if the goal is to
understand the cognitive functioning of patients in the vegetative or
minimally conscious states."
The authors of the editorial declared no conflicts of interest.
In an editorial comment on Dr. Cruse and colleagues’ study (Lancet
2011 Nov. 10 [doi:10.1016/S0140-6736(11)61591-2]), researchers Morten
Overgaard, Ph.D., of Aalborg University, in Aalborg, Denmark, and Rikke
Overgaard of Aarhus University, in Aarhus, Denmark, wrote that the
findings built on the landmark results from earlier fMRI studies to
present "good evidence that at least some patients in the vegetative
state are conscious."
The authors of the editorial comment did
not challenge the suitability or accuracy of the EEG technology used by
Dr. Cruse and his colleagues. However, they wrote, "the methods in all
these experiments are indirect and investigate a factor other than
consciousness alone."
Command following, they wrote, "might not
be an absolute measure for identification of whether a person is
conscious. Because three (25%) of the 12 healthy controls in this study
could not produce significant EEG records, command following most likely
measures something different than the presence and absence of
consciousness."
A more plausible interpretation of the study’s
findings, they wrote, "is that vegetative and minimally conscious states
distinguish between different levels of cognitive and communicative
abilities, which is a different matter than subjective experience per
se. A new classification system is necessary if the goal is to
understand the cognitive functioning of patients in the vegetative or
minimally conscious states."
The authors of the editorial declared no conflicts of interest.
In an editorial comment on Dr. Cruse and colleagues’ study (Lancet
2011 Nov. 10 [doi:10.1016/S0140-6736(11)61591-2]), researchers Morten
Overgaard, Ph.D., of Aalborg University, in Aalborg, Denmark, and Rikke
Overgaard of Aarhus University, in Aarhus, Denmark, wrote that the
findings built on the landmark results from earlier fMRI studies to
present "good evidence that at least some patients in the vegetative
state are conscious."
The authors of the editorial comment did
not challenge the suitability or accuracy of the EEG technology used by
Dr. Cruse and his colleagues. However, they wrote, "the methods in all
these experiments are indirect and investigate a factor other than
consciousness alone."
Command following, they wrote, "might not
be an absolute measure for identification of whether a person is
conscious. Because three (25%) of the 12 healthy controls in this study
could not produce significant EEG records, command following most likely
measures something different than the presence and absence of
consciousness."
A more plausible interpretation of the study’s
findings, they wrote, "is that vegetative and minimally conscious states
distinguish between different levels of cognitive and communicative
abilities, which is a different matter than subjective experience per
se. A new classification system is necessary if the goal is to
understand the cognitive functioning of patients in the vegetative or
minimally conscious states."
The authors of the editorial declared no conflicts of interest.
Researchers have developed an inexpensive technique that, they say, can detect covert awareness in people diagnosed as vegetative.
The researchers used electroencephalography (EEG), instead of functional MRI (fMRI), a technology previously shown to detect minimal consciousness in people thought to be vegetative based on an evaluation of their behavioral symptoms (N. Engl. J. Med. 2010;362:579-89).
FMRI works by detecting a patient’s ability to modulate a blood oxygen–level dependent (BOLD) response to mental imagery tasks. Barriers to its wider use include its expense; the difficulty of transporting patients to MRI-equipped facilities; imaging problems when patients cannot remain still; and the technology’s inappropriateness for patients with metal implants in their bodies.
EEG, which measures the activity of groups of cortical neurons from scalp electrodes, can be used at the bedside and is inexpensive, widely available, and unaffected by metal.
For their research, published online Nov. 10 in The Lancet (doi:10.1016/S0140-6736(11)61224-5), Damian Cruse, Ph.D., of the University of Western Ontario, London, and his colleagues in the United Kingdom and Belgium recruited 16 patients diagnosed by behavioral indicators as vegetative according to established criteria. The patients varied in age, gender, cause of injury, and time since injury. Of the 16 patients, 5 had traumatic brain injuries, 2 had had a stroke, and the rest had experienced anoxia. The researchers also recruited a group of 12 healthy individuals to serve as controls.
All of the study participants – people diagnosed as vegetative and healthy controls – were repeatedly asked to imagine the action of squeezing their right hands or wiggling all their toes at the prompt of a beep. EEG responses to the commands were measured.
Dr. Cruse and colleagues found that 3 of 16 patients diagnosed as vegetative were able to repeatedly and reliably generate EEG responses to the two different commands. All 3 responding patients were male, between the ages of 29 and 45; 2 had been diagnosed with traumatic brain injuries and 1 with injury caused by anoxia.
Of the controls, nine produced EEG responses that could be classified as significantly above chance; the researchers could not say definitively why three controls did not. However, they noted, the lack of appropriate response underscored the importance of interpreting only positive results in patients, "because this finding shows unequivocally that a null EEG outcome does not necessarily indicate an absence of awareness."
Dr. Cruse and colleagues called it "extremely unlikely" that the response patterns they detected could have been involuntary or automatic, based on the design of the study and the outcomes recorded. "Successful completion of these EEG tasks represents a substantial cognitive feat, not only for patients who were presumed to be vegetative, but also for control participants," they wrote, noting that one patient’s responses were consistent in over 100 repeated trials, better than the vast majority of controls.
While the median age for subjects with traumatic brain injuries was younger than those with non-traumatic injuries (29 years vs. 44 years), the researchers found no significant relationships between the patients’ ages or clinical histories and their ability to respond.
Dr. Cruse and colleagues wrote in their analysis that their study shows that "this EEG method can identify covert awareness in patients diagnosed in the vegetative state with a similar degree of accuracy to other methods of detection."
The Medical Research Council, James S. McDonnell Foundation, Canada Excellence Research Chairs Program, the European Commission, Fonds de la Recherche Scientifique, the Mind Science Foundation, Belgian French-Speaking Community Concerted Research Action, University Hospital of Liège, and University of Liège all contributed funding to the study. Dr. Cruse and his colleagues disclosed no conflicts of interest.
Researchers have developed an inexpensive technique that, they say, can detect covert awareness in people diagnosed as vegetative.
The researchers used electroencephalography (EEG), instead of functional MRI (fMRI), a technology previously shown to detect minimal consciousness in people thought to be vegetative based on an evaluation of their behavioral symptoms (N. Engl. J. Med. 2010;362:579-89).
FMRI works by detecting a patient’s ability to modulate a blood oxygen–level dependent (BOLD) response to mental imagery tasks. Barriers to its wider use include its expense; the difficulty of transporting patients to MRI-equipped facilities; imaging problems when patients cannot remain still; and the technology’s inappropriateness for patients with metal implants in their bodies.
EEG, which measures the activity of groups of cortical neurons from scalp electrodes, can be used at the bedside and is inexpensive, widely available, and unaffected by metal.
For their research, published online Nov. 10 in The Lancet (doi:10.1016/S0140-6736(11)61224-5), Damian Cruse, Ph.D., of the University of Western Ontario, London, and his colleagues in the United Kingdom and Belgium recruited 16 patients diagnosed by behavioral indicators as vegetative according to established criteria. The patients varied in age, gender, cause of injury, and time since injury. Of the 16 patients, 5 had traumatic brain injuries, 2 had had a stroke, and the rest had experienced anoxia. The researchers also recruited a group of 12 healthy individuals to serve as controls.
All of the study participants – people diagnosed as vegetative and healthy controls – were repeatedly asked to imagine the action of squeezing their right hands or wiggling all their toes at the prompt of a beep. EEG responses to the commands were measured.
Dr. Cruse and colleagues found that 3 of 16 patients diagnosed as vegetative were able to repeatedly and reliably generate EEG responses to the two different commands. All 3 responding patients were male, between the ages of 29 and 45; 2 had been diagnosed with traumatic brain injuries and 1 with injury caused by anoxia.
Of the controls, nine produced EEG responses that could be classified as significantly above chance; the researchers could not say definitively why three controls did not. However, they noted, the lack of appropriate response underscored the importance of interpreting only positive results in patients, "because this finding shows unequivocally that a null EEG outcome does not necessarily indicate an absence of awareness."
Dr. Cruse and colleagues called it "extremely unlikely" that the response patterns they detected could have been involuntary or automatic, based on the design of the study and the outcomes recorded. "Successful completion of these EEG tasks represents a substantial cognitive feat, not only for patients who were presumed to be vegetative, but also for control participants," they wrote, noting that one patient’s responses were consistent in over 100 repeated trials, better than the vast majority of controls.
While the median age for subjects with traumatic brain injuries was younger than those with non-traumatic injuries (29 years vs. 44 years), the researchers found no significant relationships between the patients’ ages or clinical histories and their ability to respond.
Dr. Cruse and colleagues wrote in their analysis that their study shows that "this EEG method can identify covert awareness in patients diagnosed in the vegetative state with a similar degree of accuracy to other methods of detection."
The Medical Research Council, James S. McDonnell Foundation, Canada Excellence Research Chairs Program, the European Commission, Fonds de la Recherche Scientifique, the Mind Science Foundation, Belgian French-Speaking Community Concerted Research Action, University Hospital of Liège, and University of Liège all contributed funding to the study. Dr. Cruse and his colleagues disclosed no conflicts of interest.
Major Finding: EEG responses to a specific command could be reliably and repeatedly generated in 3 of 16 patients diagnosed as vegetative.
Data Source: A prospective study compared EEG responses to a specific command between 16 patients in a vegetative state and 12 healthy individuals.
Disclosures: The Medical Research Council, James S. McDonnell Foundation, Canada Excellence Research Chairs Program, the European Commission, Fonds de la Recherche Scientifique, the Mind Science Foundation, Belgian French-Speaking Community Concerted Research Action, University Hospital of Liège, and University of Liège all contributed funding to the study. Dr. Cruse and his colleagues disclosed no conflicts of interest.
Etanercept Success in JIA Linked to Age, Gender, Disability
After 15 months of treatment with etanercept, about one-third of a cohort of children with juvenile idiopathic arthritis achieved an excellent response.
Those children who were most likely to respond had relatively recent JIA and had tried fewer other treatments prior to undertaking etanercept therapy. Those who fared poorly on etanercept were more likely to have systemic-onset disease than the others; however, a quarter of systemic-onset patients achieved an excellent response. Female sex was also associated with a poor treatment outcome.
This study of 262 children with JIA is part of a multicenter, prospective, observational register, the Arthritis and Biologics in Children (ABC) Register, which was founded with the introduction of biologics in 1999 and includes all JIA patients in the Netherlands who use or previously used biological agents.
The findings, published online Nov. 6 in JAMA (2011 [doi:10.1001/jama.2011.1671]), were simultaneously presented at the American College of Rheumatology annual scientific meeting in Chicago by Dr. Marieke H. Otten, of the pediatrics department at Erasmus Medical Center, Rotterdam, the Netherlands.
Dr. Otten and her colleagues enrolled all patients registered before October 2009 who had not been treated with a biologic agent before etanercept. Of the 262 study subjects, 71% were female and 18% had systemic-onset JIA. The median age when starting etanercept was 12.4 years.
Most of the subjects – 89% – were also taking methotrexate at the start of the study period, and more than a third were taking corticosteroids. However 69% of patients on steroids had discontinued them by the end of the study period, and 42% of patients on methotrexate had discontinued using that agent.
After 15 months of treatment with etanercept, 32% of patients were graded as excellent responders, with no clinical evidence of arthritis, uveitis, or systemic disease; 36% were intermediate responders, with 50% or better improvement using American College of Rheumatology pediatric (ACRpedi) criteria for JIA; and 32% were poor responders, defined as not achieving at least an ACRpedi 50 response after 15 months on etanercept, or discontinuing before 15 months due to ineffectiveness or adverse events.
Excellent response was associated with lower baseline scores on the Childhood Health Assessment Questionnaire (adjusted odds ratio per point increase, 0.49; 95% confidence interval, 0.33-0.74); use of fewer disease-modifying antirheumatic drugs (DMARDs, including methotrexate) before starting etanercept (adjusted OR per DMARD used, 0.64; 95% CI, 0.43-0.95); and younger age at disease onset (adjusted OR per year increase, 0.92; 95% CI, 0.84-0.99).
Having systemic-onset JIA was strongly associated with poor response, with systemic-onset patients three times more likely to see a poor treatment outcome than those with nonsystemic disease (adjusted OR systemic JIA vs. nonsystemic, 2.92; 95% CI, 1.26-6.80). However, Dr. Otten and her colleagues noted in their analysis that some 11 of the 46 patients (24%) with systemic-onset JIA nonetheless were able to reach inactive disease after 15 months on etanercept.
Female sex was also associated with poor response (adjusted OR female vs. male, 2.16; 95% CI, 1.12-4.18).
In the first 15 months of treatment, 119 of the patients in the cohort experienced an adverse event, and 13 discontinued because of adverse effects, including a total of 31 serious, 99 infectious, and 179 noninfectious adverse events. These occurred in 37 patients with an excellent response, 36 with an intermediate response, and 46 with a poor response.
Dr. Otten and her colleagues were not able to identify baseline factors predictive of adverse effects, although a possible association was seen between methotrexate use within the first 15 months of etanercept treatment and infectious adverse events. That association did not reach statistical significance.
In a secondary analysis of 262 patients with a median follow-up of 35.6 months after starting etanercept, between 37% and 49% of patients had reached inactive disease.
The investigators noted as a strength of their study the fact that it included all biological treatment–naïve JIA children and adolescents taking etanercept in the Netherlands during the study period, thereby reducing the likelihood of selection bias.
They noted as a key weakness the study’s design, which included no control group. Therefore, they wrote in their analysis, "it remains unknown whether patients with a poor response to etanercept would have responded better to other treatment options." The findings, they said, "mainly reflect overall prognostic factors [rather] than predictive factors for etanercept treatment in particular."
Funding for the ABC Register came from the Dutch Board of Health Insurance, Pfizer, and Abbott. Dr. Otten and several coauthors have received grants, fees, or other forms of support from Abbott, Bristol-Myers Squibb, Novartis, Pfizer, Roche, or Tevapharma.
After 15 months of treatment with etanercept, about one-third of a cohort of children with juvenile idiopathic arthritis achieved an excellent response.
Those children who were most likely to respond had relatively recent JIA and had tried fewer other treatments prior to undertaking etanercept therapy. Those who fared poorly on etanercept were more likely to have systemic-onset disease than the others; however, a quarter of systemic-onset patients achieved an excellent response. Female sex was also associated with a poor treatment outcome.
This study of 262 children with JIA is part of a multicenter, prospective, observational register, the Arthritis and Biologics in Children (ABC) Register, which was founded with the introduction of biologics in 1999 and includes all JIA patients in the Netherlands who use or previously used biological agents.
The findings, published online Nov. 6 in JAMA (2011 [doi:10.1001/jama.2011.1671]), were simultaneously presented at the American College of Rheumatology annual scientific meeting in Chicago by Dr. Marieke H. Otten, of the pediatrics department at Erasmus Medical Center, Rotterdam, the Netherlands.
Dr. Otten and her colleagues enrolled all patients registered before October 2009 who had not been treated with a biologic agent before etanercept. Of the 262 study subjects, 71% were female and 18% had systemic-onset JIA. The median age when starting etanercept was 12.4 years.
Most of the subjects – 89% – were also taking methotrexate at the start of the study period, and more than a third were taking corticosteroids. However 69% of patients on steroids had discontinued them by the end of the study period, and 42% of patients on methotrexate had discontinued using that agent.
After 15 months of treatment with etanercept, 32% of patients were graded as excellent responders, with no clinical evidence of arthritis, uveitis, or systemic disease; 36% were intermediate responders, with 50% or better improvement using American College of Rheumatology pediatric (ACRpedi) criteria for JIA; and 32% were poor responders, defined as not achieving at least an ACRpedi 50 response after 15 months on etanercept, or discontinuing before 15 months due to ineffectiveness or adverse events.
Excellent response was associated with lower baseline scores on the Childhood Health Assessment Questionnaire (adjusted odds ratio per point increase, 0.49; 95% confidence interval, 0.33-0.74); use of fewer disease-modifying antirheumatic drugs (DMARDs, including methotrexate) before starting etanercept (adjusted OR per DMARD used, 0.64; 95% CI, 0.43-0.95); and younger age at disease onset (adjusted OR per year increase, 0.92; 95% CI, 0.84-0.99).
Having systemic-onset JIA was strongly associated with poor response, with systemic-onset patients three times more likely to see a poor treatment outcome than those with nonsystemic disease (adjusted OR systemic JIA vs. nonsystemic, 2.92; 95% CI, 1.26-6.80). However, Dr. Otten and her colleagues noted in their analysis that some 11 of the 46 patients (24%) with systemic-onset JIA nonetheless were able to reach inactive disease after 15 months on etanercept.
Female sex was also associated with poor response (adjusted OR female vs. male, 2.16; 95% CI, 1.12-4.18).
In the first 15 months of treatment, 119 of the patients in the cohort experienced an adverse event, and 13 discontinued because of adverse effects, including a total of 31 serious, 99 infectious, and 179 noninfectious adverse events. These occurred in 37 patients with an excellent response, 36 with an intermediate response, and 46 with a poor response.
Dr. Otten and her colleagues were not able to identify baseline factors predictive of adverse effects, although a possible association was seen between methotrexate use within the first 15 months of etanercept treatment and infectious adverse events. That association did not reach statistical significance.
In a secondary analysis of 262 patients with a median follow-up of 35.6 months after starting etanercept, between 37% and 49% of patients had reached inactive disease.
The investigators noted as a strength of their study the fact that it included all biological treatment–naïve JIA children and adolescents taking etanercept in the Netherlands during the study period, thereby reducing the likelihood of selection bias.
They noted as a key weakness the study’s design, which included no control group. Therefore, they wrote in their analysis, "it remains unknown whether patients with a poor response to etanercept would have responded better to other treatment options." The findings, they said, "mainly reflect overall prognostic factors [rather] than predictive factors for etanercept treatment in particular."
Funding for the ABC Register came from the Dutch Board of Health Insurance, Pfizer, and Abbott. Dr. Otten and several coauthors have received grants, fees, or other forms of support from Abbott, Bristol-Myers Squibb, Novartis, Pfizer, Roche, or Tevapharma.
After 15 months of treatment with etanercept, about one-third of a cohort of children with juvenile idiopathic arthritis achieved an excellent response.
Those children who were most likely to respond had relatively recent JIA and had tried fewer other treatments prior to undertaking etanercept therapy. Those who fared poorly on etanercept were more likely to have systemic-onset disease than the others; however, a quarter of systemic-onset patients achieved an excellent response. Female sex was also associated with a poor treatment outcome.
This study of 262 children with JIA is part of a multicenter, prospective, observational register, the Arthritis and Biologics in Children (ABC) Register, which was founded with the introduction of biologics in 1999 and includes all JIA patients in the Netherlands who use or previously used biological agents.
The findings, published online Nov. 6 in JAMA (2011 [doi:10.1001/jama.2011.1671]), were simultaneously presented at the American College of Rheumatology annual scientific meeting in Chicago by Dr. Marieke H. Otten, of the pediatrics department at Erasmus Medical Center, Rotterdam, the Netherlands.
Dr. Otten and her colleagues enrolled all patients registered before October 2009 who had not been treated with a biologic agent before etanercept. Of the 262 study subjects, 71% were female and 18% had systemic-onset JIA. The median age when starting etanercept was 12.4 years.
Most of the subjects – 89% – were also taking methotrexate at the start of the study period, and more than a third were taking corticosteroids. However 69% of patients on steroids had discontinued them by the end of the study period, and 42% of patients on methotrexate had discontinued using that agent.
After 15 months of treatment with etanercept, 32% of patients were graded as excellent responders, with no clinical evidence of arthritis, uveitis, or systemic disease; 36% were intermediate responders, with 50% or better improvement using American College of Rheumatology pediatric (ACRpedi) criteria for JIA; and 32% were poor responders, defined as not achieving at least an ACRpedi 50 response after 15 months on etanercept, or discontinuing before 15 months due to ineffectiveness or adverse events.
Excellent response was associated with lower baseline scores on the Childhood Health Assessment Questionnaire (adjusted odds ratio per point increase, 0.49; 95% confidence interval, 0.33-0.74); use of fewer disease-modifying antirheumatic drugs (DMARDs, including methotrexate) before starting etanercept (adjusted OR per DMARD used, 0.64; 95% CI, 0.43-0.95); and younger age at disease onset (adjusted OR per year increase, 0.92; 95% CI, 0.84-0.99).
Having systemic-onset JIA was strongly associated with poor response, with systemic-onset patients three times more likely to see a poor treatment outcome than those with nonsystemic disease (adjusted OR systemic JIA vs. nonsystemic, 2.92; 95% CI, 1.26-6.80). However, Dr. Otten and her colleagues noted in their analysis that some 11 of the 46 patients (24%) with systemic-onset JIA nonetheless were able to reach inactive disease after 15 months on etanercept.
Female sex was also associated with poor response (adjusted OR female vs. male, 2.16; 95% CI, 1.12-4.18).
In the first 15 months of treatment, 119 of the patients in the cohort experienced an adverse event, and 13 discontinued because of adverse effects, including a total of 31 serious, 99 infectious, and 179 noninfectious adverse events. These occurred in 37 patients with an excellent response, 36 with an intermediate response, and 46 with a poor response.
Dr. Otten and her colleagues were not able to identify baseline factors predictive of adverse effects, although a possible association was seen between methotrexate use within the first 15 months of etanercept treatment and infectious adverse events. That association did not reach statistical significance.
In a secondary analysis of 262 patients with a median follow-up of 35.6 months after starting etanercept, between 37% and 49% of patients had reached inactive disease.
The investigators noted as a strength of their study the fact that it included all biological treatment–naïve JIA children and adolescents taking etanercept in the Netherlands during the study period, thereby reducing the likelihood of selection bias.
They noted as a key weakness the study’s design, which included no control group. Therefore, they wrote in their analysis, "it remains unknown whether patients with a poor response to etanercept would have responded better to other treatment options." The findings, they said, "mainly reflect overall prognostic factors [rather] than predictive factors for etanercept treatment in particular."
Funding for the ABC Register came from the Dutch Board of Health Insurance, Pfizer, and Abbott. Dr. Otten and several coauthors have received grants, fees, or other forms of support from Abbott, Bristol-Myers Squibb, Novartis, Pfizer, Roche, or Tevapharma.
FROM JAMA
Major Finding: After 15 months of treatment with etanercept, 85 of 262 children with juvenile idiopathic arthritis achieved an excellent response, 92 achieved an intermediate response, and another 85 had a poor response. Factors associated with excellent response included younger age at disease onset and fewer other agents tried before etanercept.
Data Source: The Arthritis and Biologics in Children Register, an ongoing national registry of all Dutch children with JIA treated with biological agents.
Disclosures: Funding for the ABC Register came from the Dutch Board of Health Insurance, Pfizer, and Abbott. Dr. Otten and several coauthors have received grants, fees, or other forms of support from Abbott, Bristol-Myers Squibb, Novartis, Pfizer, Roche, or Tevapharma.
FDA Approves New Indication for Exenatide
The Food and Drug administration has approved a new indication for fixed-dose exenatide injections.
The medication's manufacturers, Amylin and Eli Lilly, announced that the exenatide injections, marketed as Byetta, had been approved as an add-on therapy to insulin glargine, with or without metformin and/or a thiazolidinedione, for adults with type 2 diabetes who are not achieving adequate glycemic control on long-acting insulin alone.
Exenatide was initially approved by the FDA in 2005 for use in combination with metformin with or without a sulfonylurea, and later for use with thiazolidinediones (TZDs). The medicine is modeled on a protein found in the saliva of Gila monsters, and is similar to glucose-dependent insulinotropic peptide or GLP-1, but lasts longer in the body.
In a phase III, manufacturer-sponsored, randomized, controlled trial of exenatide injections (Ann. Intern. Med. 2011;154:103-12), the findings of which were submitted to the FDA in support of the new indication, 261 patients receiving insulin glargine, with or without metformin and/or a TZD were randomized to receive exenatide 10 mcg twice daily or placebo in addition to aggressive insulin titration for 30 weeks.
Hemoglobin A1c was seen to decrease by 1.74 percentage points after 30 weeks in patients in the exenatide arm, and by 1.04 points in those treated with insulin alone. Patients on exenatide required less insulin (increases in insulin dosage of 13 U/day for the treatment arm vs. 20 U/day in the control arm). The incidence of hypoglycemia was similar between arms.
Patients' weights in the exenatide arm decreased by 1.8 kg, compared with an increase of 1 kg in the control arm, suggesting that exenatide improved glycemic control without causing weight gain. Nausea was the most frequently reported adverse event, affecting 41% in the treatment arm and 8% in the control arm.
Letters criticizing the study appeared after its publication. One questioned whether it was adequately powered to detect some of the reported effects, and another took issue with its short duration and use of HbA1c as an outcome measure, when other, longer studies had not shown correlations between improvements in HbA1c and diabetes mortality or vascular complications.
The Food and Drug administration has approved a new indication for fixed-dose exenatide injections.
The medication's manufacturers, Amylin and Eli Lilly, announced that the exenatide injections, marketed as Byetta, had been approved as an add-on therapy to insulin glargine, with or without metformin and/or a thiazolidinedione, for adults with type 2 diabetes who are not achieving adequate glycemic control on long-acting insulin alone.
Exenatide was initially approved by the FDA in 2005 for use in combination with metformin with or without a sulfonylurea, and later for use with thiazolidinediones (TZDs). The medicine is modeled on a protein found in the saliva of Gila monsters, and is similar to glucose-dependent insulinotropic peptide or GLP-1, but lasts longer in the body.
In a phase III, manufacturer-sponsored, randomized, controlled trial of exenatide injections (Ann. Intern. Med. 2011;154:103-12), the findings of which were submitted to the FDA in support of the new indication, 261 patients receiving insulin glargine, with or without metformin and/or a TZD were randomized to receive exenatide 10 mcg twice daily or placebo in addition to aggressive insulin titration for 30 weeks.
Hemoglobin A1c was seen to decrease by 1.74 percentage points after 30 weeks in patients in the exenatide arm, and by 1.04 points in those treated with insulin alone. Patients on exenatide required less insulin (increases in insulin dosage of 13 U/day for the treatment arm vs. 20 U/day in the control arm). The incidence of hypoglycemia was similar between arms.
Patients' weights in the exenatide arm decreased by 1.8 kg, compared with an increase of 1 kg in the control arm, suggesting that exenatide improved glycemic control without causing weight gain. Nausea was the most frequently reported adverse event, affecting 41% in the treatment arm and 8% in the control arm.
Letters criticizing the study appeared after its publication. One questioned whether it was adequately powered to detect some of the reported effects, and another took issue with its short duration and use of HbA1c as an outcome measure, when other, longer studies had not shown correlations between improvements in HbA1c and diabetes mortality or vascular complications.
The Food and Drug administration has approved a new indication for fixed-dose exenatide injections.
The medication's manufacturers, Amylin and Eli Lilly, announced that the exenatide injections, marketed as Byetta, had been approved as an add-on therapy to insulin glargine, with or without metformin and/or a thiazolidinedione, for adults with type 2 diabetes who are not achieving adequate glycemic control on long-acting insulin alone.
Exenatide was initially approved by the FDA in 2005 for use in combination with metformin with or without a sulfonylurea, and later for use with thiazolidinediones (TZDs). The medicine is modeled on a protein found in the saliva of Gila monsters, and is similar to glucose-dependent insulinotropic peptide or GLP-1, but lasts longer in the body.
In a phase III, manufacturer-sponsored, randomized, controlled trial of exenatide injections (Ann. Intern. Med. 2011;154:103-12), the findings of which were submitted to the FDA in support of the new indication, 261 patients receiving insulin glargine, with or without metformin and/or a TZD were randomized to receive exenatide 10 mcg twice daily or placebo in addition to aggressive insulin titration for 30 weeks.
Hemoglobin A1c was seen to decrease by 1.74 percentage points after 30 weeks in patients in the exenatide arm, and by 1.04 points in those treated with insulin alone. Patients on exenatide required less insulin (increases in insulin dosage of 13 U/day for the treatment arm vs. 20 U/day in the control arm). The incidence of hypoglycemia was similar between arms.
Patients' weights in the exenatide arm decreased by 1.8 kg, compared with an increase of 1 kg in the control arm, suggesting that exenatide improved glycemic control without causing weight gain. Nausea was the most frequently reported adverse event, affecting 41% in the treatment arm and 8% in the control arm.
Letters criticizing the study appeared after its publication. One questioned whether it was adequately powered to detect some of the reported effects, and another took issue with its short duration and use of HbA1c as an outcome measure, when other, longer studies had not shown correlations between improvements in HbA1c and diabetes mortality or vascular complications.
Tremor Guideline Reconsiders Some Therapies
A new evidence-based guideline issued by the American Academy of Neurology for the treatment of essential tremor reinforces the use of propranolol and primidone as the go-to agents for the disease.
However, these first-line agents – used as monotherapy or combination therapy since the 1980s – do not work in between 30% and 50% of people with essential tremor (ET). Moreover, a 2010 study of 223 ET patients in a clinical database revealed that more than half of patients taking primidone and/or propranolol had discontinued them, suggesting that the need for alternatives is great (Parkinsonism Relat. Disord. 2010;16:604-7). htimidone and propranolol are known to cause side effects at higher doses.
Essential tremor is a common, progressive neurological disease, formerly called “benign essential tremor,” that causes a rhythmic trembling of the hands, head, voice, legs, or trunk, and is sometimes mistaken for Parkinson's disease.
In its new ET guideline, published online Oct. 19 as an update of its 2005 guideline for ET, the AAN continues to recommend topiramate, alprazolam, atenolol, gabapentin, and sotalol as second-line treatments, based on clinical evidence that they are probably effective. The AAN's new recommendations are based on reviews of 589 articles (252 of these complete reviews) of randomized controlled trials, observational studies, cohort studies, and case series published between 2004 and 2010 (Neurology 2011 Oct. 19 [Epub ahead of print]).
The AAN's team of reviewers, led by Dr. Theresa A. Zesiewicz of the University of South Florida in Tampa, found that they could not recommend levetiracetam and 3,4-diaminopyridine as second-line agents, based on quality (level B) clinical evidence that they do not reduce limb tremor. The evidence on flunarizine suggests that it is probably ineffective in reducing limb tremor. And the reviewers could not recommend pregabalin, zonisamide, and clozapine, based on insufficient evidence to support or refute their use in ET.
“There were some agents we had some hopes for that didn't pan out, and levetiracetam was one of them,” Dr. Zesiewicz said in an interview, adding that patients not responding to primidone or propranolol, or in whom these are contraindicated, might benefit from any of the currently recommended second-line agents with level B evidence supporting them. Of these, she said, topiramate is supported by the largest cohort studies, but “any of the level B, or level C agents” can be tried. Surgical interventions in ET patients, though seen to have greater treatment effect than medications, are seldom tried before a second-line agent doesn't work and a tremor becomes debilitating. “The reason we don't go to [surgery] right away is because when the side effects do occur – which is relatively rare – they can be serious,” Dr. Zesiewicz said.
The guideline's advice on surgical interventions for ET remain unchanged from 2005, with deep brain stimulation (DBS) still recommended. DBS, by which a device is implanted in the brain to transmit electrical impulses, “has really become the surgery of choice,” Dr. Zesiewicz said.
There is still too little evidence for the AAN to recommend gamma knife thalamotomy, which uses targeted radiotherapy, and concern remains about rare but serious side effects with the procedure. Nonetheless, “the story about gamma knife has yet to be completely written,” Dr. Zesiewicz said.
Another surgical intervention currently being explored, which uses MR-guided focused ultrasound, was not mentioned in the current guidance, but Dr. Zesiewicz called it “extremely interesting,” and hopes that the procedure, pioneered by Dr. W. Jeffrey Elias of the University of Virginia, Charlottesville, will hold up in long-term safety studies and randomized controlled trials. “Gamma ray looked good too,” she noted – until some rare but severe delayed adverse effects were seen.
Dr. Zesiewicz and her colleagues noted that more and larger randomized controlled trials, with standardized outcome measures, were needed for ET treatments.
“We lost a lot of ground in research because of the [former] name 'benign essential tremor,'” Dr. Zesiewicz said. “Once that 'benign' was dropped it became a more serious priority. Hopefully we'll be able to gain ground now that we know that this is a serious condition, it is a disease, and it's certainly not benign.”
However, the pathology of ET, now thought to be a heterogeneous set of degenerative changes in the brain, has become much better understood in recent years, thanks to researchers' postmortem studies of the brains of ET patients at Columbia University in New York.
The Columbia brain bank's research is being led by Dr. Elan Louis, one of the new ET guideline's coauthors. Dr. Louis and colleagues have made “tremendous headway,” Dr. Zesiewicz said, in elucidating the causes of ET.
Dr. Zesiewicz said she hopes new agents will be designed to target ET specifically. The currently recommended agents range from antiepileptics to medications used to treat schizophrenia – and only one, propranolol, is approved by the U.S. Food and Drug Administration to treat ET. (Even primidone is not FDA-approved, despite its widespread, long-term use.)
“What's important to understand is that ET may be a heterogeneous condition,” Dr. Zesiewicz said. “When we pick that apart and truly understand the mechanisms by which ET occurs, we may be able to develop research and medications specific to the problem.”
Dr. Zesiewicz disclosed having received speakers' fees other forms of support from Teva, Boehringer Ingelheim, Allergan, and Novartis, along with research support from Pfizer, and is an inventor on a provisional patent on the use of nicotinic modulators in treating ataxia and imbalance held by the University of South Florida. Several of Dr. Zesiewicz's coauthors on the ET guideline acknowledged support from these and other companies, including GlaxoSmithKline, Phytopharm, Janssen, Allergan, Novartis, Ipsen, Merz, Lundbeck, and Bayer.
A new evidence-based guideline issued by the American Academy of Neurology for the treatment of essential tremor reinforces the use of propranolol and primidone as the go-to agents for the disease.
However, these first-line agents – used as monotherapy or combination therapy since the 1980s – do not work in between 30% and 50% of people with essential tremor (ET). Moreover, a 2010 study of 223 ET patients in a clinical database revealed that more than half of patients taking primidone and/or propranolol had discontinued them, suggesting that the need for alternatives is great (Parkinsonism Relat. Disord. 2010;16:604-7). htimidone and propranolol are known to cause side effects at higher doses.
Essential tremor is a common, progressive neurological disease, formerly called “benign essential tremor,” that causes a rhythmic trembling of the hands, head, voice, legs, or trunk, and is sometimes mistaken for Parkinson's disease.
In its new ET guideline, published online Oct. 19 as an update of its 2005 guideline for ET, the AAN continues to recommend topiramate, alprazolam, atenolol, gabapentin, and sotalol as second-line treatments, based on clinical evidence that they are probably effective. The AAN's new recommendations are based on reviews of 589 articles (252 of these complete reviews) of randomized controlled trials, observational studies, cohort studies, and case series published between 2004 and 2010 (Neurology 2011 Oct. 19 [Epub ahead of print]).
The AAN's team of reviewers, led by Dr. Theresa A. Zesiewicz of the University of South Florida in Tampa, found that they could not recommend levetiracetam and 3,4-diaminopyridine as second-line agents, based on quality (level B) clinical evidence that they do not reduce limb tremor. The evidence on flunarizine suggests that it is probably ineffective in reducing limb tremor. And the reviewers could not recommend pregabalin, zonisamide, and clozapine, based on insufficient evidence to support or refute their use in ET.
“There were some agents we had some hopes for that didn't pan out, and levetiracetam was one of them,” Dr. Zesiewicz said in an interview, adding that patients not responding to primidone or propranolol, or in whom these are contraindicated, might benefit from any of the currently recommended second-line agents with level B evidence supporting them. Of these, she said, topiramate is supported by the largest cohort studies, but “any of the level B, or level C agents” can be tried. Surgical interventions in ET patients, though seen to have greater treatment effect than medications, are seldom tried before a second-line agent doesn't work and a tremor becomes debilitating. “The reason we don't go to [surgery] right away is because when the side effects do occur – which is relatively rare – they can be serious,” Dr. Zesiewicz said.
The guideline's advice on surgical interventions for ET remain unchanged from 2005, with deep brain stimulation (DBS) still recommended. DBS, by which a device is implanted in the brain to transmit electrical impulses, “has really become the surgery of choice,” Dr. Zesiewicz said.
There is still too little evidence for the AAN to recommend gamma knife thalamotomy, which uses targeted radiotherapy, and concern remains about rare but serious side effects with the procedure. Nonetheless, “the story about gamma knife has yet to be completely written,” Dr. Zesiewicz said.
Another surgical intervention currently being explored, which uses MR-guided focused ultrasound, was not mentioned in the current guidance, but Dr. Zesiewicz called it “extremely interesting,” and hopes that the procedure, pioneered by Dr. W. Jeffrey Elias of the University of Virginia, Charlottesville, will hold up in long-term safety studies and randomized controlled trials. “Gamma ray looked good too,” she noted – until some rare but severe delayed adverse effects were seen.
Dr. Zesiewicz and her colleagues noted that more and larger randomized controlled trials, with standardized outcome measures, were needed for ET treatments.
“We lost a lot of ground in research because of the [former] name 'benign essential tremor,'” Dr. Zesiewicz said. “Once that 'benign' was dropped it became a more serious priority. Hopefully we'll be able to gain ground now that we know that this is a serious condition, it is a disease, and it's certainly not benign.”
However, the pathology of ET, now thought to be a heterogeneous set of degenerative changes in the brain, has become much better understood in recent years, thanks to researchers' postmortem studies of the brains of ET patients at Columbia University in New York.
The Columbia brain bank's research is being led by Dr. Elan Louis, one of the new ET guideline's coauthors. Dr. Louis and colleagues have made “tremendous headway,” Dr. Zesiewicz said, in elucidating the causes of ET.
Dr. Zesiewicz said she hopes new agents will be designed to target ET specifically. The currently recommended agents range from antiepileptics to medications used to treat schizophrenia – and only one, propranolol, is approved by the U.S. Food and Drug Administration to treat ET. (Even primidone is not FDA-approved, despite its widespread, long-term use.)
“What's important to understand is that ET may be a heterogeneous condition,” Dr. Zesiewicz said. “When we pick that apart and truly understand the mechanisms by which ET occurs, we may be able to develop research and medications specific to the problem.”
Dr. Zesiewicz disclosed having received speakers' fees other forms of support from Teva, Boehringer Ingelheim, Allergan, and Novartis, along with research support from Pfizer, and is an inventor on a provisional patent on the use of nicotinic modulators in treating ataxia and imbalance held by the University of South Florida. Several of Dr. Zesiewicz's coauthors on the ET guideline acknowledged support from these and other companies, including GlaxoSmithKline, Phytopharm, Janssen, Allergan, Novartis, Ipsen, Merz, Lundbeck, and Bayer.
A new evidence-based guideline issued by the American Academy of Neurology for the treatment of essential tremor reinforces the use of propranolol and primidone as the go-to agents for the disease.
However, these first-line agents – used as monotherapy or combination therapy since the 1980s – do not work in between 30% and 50% of people with essential tremor (ET). Moreover, a 2010 study of 223 ET patients in a clinical database revealed that more than half of patients taking primidone and/or propranolol had discontinued them, suggesting that the need for alternatives is great (Parkinsonism Relat. Disord. 2010;16:604-7). htimidone and propranolol are known to cause side effects at higher doses.
Essential tremor is a common, progressive neurological disease, formerly called “benign essential tremor,” that causes a rhythmic trembling of the hands, head, voice, legs, or trunk, and is sometimes mistaken for Parkinson's disease.
In its new ET guideline, published online Oct. 19 as an update of its 2005 guideline for ET, the AAN continues to recommend topiramate, alprazolam, atenolol, gabapentin, and sotalol as second-line treatments, based on clinical evidence that they are probably effective. The AAN's new recommendations are based on reviews of 589 articles (252 of these complete reviews) of randomized controlled trials, observational studies, cohort studies, and case series published between 2004 and 2010 (Neurology 2011 Oct. 19 [Epub ahead of print]).
The AAN's team of reviewers, led by Dr. Theresa A. Zesiewicz of the University of South Florida in Tampa, found that they could not recommend levetiracetam and 3,4-diaminopyridine as second-line agents, based on quality (level B) clinical evidence that they do not reduce limb tremor. The evidence on flunarizine suggests that it is probably ineffective in reducing limb tremor. And the reviewers could not recommend pregabalin, zonisamide, and clozapine, based on insufficient evidence to support or refute their use in ET.
“There were some agents we had some hopes for that didn't pan out, and levetiracetam was one of them,” Dr. Zesiewicz said in an interview, adding that patients not responding to primidone or propranolol, or in whom these are contraindicated, might benefit from any of the currently recommended second-line agents with level B evidence supporting them. Of these, she said, topiramate is supported by the largest cohort studies, but “any of the level B, or level C agents” can be tried. Surgical interventions in ET patients, though seen to have greater treatment effect than medications, are seldom tried before a second-line agent doesn't work and a tremor becomes debilitating. “The reason we don't go to [surgery] right away is because when the side effects do occur – which is relatively rare – they can be serious,” Dr. Zesiewicz said.
The guideline's advice on surgical interventions for ET remain unchanged from 2005, with deep brain stimulation (DBS) still recommended. DBS, by which a device is implanted in the brain to transmit electrical impulses, “has really become the surgery of choice,” Dr. Zesiewicz said.
There is still too little evidence for the AAN to recommend gamma knife thalamotomy, which uses targeted radiotherapy, and concern remains about rare but serious side effects with the procedure. Nonetheless, “the story about gamma knife has yet to be completely written,” Dr. Zesiewicz said.
Another surgical intervention currently being explored, which uses MR-guided focused ultrasound, was not mentioned in the current guidance, but Dr. Zesiewicz called it “extremely interesting,” and hopes that the procedure, pioneered by Dr. W. Jeffrey Elias of the University of Virginia, Charlottesville, will hold up in long-term safety studies and randomized controlled trials. “Gamma ray looked good too,” she noted – until some rare but severe delayed adverse effects were seen.
Dr. Zesiewicz and her colleagues noted that more and larger randomized controlled trials, with standardized outcome measures, were needed for ET treatments.
“We lost a lot of ground in research because of the [former] name 'benign essential tremor,'” Dr. Zesiewicz said. “Once that 'benign' was dropped it became a more serious priority. Hopefully we'll be able to gain ground now that we know that this is a serious condition, it is a disease, and it's certainly not benign.”
However, the pathology of ET, now thought to be a heterogeneous set of degenerative changes in the brain, has become much better understood in recent years, thanks to researchers' postmortem studies of the brains of ET patients at Columbia University in New York.
The Columbia brain bank's research is being led by Dr. Elan Louis, one of the new ET guideline's coauthors. Dr. Louis and colleagues have made “tremendous headway,” Dr. Zesiewicz said, in elucidating the causes of ET.
Dr. Zesiewicz said she hopes new agents will be designed to target ET specifically. The currently recommended agents range from antiepileptics to medications used to treat schizophrenia – and only one, propranolol, is approved by the U.S. Food and Drug Administration to treat ET. (Even primidone is not FDA-approved, despite its widespread, long-term use.)
“What's important to understand is that ET may be a heterogeneous condition,” Dr. Zesiewicz said. “When we pick that apart and truly understand the mechanisms by which ET occurs, we may be able to develop research and medications specific to the problem.”
Dr. Zesiewicz disclosed having received speakers' fees other forms of support from Teva, Boehringer Ingelheim, Allergan, and Novartis, along with research support from Pfizer, and is an inventor on a provisional patent on the use of nicotinic modulators in treating ataxia and imbalance held by the University of South Florida. Several of Dr. Zesiewicz's coauthors on the ET guideline acknowledged support from these and other companies, including GlaxoSmithKline, Phytopharm, Janssen, Allergan, Novartis, Ipsen, Merz, Lundbeck, and Bayer.
Ovarian Malignancy Risk Seen Doubled 15 Years After IVF
Women who have undergone in vitro fertilization appear to have a twofold risk of ovarian malignancies later in life, compared with women with fertility problems who never used IVF.
However, the risk of invasive ovarian cancer was not significantly increased in IVF-treated women until 15 years after IVF treatment, the results of the study found.
Results from a large Dutch cohort study of 25,152 women using linked medical records to identify women who had been seen for infertility and/or treated with IVF from 1983 to 1995 showed that borderline ovarian tumors accounted for most of the increase in risk after a median 15 years of follow-up. Most of the women were in their late 40s at the study end point.
The investigators of the study, which was published Oct. 26 in Human Reproduction, compared the 19,146 IVF-treated women in the cohort with a control group of 6,006 women who had been seen for fertility problems but had not undergone IVF (although they may have received other forms of treatment, including drugs). The investigators also looked at rates of ovarian malignancies in the general population (Hum. Reprod. 2011 [doi:10.1093/humrep/der322]).
Having subfertile controls was important, the investigators said, because women with infertility have a different risk profile for ovarian malignancies than do women in the population at large. Causes of infertility in the study included fallopian tube disorders, subfertility of a male partner, cervical factor, and endometriosis.
The investigators, led by Flora E. van Leeuwen, Ph.D., of the Netherlands Cancer Institute in Amsterdam, noted that the findings of a risk increase for ovarian malignancies confirmed older findings from smaller cohort studies. Borderline tumors are considered to have a low malignancy potential, and not much is known about which will become invasive, but these tumors do require treatment.
Nearly half of the 61 malignancies detected in the IVF-treated women were borderline tumors, while in the general population of women under age 50 years, these normally account for 15%-30% of malignancies, Dr. van Leeuwen and her colleagues found. A high proportion – 63% – of the borderline tumors seen in the IVF-treated group were serous, while mucinous tumors are more frequent in the general population.
After the researchers adjusted for such potential confounding factors as age, parity, and causes of infertility, IVF-treated women saw a significantly elevated risk for borderline ovarian tumors, compared with subfertile controls (hazard ratio 4.23) and for all ovarian malignancies combined, compared with controls (HR 2.14).
Risk of invasive ovarian cancer was not seen as significantly increased in the IVF-treated women, compared with controls (HR 1.51). However, compared with the general population, the IVF-treated women’s risk of developing invasive ovarian cancer was higher 15 years after IVF treatment, with a standard incidence ratio of 3.54. No increased risk was reported for non-IVF controls, compared with the general population.
Dr. van Leeuwen and her colleagues noted that they did not find evidence that repeated cycles of IVF increased the risk of malignancies, as might be expected. However, they wrote, the powers of their analyses were reduced by missing data and small numbers of women in the subgroups. In the IVF group, 40% of women had one to two stimulated IVF cycles, 39% had three to four cycles, and 21% received five or more cycles.
The type of infertility treatments were as follows: clomiphene/hMG (human menopausal gonadotropins) or FSH (follicle stimulating hormone)/hMG stimulation protocols were used until 1988-1989, whereas stimulation with GnRH (gonadotropin-releasing hormone) agonists became common after 1990 (from 20% in 1986 to about 90% after 1990), the investigators said.
Dr. van Leeuwen and her colleagues cited the large cohort size and long follow-up period as strengths of their study, as well as linkages to population-based cancer and pathology registries, which enabled the investigators to also evaluate the occurrence of borderline ovarian tumors.
They noted as a weakness of their study the fact that their group of subfertile controls was relatively small and that 40% of controls had been prescribed clomiphene, meaning that they were not truly unexposed if the cause of the malignancies was drug related and not related to ovarian puncture. The study was based on IVF treatment protocols through 1995 only, they added.
Still, the researchers concluded that they had demonstrated sufficient risk for women and their physicians to consider when deciding whether to start or continue IVF treatment.
The study was funded by the Dutch Ministry of Health, the Health Research and Development Counsel, and the Netherlands Cancer Institute. J.L.H. Evers declared that he works in a department that has received unrestricted research grants from Merck and Ferring. Neither Dr. van Leeuwen nor any other of her colleagues declared any relevant financial disclosures.
Women who have undergone in vitro fertilization appear to have a twofold risk of ovarian malignancies later in life, compared with women with fertility problems who never used IVF.
However, the risk of invasive ovarian cancer was not significantly increased in IVF-treated women until 15 years after IVF treatment, the results of the study found.
Results from a large Dutch cohort study of 25,152 women using linked medical records to identify women who had been seen for infertility and/or treated with IVF from 1983 to 1995 showed that borderline ovarian tumors accounted for most of the increase in risk after a median 15 years of follow-up. Most of the women were in their late 40s at the study end point.
The investigators of the study, which was published Oct. 26 in Human Reproduction, compared the 19,146 IVF-treated women in the cohort with a control group of 6,006 women who had been seen for fertility problems but had not undergone IVF (although they may have received other forms of treatment, including drugs). The investigators also looked at rates of ovarian malignancies in the general population (Hum. Reprod. 2011 [doi:10.1093/humrep/der322]).
Having subfertile controls was important, the investigators said, because women with infertility have a different risk profile for ovarian malignancies than do women in the population at large. Causes of infertility in the study included fallopian tube disorders, subfertility of a male partner, cervical factor, and endometriosis.
The investigators, led by Flora E. van Leeuwen, Ph.D., of the Netherlands Cancer Institute in Amsterdam, noted that the findings of a risk increase for ovarian malignancies confirmed older findings from smaller cohort studies. Borderline tumors are considered to have a low malignancy potential, and not much is known about which will become invasive, but these tumors do require treatment.
Nearly half of the 61 malignancies detected in the IVF-treated women were borderline tumors, while in the general population of women under age 50 years, these normally account for 15%-30% of malignancies, Dr. van Leeuwen and her colleagues found. A high proportion – 63% – of the borderline tumors seen in the IVF-treated group were serous, while mucinous tumors are more frequent in the general population.
After the researchers adjusted for such potential confounding factors as age, parity, and causes of infertility, IVF-treated women saw a significantly elevated risk for borderline ovarian tumors, compared with subfertile controls (hazard ratio 4.23) and for all ovarian malignancies combined, compared with controls (HR 2.14).
Risk of invasive ovarian cancer was not seen as significantly increased in the IVF-treated women, compared with controls (HR 1.51). However, compared with the general population, the IVF-treated women’s risk of developing invasive ovarian cancer was higher 15 years after IVF treatment, with a standard incidence ratio of 3.54. No increased risk was reported for non-IVF controls, compared with the general population.
Dr. van Leeuwen and her colleagues noted that they did not find evidence that repeated cycles of IVF increased the risk of malignancies, as might be expected. However, they wrote, the powers of their analyses were reduced by missing data and small numbers of women in the subgroups. In the IVF group, 40% of women had one to two stimulated IVF cycles, 39% had three to four cycles, and 21% received five or more cycles.
The type of infertility treatments were as follows: clomiphene/hMG (human menopausal gonadotropins) or FSH (follicle stimulating hormone)/hMG stimulation protocols were used until 1988-1989, whereas stimulation with GnRH (gonadotropin-releasing hormone) agonists became common after 1990 (from 20% in 1986 to about 90% after 1990), the investigators said.
Dr. van Leeuwen and her colleagues cited the large cohort size and long follow-up period as strengths of their study, as well as linkages to population-based cancer and pathology registries, which enabled the investigators to also evaluate the occurrence of borderline ovarian tumors.
They noted as a weakness of their study the fact that their group of subfertile controls was relatively small and that 40% of controls had been prescribed clomiphene, meaning that they were not truly unexposed if the cause of the malignancies was drug related and not related to ovarian puncture. The study was based on IVF treatment protocols through 1995 only, they added.
Still, the researchers concluded that they had demonstrated sufficient risk for women and their physicians to consider when deciding whether to start or continue IVF treatment.
The study was funded by the Dutch Ministry of Health, the Health Research and Development Counsel, and the Netherlands Cancer Institute. J.L.H. Evers declared that he works in a department that has received unrestricted research grants from Merck and Ferring. Neither Dr. van Leeuwen nor any other of her colleagues declared any relevant financial disclosures.
Women who have undergone in vitro fertilization appear to have a twofold risk of ovarian malignancies later in life, compared with women with fertility problems who never used IVF.
However, the risk of invasive ovarian cancer was not significantly increased in IVF-treated women until 15 years after IVF treatment, the results of the study found.
Results from a large Dutch cohort study of 25,152 women using linked medical records to identify women who had been seen for infertility and/or treated with IVF from 1983 to 1995 showed that borderline ovarian tumors accounted for most of the increase in risk after a median 15 years of follow-up. Most of the women were in their late 40s at the study end point.
The investigators of the study, which was published Oct. 26 in Human Reproduction, compared the 19,146 IVF-treated women in the cohort with a control group of 6,006 women who had been seen for fertility problems but had not undergone IVF (although they may have received other forms of treatment, including drugs). The investigators also looked at rates of ovarian malignancies in the general population (Hum. Reprod. 2011 [doi:10.1093/humrep/der322]).
Having subfertile controls was important, the investigators said, because women with infertility have a different risk profile for ovarian malignancies than do women in the population at large. Causes of infertility in the study included fallopian tube disorders, subfertility of a male partner, cervical factor, and endometriosis.
The investigators, led by Flora E. van Leeuwen, Ph.D., of the Netherlands Cancer Institute in Amsterdam, noted that the findings of a risk increase for ovarian malignancies confirmed older findings from smaller cohort studies. Borderline tumors are considered to have a low malignancy potential, and not much is known about which will become invasive, but these tumors do require treatment.
Nearly half of the 61 malignancies detected in the IVF-treated women were borderline tumors, while in the general population of women under age 50 years, these normally account for 15%-30% of malignancies, Dr. van Leeuwen and her colleagues found. A high proportion – 63% – of the borderline tumors seen in the IVF-treated group were serous, while mucinous tumors are more frequent in the general population.
After the researchers adjusted for such potential confounding factors as age, parity, and causes of infertility, IVF-treated women saw a significantly elevated risk for borderline ovarian tumors, compared with subfertile controls (hazard ratio 4.23) and for all ovarian malignancies combined, compared with controls (HR 2.14).
Risk of invasive ovarian cancer was not seen as significantly increased in the IVF-treated women, compared with controls (HR 1.51). However, compared with the general population, the IVF-treated women’s risk of developing invasive ovarian cancer was higher 15 years after IVF treatment, with a standard incidence ratio of 3.54. No increased risk was reported for non-IVF controls, compared with the general population.
Dr. van Leeuwen and her colleagues noted that they did not find evidence that repeated cycles of IVF increased the risk of malignancies, as might be expected. However, they wrote, the powers of their analyses were reduced by missing data and small numbers of women in the subgroups. In the IVF group, 40% of women had one to two stimulated IVF cycles, 39% had three to four cycles, and 21% received five or more cycles.
The type of infertility treatments were as follows: clomiphene/hMG (human menopausal gonadotropins) or FSH (follicle stimulating hormone)/hMG stimulation protocols were used until 1988-1989, whereas stimulation with GnRH (gonadotropin-releasing hormone) agonists became common after 1990 (from 20% in 1986 to about 90% after 1990), the investigators said.
Dr. van Leeuwen and her colleagues cited the large cohort size and long follow-up period as strengths of their study, as well as linkages to population-based cancer and pathology registries, which enabled the investigators to also evaluate the occurrence of borderline ovarian tumors.
They noted as a weakness of their study the fact that their group of subfertile controls was relatively small and that 40% of controls had been prescribed clomiphene, meaning that they were not truly unexposed if the cause of the malignancies was drug related and not related to ovarian puncture. The study was based on IVF treatment protocols through 1995 only, they added.
Still, the researchers concluded that they had demonstrated sufficient risk for women and their physicians to consider when deciding whether to start or continue IVF treatment.
The study was funded by the Dutch Ministry of Health, the Health Research and Development Counsel, and the Netherlands Cancer Institute. J.L.H. Evers declared that he works in a department that has received unrestricted research grants from Merck and Ferring. Neither Dr. van Leeuwen nor any other of her colleagues declared any relevant financial disclosures.
FROM HUMAN REPRODUCTION
Major Finding: After researchers adjusted for such potential confounding factors as age, parity, and causes of infertility, IVF-treated women saw a significantly elevated risk for borderline ovarian tumors, compared with subfertile controls (hazard ratio, 4.23) and for all ovarian malignancies combined, compared with controls (HR, 2.14).
Data Source: A study of 19,146 IVF-treated women and a control group of 6,006 women who had been seen for fertility problems but had not undergone IVF (although they may have received other forms of treatment, including drugs).
Disclosures: The study was funded by the Dutch Ministry of Health, the Health Research and Development Counsel, and the Netherlands Cancer Institute. J.L.H. Evers declared that he works in a department that has received unrestricted research grants from Merck and Ferring. Neither Dr. van Leeuwen nor any other of her colleagues declared any relevant financial disclosures.
OC Study Confirms VTE Risk of Newer Progestogens
Oral contraceptives containing the newer progestogen types desogestrel, drospirenone, and gestodene have been associated with twice the risk of venous thromboembolism as those containing levonorgestrel, an older agent.
Women taking combination oral contraceptives (OCs) with levonorgestrel were at a threefold increased risk for confirmed venous thromboembolism (VTE), compared with women not taking any contraceptive pills, while users of OCs containing desogestrel, drospirenone, and gestodene saw a sixfold increased risk. The risk for drospirenone was seen as comparable to that of desogestrel and gestodene.
However, a lower dose of estrogen (20 mcg instead of 30 mcg) was not seen to lessen the risk associated with drospirenone-containing pills, the investigators found, while with desogestrel and gestodene, lower-estrogen preparations were associated with lower risk. (The OCs with desogestrel or gestodene and 20 mcg of ethinyl estradiol implied relative risks of VTE that were 23% and 17% lower, respectively, than the risks for the same progestogens with 30 mcg of ethinyl estradiol.)
The results, published online Oct. 25 in BMJ (doi: 10.1136/bmj.d6423), confirm those of a previous study by the same Denmark-based team of investigators, who in 2009 reported a significantly higher risk of VTE for OCs containing these three progestogens than for OCs with levonorgestrel (BMJ 2009;339:b2890 [doi: 10.1136/bmj.b2890]).
Both studies were led by Dr. Øjvind Lidegaard, professor of obstetrics and gynecology at the University of Copenhagen, and his colleagues, who used the same registry-based cohort of all Danish women aged 15-49 years with no history of VTE and who were not pregnant. The new study followed the women from 2001 to 2009, 4 years longer than the previous study (though their prescription information was collected from 1995), and the study collected more detailed information on OC use and VTE events.
During the study period, which comprised more than 8 million woman-years of observation, 4,246 first episodes of VTE occurred. After adjustment for age, calendar year, education, and length of OC use, the relative risk of VTE risk in women who used pills with desogestrel, drospirenone, or gestodene was found to be twice that of women on levonorgestrel-containing pills.
Dr. Lidegaard and his colleagues found that, compared with women not using hormonal contraception, the relative risk of confirmed VTE in users of OCs containing 30-40 mcg of ethinyl estradiol with levonorgestrel was 2.9 (95% confidence interval, 2.2-3.8), compared with 6.6 in women using OCs containing desogestrel (95% CI, 5.6-7.8), 6.2 in users of gestodene (5.6-7.0), and 6.4 in women taking drospirenone (5.4-7.5).
With users of OCs containing levonorgestrel as a reference, and after adjustment for length of use, the rate ratio of confirmed VTE for users of OCs with desogestrel was 2.2 (95% CI, 1.7-3.0), with gestodene it was 2.1 (95% CI, 1.6-2.8), and with drospirenone it was 2.1 (1.6-2.8).
To prevent one VTE per year, approximately 2,000 women would need to switch from a pill containing desogestrel, gestodene, or drospirenone to one with levonorgestrel, the researchers concluded.
Critics of Dr. Lidegaard and colleagues’ previous study, which revealed similar differences in risk between levonorgestrel and the newer progestogens, argued that because no declining risk was seen after the first few months of use for women using levonorgestrel-containing pills, as would be expected, left-censoring bias might have occurred, making the risk of VTE associated with levonorgestrel seem artificially low compared with that seen with drospirenone, which was introduced in 2001.
Dr. Lidegaard and his colleagues described several changes in their new study’s design to strengthen it, noting that they had eliminated left-censoring bias by letting the new study period begin in 2001, which marked the introduction of drospirenone-containing OCs in Denmark, but still collected the women’s full OC exposure history for the previous 6 years. They also defined length of OC use more precisely than in the previous study, stratified analyses into confirmed and unconfirmed VTE events, and better excluded women predisposed to VTE, they said.
The investigators acknowledged as a weakness of the study that they could not control for family disposition and body mass index. However, they noted, other studies had not shown a strong confounding effect for those factors even when data were available.
The study was commissioned by the European Medicines Agency. Bayer Schering Pharma covered the expenses of the analysis with payment to Dr. Lidegaard’s institution, though not to Dr. Lidegaard.
Dr. Lidegaard disclosed having received honoraria for speeches from Bayer Pharma Denmark and Novo Nordisk, and ongoing work as an expert witness for plaintiffs in a legal case in the United States. One of Dr. Lidegaard’s coauthors, Dr. Finn Egil Skjeldestad, acknowledged receiving compensation for his work on the steering committee of the European Medicines Agency report.
This new study has tackled many of the concerns expressed about the earlier investigation. Although unpalatable to some, it is difficult not to conclude that combined oral contraceptives with desogestrel, gestodene, or drospirenone confer a higher risk of venous thromboembolism than those with levonorgestrel. Many clinicians will choose to minimize the risk by prescribing a combined oral contraceptive with levonorgestrel whenever possible. It is crucial, however, not to exaggerate the risk – oral contraceptives are remarkably safe and may confer important long-term benefits in relation to cancer and mortality.
Dr. Philip Hannaford is Grampian Health Board Chair of Primary Care, University of Aberdeen, Scotland. His remarks are taken from an editorial accompanying the study (doi: 10.1136/bmj.d6423).
This new study has tackled many of the concerns expressed about the earlier investigation. Although unpalatable to some, it is difficult not to conclude that combined oral contraceptives with desogestrel, gestodene, or drospirenone confer a higher risk of venous thromboembolism than those with levonorgestrel. Many clinicians will choose to minimize the risk by prescribing a combined oral contraceptive with levonorgestrel whenever possible. It is crucial, however, not to exaggerate the risk – oral contraceptives are remarkably safe and may confer important long-term benefits in relation to cancer and mortality.
Dr. Philip Hannaford is Grampian Health Board Chair of Primary Care, University of Aberdeen, Scotland. His remarks are taken from an editorial accompanying the study (doi: 10.1136/bmj.d6423).
This new study has tackled many of the concerns expressed about the earlier investigation. Although unpalatable to some, it is difficult not to conclude that combined oral contraceptives with desogestrel, gestodene, or drospirenone confer a higher risk of venous thromboembolism than those with levonorgestrel. Many clinicians will choose to minimize the risk by prescribing a combined oral contraceptive with levonorgestrel whenever possible. It is crucial, however, not to exaggerate the risk – oral contraceptives are remarkably safe and may confer important long-term benefits in relation to cancer and mortality.
Dr. Philip Hannaford is Grampian Health Board Chair of Primary Care, University of Aberdeen, Scotland. His remarks are taken from an editorial accompanying the study (doi: 10.1136/bmj.d6423).
Oral contraceptives containing the newer progestogen types desogestrel, drospirenone, and gestodene have been associated with twice the risk of venous thromboembolism as those containing levonorgestrel, an older agent.
Women taking combination oral contraceptives (OCs) with levonorgestrel were at a threefold increased risk for confirmed venous thromboembolism (VTE), compared with women not taking any contraceptive pills, while users of OCs containing desogestrel, drospirenone, and gestodene saw a sixfold increased risk. The risk for drospirenone was seen as comparable to that of desogestrel and gestodene.
However, a lower dose of estrogen (20 mcg instead of 30 mcg) was not seen to lessen the risk associated with drospirenone-containing pills, the investigators found, while with desogestrel and gestodene, lower-estrogen preparations were associated with lower risk. (The OCs with desogestrel or gestodene and 20 mcg of ethinyl estradiol implied relative risks of VTE that were 23% and 17% lower, respectively, than the risks for the same progestogens with 30 mcg of ethinyl estradiol.)
The results, published online Oct. 25 in BMJ (doi: 10.1136/bmj.d6423), confirm those of a previous study by the same Denmark-based team of investigators, who in 2009 reported a significantly higher risk of VTE for OCs containing these three progestogens than for OCs with levonorgestrel (BMJ 2009;339:b2890 [doi: 10.1136/bmj.b2890]).
Both studies were led by Dr. Øjvind Lidegaard, professor of obstetrics and gynecology at the University of Copenhagen, and his colleagues, who used the same registry-based cohort of all Danish women aged 15-49 years with no history of VTE and who were not pregnant. The new study followed the women from 2001 to 2009, 4 years longer than the previous study (though their prescription information was collected from 1995), and the study collected more detailed information on OC use and VTE events.
During the study period, which comprised more than 8 million woman-years of observation, 4,246 first episodes of VTE occurred. After adjustment for age, calendar year, education, and length of OC use, the relative risk of VTE risk in women who used pills with desogestrel, drospirenone, or gestodene was found to be twice that of women on levonorgestrel-containing pills.
Dr. Lidegaard and his colleagues found that, compared with women not using hormonal contraception, the relative risk of confirmed VTE in users of OCs containing 30-40 mcg of ethinyl estradiol with levonorgestrel was 2.9 (95% confidence interval, 2.2-3.8), compared with 6.6 in women using OCs containing desogestrel (95% CI, 5.6-7.8), 6.2 in users of gestodene (5.6-7.0), and 6.4 in women taking drospirenone (5.4-7.5).
With users of OCs containing levonorgestrel as a reference, and after adjustment for length of use, the rate ratio of confirmed VTE for users of OCs with desogestrel was 2.2 (95% CI, 1.7-3.0), with gestodene it was 2.1 (95% CI, 1.6-2.8), and with drospirenone it was 2.1 (1.6-2.8).
To prevent one VTE per year, approximately 2,000 women would need to switch from a pill containing desogestrel, gestodene, or drospirenone to one with levonorgestrel, the researchers concluded.
Critics of Dr. Lidegaard and colleagues’ previous study, which revealed similar differences in risk between levonorgestrel and the newer progestogens, argued that because no declining risk was seen after the first few months of use for women using levonorgestrel-containing pills, as would be expected, left-censoring bias might have occurred, making the risk of VTE associated with levonorgestrel seem artificially low compared with that seen with drospirenone, which was introduced in 2001.
Dr. Lidegaard and his colleagues described several changes in their new study’s design to strengthen it, noting that they had eliminated left-censoring bias by letting the new study period begin in 2001, which marked the introduction of drospirenone-containing OCs in Denmark, but still collected the women’s full OC exposure history for the previous 6 years. They also defined length of OC use more precisely than in the previous study, stratified analyses into confirmed and unconfirmed VTE events, and better excluded women predisposed to VTE, they said.
The investigators acknowledged as a weakness of the study that they could not control for family disposition and body mass index. However, they noted, other studies had not shown a strong confounding effect for those factors even when data were available.
The study was commissioned by the European Medicines Agency. Bayer Schering Pharma covered the expenses of the analysis with payment to Dr. Lidegaard’s institution, though not to Dr. Lidegaard.
Dr. Lidegaard disclosed having received honoraria for speeches from Bayer Pharma Denmark and Novo Nordisk, and ongoing work as an expert witness for plaintiffs in a legal case in the United States. One of Dr. Lidegaard’s coauthors, Dr. Finn Egil Skjeldestad, acknowledged receiving compensation for his work on the steering committee of the European Medicines Agency report.
Oral contraceptives containing the newer progestogen types desogestrel, drospirenone, and gestodene have been associated with twice the risk of venous thromboembolism as those containing levonorgestrel, an older agent.
Women taking combination oral contraceptives (OCs) with levonorgestrel were at a threefold increased risk for confirmed venous thromboembolism (VTE), compared with women not taking any contraceptive pills, while users of OCs containing desogestrel, drospirenone, and gestodene saw a sixfold increased risk. The risk for drospirenone was seen as comparable to that of desogestrel and gestodene.
However, a lower dose of estrogen (20 mcg instead of 30 mcg) was not seen to lessen the risk associated with drospirenone-containing pills, the investigators found, while with desogestrel and gestodene, lower-estrogen preparations were associated with lower risk. (The OCs with desogestrel or gestodene and 20 mcg of ethinyl estradiol implied relative risks of VTE that were 23% and 17% lower, respectively, than the risks for the same progestogens with 30 mcg of ethinyl estradiol.)
The results, published online Oct. 25 in BMJ (doi: 10.1136/bmj.d6423), confirm those of a previous study by the same Denmark-based team of investigators, who in 2009 reported a significantly higher risk of VTE for OCs containing these three progestogens than for OCs with levonorgestrel (BMJ 2009;339:b2890 [doi: 10.1136/bmj.b2890]).
Both studies were led by Dr. Øjvind Lidegaard, professor of obstetrics and gynecology at the University of Copenhagen, and his colleagues, who used the same registry-based cohort of all Danish women aged 15-49 years with no history of VTE and who were not pregnant. The new study followed the women from 2001 to 2009, 4 years longer than the previous study (though their prescription information was collected from 1995), and the study collected more detailed information on OC use and VTE events.
During the study period, which comprised more than 8 million woman-years of observation, 4,246 first episodes of VTE occurred. After adjustment for age, calendar year, education, and length of OC use, the relative risk of VTE risk in women who used pills with desogestrel, drospirenone, or gestodene was found to be twice that of women on levonorgestrel-containing pills.
Dr. Lidegaard and his colleagues found that, compared with women not using hormonal contraception, the relative risk of confirmed VTE in users of OCs containing 30-40 mcg of ethinyl estradiol with levonorgestrel was 2.9 (95% confidence interval, 2.2-3.8), compared with 6.6 in women using OCs containing desogestrel (95% CI, 5.6-7.8), 6.2 in users of gestodene (5.6-7.0), and 6.4 in women taking drospirenone (5.4-7.5).
With users of OCs containing levonorgestrel as a reference, and after adjustment for length of use, the rate ratio of confirmed VTE for users of OCs with desogestrel was 2.2 (95% CI, 1.7-3.0), with gestodene it was 2.1 (95% CI, 1.6-2.8), and with drospirenone it was 2.1 (1.6-2.8).
To prevent one VTE per year, approximately 2,000 women would need to switch from a pill containing desogestrel, gestodene, or drospirenone to one with levonorgestrel, the researchers concluded.
Critics of Dr. Lidegaard and colleagues’ previous study, which revealed similar differences in risk between levonorgestrel and the newer progestogens, argued that because no declining risk was seen after the first few months of use for women using levonorgestrel-containing pills, as would be expected, left-censoring bias might have occurred, making the risk of VTE associated with levonorgestrel seem artificially low compared with that seen with drospirenone, which was introduced in 2001.
Dr. Lidegaard and his colleagues described several changes in their new study’s design to strengthen it, noting that they had eliminated left-censoring bias by letting the new study period begin in 2001, which marked the introduction of drospirenone-containing OCs in Denmark, but still collected the women’s full OC exposure history for the previous 6 years. They also defined length of OC use more precisely than in the previous study, stratified analyses into confirmed and unconfirmed VTE events, and better excluded women predisposed to VTE, they said.
The investigators acknowledged as a weakness of the study that they could not control for family disposition and body mass index. However, they noted, other studies had not shown a strong confounding effect for those factors even when data were available.
The study was commissioned by the European Medicines Agency. Bayer Schering Pharma covered the expenses of the analysis with payment to Dr. Lidegaard’s institution, though not to Dr. Lidegaard.
Dr. Lidegaard disclosed having received honoraria for speeches from Bayer Pharma Denmark and Novo Nordisk, and ongoing work as an expert witness for plaintiffs in a legal case in the United States. One of Dr. Lidegaard’s coauthors, Dr. Finn Egil Skjeldestad, acknowledged receiving compensation for his work on the steering committee of the European Medicines Agency report.
FROM BMJ
Major Finding: Combination oral contraceptives containing desogestrel, drospirenone, and gestodene are associated with twice the risk of first-time VTE as those containing levonorgestrel.
Data Source: A national health registry of all Danish women aged 15-49 years between 2001 and 2009, with prescription histories dating to 1995. The cohort represents more than 8 million woman-years of observation.
Disclosures: Dr. Lidegaard disclosed having received honoraria for speeches from Bayer Pharma Denmark and Novo Nordisk, and ongoing work as an expert witness for plaintiffs in a legal case in the United States. One of Dr. Lidegaard’s coauthors, Dr. Finn Egil Skjeldestad, acknowledged receiving compensation for his work on the steering committee of the European Medicines Agency report. Dr. Hannaford had no involvement in the study.
Registry Updates Blau Diagnostic Criteria
The 82 reported cases of Blau syndrome in the 6-year-old international registry are likely far from the entire catalog of affected children.
To be included in the registry, cases must involve the mutations in the nucleotide oligomerization domain 2 (NOD2) gene, a gene that is also involved in Crohn’s disease, according to Dr. Carlos Rosé, who maintains the registry along with his colleagues Tammy Martin, Ph.D., of the Casey Eye Institute at Oregon Health and Science University, Portland, and Dr. Carine Wouters of the Catholic University of Leuven (Belgium). An additional 100-plus patients have symptoms related to those seen in Blau patients, but do not have the NOD2 mutation.
Most clinicians "have never seen a case of Blau syndrome, or think they haven’t," said immunologist Dr. Martin, who with Dr. Rosé documented that Blau syndrome could occur sporadically through a germline mutation (J. Rheumatol. 2005;32:373-5).
Long believed to be strictly familial, Blau syndrome has been found to emerge sporadically from de novo mutations as well; such cases have sometimes been classified as early-onset sarcoidosis.
Blau – whether familial or sporadic – is by all measures rare. Dr. Martin said that she has introduced Blau families to one another, helping them share information, because "chances are that wherever they live, no one in their local community has Blau." Even Wikipedia’s Blau syndrome entry is classified as a "stub" awaiting further elaboration. Epidemiologic data on Blau are scarce, and are limited mostly to Denmark, although the disease occurs all around the world.
But new information on Blau is emerging rapidly, thanks in large part to the international registry. At the 18th European Pediatric Rheumatology Congress this fall in Bruges, Belgium, Dr. Rosé of the Alfred I. duPont Hospital for Children in Wilmington, Del. updated physicians on the newly expanded phenotype for Blau, which he published, along with Dr. Martin and Dr. Wouters in September (Curr. Opin. Rheumatol. 2011;23:411-8).
The international registry, established in 2005, has revealed that a substantial minority – up to one-third – of pediatric Blau patients also have systemic disease, which can include vasculitis; renal, hepatic, or lung involvement; and severe hypertension.
Clinical presentations in the registry vary broadly, from a girl in India with cardiomyopathy and aortoarteritis to a boy in Argentina with severe renal involvement. Fever is also now seen as a characteristic of Blau flare-ups. Little of this was known 6 years ago, according to Dr. Rosé.
But the registry also points to some consistencies, which should be heartening to pediatric rheumatologists who are presented with a possible Blau case. The triad of skin, joint, and eye involvement that was first described by pediatric nephrologist Edward Blau is still considered valid, although "it is a triad over time," which makes it less diagnostically helpful, Dr. Rosé said. For example, an ichthyosis-like rash in infancy may be a consistent feature of Blau, but it is also transient, and without a biopsy it will resemble common childhood rashes.
Rather, "bogginess of joints, familial history of the same phenotype, eye disease, and negative antinuclear antibodies [ANA] are the four bullets that should raise suspicion," Dr. Rosé said, noting that eye disease in juvenile idiopathic arthritis (JIA) is usually accompanied by positive ANA.
An unexplained fever – one that is "not periodic or hectic, [like those] you see in the autoinflammatory diseases" – should also be considered in the context of possible Blau, according to Dr. Rosé.
Dr. Rosé, who currently treats children in two unrelated families with Blau, has found that the inflammatory symptoms can be managed with infliximab, which is a TNF (tumor necrosis factor) inhibitor, and that other symptoms such as hypertension can generally be controlled with appropriate drugs. Infliximab is the most commonly used medication worldwide for Blau, he said.
Thalidomide, which targets a different signaling pathway than does a TNF inhibitor, was recently used by a Japanese team to treat Blau patients successfully (Arthritis Rheum. 2010;62:250-7). Dr. Rosé said he would be hesitant to try it, however, and didn’t know of clinicians outside Japan who had. "We’re a little nervous using thalidomide in children," he said.
Of all the Blau symptoms, uveitis is "by far the most problematic" to manage, said Dr. Rosé, who estimates that 60% of Blau patients will end up with eye disease.
Dr. Martin explained that the uveitis that occurs in Blau (compared with that in JIA and other rheumatic disorders) is typically "more severe, bilateral, and generally it involves the back of the eye," in addition to the front. Unlike JIA, the uveitis in Blau will not resolve spontaneously, which is why frequent monitoring is essential. And because it involves a different part of the eye, it cannot easily be treated with steroid drops.
Dr. Rosé said that he uses "a lot of oral prednisone" to combat uveitis in his Blau patients, and recommends that all Blau patients undergo a slit-lamp examination every 3 months. Although oral steroids are "not a solution," he said, "sometimes they are the only thing you can offer."
Dr. Martin has been studying an unusual family of uveitis patients and looking for clues to solve some of the many genetic mysteries Blau presents.
Asked to consult on a family with severe bilateral uveitis with onset in early adulthood instead of childhood and no arthritis or other symptoms of Blau, Dr. Martin subsequently found that the family has an NOD2 mutation that is slightly different from the mutation seen in most Blau cases.
Another family in the registry has incomplete penetrance; the father of an affected and mutation-positive child carried the same NOD2 mutation but never developed the disease (Arthritis Rheum. 2009:60:1804-6). "There’s some genetic or environmental modifier that’s quenching that NOD2 mutation," she said.
Finding it will entail deeper investigations into the NOD2 mutations, and other mutations that may produce Blau-like pathology. The 100-plus patients in the international registry who have Blau-like symptoms but lack NOD2 mutations may in fact have other, yet-undescribed syndromes that further genetic work may reveal.
"We’re finding so many new mutations," Dr. Martin said, as well as new sorts of disease within the registry. One small group in the registry presented atypical for Blau and had infantile panniculitis, along with fever, uveitis, and systemic granulomatous inflammation (J. Pediatr. 2007;151:707-9).
The finding suggests, Dr. Martin said, that the registry contains unknown diseases that are not truly Blau syndrome but that may be identified through genotyping, which "is starting to get cheap enough that we can do it for a reasonable amount of money."
The genetics, Dr. Martin said, are "helping us find that Blau," – whatever it is, and however it is ultimately defined – "may not be as rare as we thought."
At the same conference, Kevin Foley, Ph.D., a researcher at GlaxoSmithKline, presented new data on Blau biomarkers (Pediatric Rheumatology 2011, 9 [suppl. 1]:O25), which may prove helpful in developing agents targeting the NOD2 signaling pathway.
GlaxoSmithKline is investigating a medication – currently in preclinical testing – that inhibits RIP-2, one of the proteins involved in NOD2 signaling. The company is also funding a prospective cohort study, led by Dr. Rosé, that aims to describe the natural history of Blau from infancy and to isolate additional biomarkers of inflammation driven by hyperactive RIP-2.
John Bertin, Ph.D., head of GlaxoSmithKline’s pattern recognition receptor discovery unit, said in an interview that he hopes the Blau cohort "will provide information that will enable us to determine the feasibility of performing a clinical study in this patient population."
And because hyperactive RIP-2 signaling drives proinflammatory cytokine production in Crohn’s and ulcerative colitis, Dr. Bertin said, a RIP-2 inhibitor could offer promise treating those diseases as well.
Dr. Martin reported having no relevant financial disclosures. Dr. Rosé has an unrestricted grant to study Blau syndrome funded by GlaxoSmithKline and administered by the University of Leuven. Dr. Bertin and Dr. Foley are employees of GlaxoSmithKline.
The 82 reported cases of Blau syndrome in the 6-year-old international registry are likely far from the entire catalog of affected children.
To be included in the registry, cases must involve the mutations in the nucleotide oligomerization domain 2 (NOD2) gene, a gene that is also involved in Crohn’s disease, according to Dr. Carlos Rosé, who maintains the registry along with his colleagues Tammy Martin, Ph.D., of the Casey Eye Institute at Oregon Health and Science University, Portland, and Dr. Carine Wouters of the Catholic University of Leuven (Belgium). An additional 100-plus patients have symptoms related to those seen in Blau patients, but do not have the NOD2 mutation.
Most clinicians "have never seen a case of Blau syndrome, or think they haven’t," said immunologist Dr. Martin, who with Dr. Rosé documented that Blau syndrome could occur sporadically through a germline mutation (J. Rheumatol. 2005;32:373-5).
Long believed to be strictly familial, Blau syndrome has been found to emerge sporadically from de novo mutations as well; such cases have sometimes been classified as early-onset sarcoidosis.
Blau – whether familial or sporadic – is by all measures rare. Dr. Martin said that she has introduced Blau families to one another, helping them share information, because "chances are that wherever they live, no one in their local community has Blau." Even Wikipedia’s Blau syndrome entry is classified as a "stub" awaiting further elaboration. Epidemiologic data on Blau are scarce, and are limited mostly to Denmark, although the disease occurs all around the world.
But new information on Blau is emerging rapidly, thanks in large part to the international registry. At the 18th European Pediatric Rheumatology Congress this fall in Bruges, Belgium, Dr. Rosé of the Alfred I. duPont Hospital for Children in Wilmington, Del. updated physicians on the newly expanded phenotype for Blau, which he published, along with Dr. Martin and Dr. Wouters in September (Curr. Opin. Rheumatol. 2011;23:411-8).
The international registry, established in 2005, has revealed that a substantial minority – up to one-third – of pediatric Blau patients also have systemic disease, which can include vasculitis; renal, hepatic, or lung involvement; and severe hypertension.
Clinical presentations in the registry vary broadly, from a girl in India with cardiomyopathy and aortoarteritis to a boy in Argentina with severe renal involvement. Fever is also now seen as a characteristic of Blau flare-ups. Little of this was known 6 years ago, according to Dr. Rosé.
But the registry also points to some consistencies, which should be heartening to pediatric rheumatologists who are presented with a possible Blau case. The triad of skin, joint, and eye involvement that was first described by pediatric nephrologist Edward Blau is still considered valid, although "it is a triad over time," which makes it less diagnostically helpful, Dr. Rosé said. For example, an ichthyosis-like rash in infancy may be a consistent feature of Blau, but it is also transient, and without a biopsy it will resemble common childhood rashes.
Rather, "bogginess of joints, familial history of the same phenotype, eye disease, and negative antinuclear antibodies [ANA] are the four bullets that should raise suspicion," Dr. Rosé said, noting that eye disease in juvenile idiopathic arthritis (JIA) is usually accompanied by positive ANA.
An unexplained fever – one that is "not periodic or hectic, [like those] you see in the autoinflammatory diseases" – should also be considered in the context of possible Blau, according to Dr. Rosé.
Dr. Rosé, who currently treats children in two unrelated families with Blau, has found that the inflammatory symptoms can be managed with infliximab, which is a TNF (tumor necrosis factor) inhibitor, and that other symptoms such as hypertension can generally be controlled with appropriate drugs. Infliximab is the most commonly used medication worldwide for Blau, he said.
Thalidomide, which targets a different signaling pathway than does a TNF inhibitor, was recently used by a Japanese team to treat Blau patients successfully (Arthritis Rheum. 2010;62:250-7). Dr. Rosé said he would be hesitant to try it, however, and didn’t know of clinicians outside Japan who had. "We’re a little nervous using thalidomide in children," he said.
Of all the Blau symptoms, uveitis is "by far the most problematic" to manage, said Dr. Rosé, who estimates that 60% of Blau patients will end up with eye disease.
Dr. Martin explained that the uveitis that occurs in Blau (compared with that in JIA and other rheumatic disorders) is typically "more severe, bilateral, and generally it involves the back of the eye," in addition to the front. Unlike JIA, the uveitis in Blau will not resolve spontaneously, which is why frequent monitoring is essential. And because it involves a different part of the eye, it cannot easily be treated with steroid drops.
Dr. Rosé said that he uses "a lot of oral prednisone" to combat uveitis in his Blau patients, and recommends that all Blau patients undergo a slit-lamp examination every 3 months. Although oral steroids are "not a solution," he said, "sometimes they are the only thing you can offer."
Dr. Martin has been studying an unusual family of uveitis patients and looking for clues to solve some of the many genetic mysteries Blau presents.
Asked to consult on a family with severe bilateral uveitis with onset in early adulthood instead of childhood and no arthritis or other symptoms of Blau, Dr. Martin subsequently found that the family has an NOD2 mutation that is slightly different from the mutation seen in most Blau cases.
Another family in the registry has incomplete penetrance; the father of an affected and mutation-positive child carried the same NOD2 mutation but never developed the disease (Arthritis Rheum. 2009:60:1804-6). "There’s some genetic or environmental modifier that’s quenching that NOD2 mutation," she said.
Finding it will entail deeper investigations into the NOD2 mutations, and other mutations that may produce Blau-like pathology. The 100-plus patients in the international registry who have Blau-like symptoms but lack NOD2 mutations may in fact have other, yet-undescribed syndromes that further genetic work may reveal.
"We’re finding so many new mutations," Dr. Martin said, as well as new sorts of disease within the registry. One small group in the registry presented atypical for Blau and had infantile panniculitis, along with fever, uveitis, and systemic granulomatous inflammation (J. Pediatr. 2007;151:707-9).
The finding suggests, Dr. Martin said, that the registry contains unknown diseases that are not truly Blau syndrome but that may be identified through genotyping, which "is starting to get cheap enough that we can do it for a reasonable amount of money."
The genetics, Dr. Martin said, are "helping us find that Blau," – whatever it is, and however it is ultimately defined – "may not be as rare as we thought."
At the same conference, Kevin Foley, Ph.D., a researcher at GlaxoSmithKline, presented new data on Blau biomarkers (Pediatric Rheumatology 2011, 9 [suppl. 1]:O25), which may prove helpful in developing agents targeting the NOD2 signaling pathway.
GlaxoSmithKline is investigating a medication – currently in preclinical testing – that inhibits RIP-2, one of the proteins involved in NOD2 signaling. The company is also funding a prospective cohort study, led by Dr. Rosé, that aims to describe the natural history of Blau from infancy and to isolate additional biomarkers of inflammation driven by hyperactive RIP-2.
John Bertin, Ph.D., head of GlaxoSmithKline’s pattern recognition receptor discovery unit, said in an interview that he hopes the Blau cohort "will provide information that will enable us to determine the feasibility of performing a clinical study in this patient population."
And because hyperactive RIP-2 signaling drives proinflammatory cytokine production in Crohn’s and ulcerative colitis, Dr. Bertin said, a RIP-2 inhibitor could offer promise treating those diseases as well.
Dr. Martin reported having no relevant financial disclosures. Dr. Rosé has an unrestricted grant to study Blau syndrome funded by GlaxoSmithKline and administered by the University of Leuven. Dr. Bertin and Dr. Foley are employees of GlaxoSmithKline.
The 82 reported cases of Blau syndrome in the 6-year-old international registry are likely far from the entire catalog of affected children.
To be included in the registry, cases must involve the mutations in the nucleotide oligomerization domain 2 (NOD2) gene, a gene that is also involved in Crohn’s disease, according to Dr. Carlos Rosé, who maintains the registry along with his colleagues Tammy Martin, Ph.D., of the Casey Eye Institute at Oregon Health and Science University, Portland, and Dr. Carine Wouters of the Catholic University of Leuven (Belgium). An additional 100-plus patients have symptoms related to those seen in Blau patients, but do not have the NOD2 mutation.
Most clinicians "have never seen a case of Blau syndrome, or think they haven’t," said immunologist Dr. Martin, who with Dr. Rosé documented that Blau syndrome could occur sporadically through a germline mutation (J. Rheumatol. 2005;32:373-5).
Long believed to be strictly familial, Blau syndrome has been found to emerge sporadically from de novo mutations as well; such cases have sometimes been classified as early-onset sarcoidosis.
Blau – whether familial or sporadic – is by all measures rare. Dr. Martin said that she has introduced Blau families to one another, helping them share information, because "chances are that wherever they live, no one in their local community has Blau." Even Wikipedia’s Blau syndrome entry is classified as a "stub" awaiting further elaboration. Epidemiologic data on Blau are scarce, and are limited mostly to Denmark, although the disease occurs all around the world.
But new information on Blau is emerging rapidly, thanks in large part to the international registry. At the 18th European Pediatric Rheumatology Congress this fall in Bruges, Belgium, Dr. Rosé of the Alfred I. duPont Hospital for Children in Wilmington, Del. updated physicians on the newly expanded phenotype for Blau, which he published, along with Dr. Martin and Dr. Wouters in September (Curr. Opin. Rheumatol. 2011;23:411-8).
The international registry, established in 2005, has revealed that a substantial minority – up to one-third – of pediatric Blau patients also have systemic disease, which can include vasculitis; renal, hepatic, or lung involvement; and severe hypertension.
Clinical presentations in the registry vary broadly, from a girl in India with cardiomyopathy and aortoarteritis to a boy in Argentina with severe renal involvement. Fever is also now seen as a characteristic of Blau flare-ups. Little of this was known 6 years ago, according to Dr. Rosé.
But the registry also points to some consistencies, which should be heartening to pediatric rheumatologists who are presented with a possible Blau case. The triad of skin, joint, and eye involvement that was first described by pediatric nephrologist Edward Blau is still considered valid, although "it is a triad over time," which makes it less diagnostically helpful, Dr. Rosé said. For example, an ichthyosis-like rash in infancy may be a consistent feature of Blau, but it is also transient, and without a biopsy it will resemble common childhood rashes.
Rather, "bogginess of joints, familial history of the same phenotype, eye disease, and negative antinuclear antibodies [ANA] are the four bullets that should raise suspicion," Dr. Rosé said, noting that eye disease in juvenile idiopathic arthritis (JIA) is usually accompanied by positive ANA.
An unexplained fever – one that is "not periodic or hectic, [like those] you see in the autoinflammatory diseases" – should also be considered in the context of possible Blau, according to Dr. Rosé.
Dr. Rosé, who currently treats children in two unrelated families with Blau, has found that the inflammatory symptoms can be managed with infliximab, which is a TNF (tumor necrosis factor) inhibitor, and that other symptoms such as hypertension can generally be controlled with appropriate drugs. Infliximab is the most commonly used medication worldwide for Blau, he said.
Thalidomide, which targets a different signaling pathway than does a TNF inhibitor, was recently used by a Japanese team to treat Blau patients successfully (Arthritis Rheum. 2010;62:250-7). Dr. Rosé said he would be hesitant to try it, however, and didn’t know of clinicians outside Japan who had. "We’re a little nervous using thalidomide in children," he said.
Of all the Blau symptoms, uveitis is "by far the most problematic" to manage, said Dr. Rosé, who estimates that 60% of Blau patients will end up with eye disease.
Dr. Martin explained that the uveitis that occurs in Blau (compared with that in JIA and other rheumatic disorders) is typically "more severe, bilateral, and generally it involves the back of the eye," in addition to the front. Unlike JIA, the uveitis in Blau will not resolve spontaneously, which is why frequent monitoring is essential. And because it involves a different part of the eye, it cannot easily be treated with steroid drops.
Dr. Rosé said that he uses "a lot of oral prednisone" to combat uveitis in his Blau patients, and recommends that all Blau patients undergo a slit-lamp examination every 3 months. Although oral steroids are "not a solution," he said, "sometimes they are the only thing you can offer."
Dr. Martin has been studying an unusual family of uveitis patients and looking for clues to solve some of the many genetic mysteries Blau presents.
Asked to consult on a family with severe bilateral uveitis with onset in early adulthood instead of childhood and no arthritis or other symptoms of Blau, Dr. Martin subsequently found that the family has an NOD2 mutation that is slightly different from the mutation seen in most Blau cases.
Another family in the registry has incomplete penetrance; the father of an affected and mutation-positive child carried the same NOD2 mutation but never developed the disease (Arthritis Rheum. 2009:60:1804-6). "There’s some genetic or environmental modifier that’s quenching that NOD2 mutation," she said.
Finding it will entail deeper investigations into the NOD2 mutations, and other mutations that may produce Blau-like pathology. The 100-plus patients in the international registry who have Blau-like symptoms but lack NOD2 mutations may in fact have other, yet-undescribed syndromes that further genetic work may reveal.
"We’re finding so many new mutations," Dr. Martin said, as well as new sorts of disease within the registry. One small group in the registry presented atypical for Blau and had infantile panniculitis, along with fever, uveitis, and systemic granulomatous inflammation (J. Pediatr. 2007;151:707-9).
The finding suggests, Dr. Martin said, that the registry contains unknown diseases that are not truly Blau syndrome but that may be identified through genotyping, which "is starting to get cheap enough that we can do it for a reasonable amount of money."
The genetics, Dr. Martin said, are "helping us find that Blau," – whatever it is, and however it is ultimately defined – "may not be as rare as we thought."
At the same conference, Kevin Foley, Ph.D., a researcher at GlaxoSmithKline, presented new data on Blau biomarkers (Pediatric Rheumatology 2011, 9 [suppl. 1]:O25), which may prove helpful in developing agents targeting the NOD2 signaling pathway.
GlaxoSmithKline is investigating a medication – currently in preclinical testing – that inhibits RIP-2, one of the proteins involved in NOD2 signaling. The company is also funding a prospective cohort study, led by Dr. Rosé, that aims to describe the natural history of Blau from infancy and to isolate additional biomarkers of inflammation driven by hyperactive RIP-2.
John Bertin, Ph.D., head of GlaxoSmithKline’s pattern recognition receptor discovery unit, said in an interview that he hopes the Blau cohort "will provide information that will enable us to determine the feasibility of performing a clinical study in this patient population."
And because hyperactive RIP-2 signaling drives proinflammatory cytokine production in Crohn’s and ulcerative colitis, Dr. Bertin said, a RIP-2 inhibitor could offer promise treating those diseases as well.
Dr. Martin reported having no relevant financial disclosures. Dr. Rosé has an unrestricted grant to study Blau syndrome funded by GlaxoSmithKline and administered by the University of Leuven. Dr. Bertin and Dr. Foley are employees of GlaxoSmithKline.
EMA: No Cancer Link for ARBs
The European Medicines Agency said on Oct. 20 that it had completed a safety review seeking a possible link between angiotensin II receptor antagonists and increased cancer risk – and found none.
ARBs, which are used to treat hypertension, heart failure, diabetic nephropathy, and to reduce cardiovascular risk, have been authorized in the European Union since the 1990s.
The review was initiated at the request of the Italian Medicines Agency, the EMA said, following the June 2010 publication of a meta-analysis in the Lancet Oncology (doi:10.1016/S1470-2045(10)70106-6), which saw a 7% risk of new cancers, particularly lung cancers, among people taking ARBs. The authors of that study found the risk to be slightly lower – 6% – for people taking other types of heart medicines or no medicines.
The EMA said that it found aspects of the meta-analysis weak and noted "several problems with the quality of the data." Patients in the trials reviewed in the meta-analysis "were not followed-up for long enough to clearly establish a link between ARBs and cancer, information on the risk of cancer before start of treatment was lacking, and there was a possibility of publication bias," the EMA said in a news release.
The agency added that it had reviewed additional meta-analyses and population-based studies to confirm a lack of raised risk.
In a separate statement Oct. 20, EMA said that it had initiated a review of strontium ranelate–containing osteoporosis medicines, to better understand their risk-benefit profile.
The drugs are known to be associated with a raised risk of venous thromboembolism, and also drug rash with eosinophilia and systemic symptoms, or DRESS. Authors of a recent French study (Presse Med. 2011;40:e453-e62) concluded that the VTE risk might be reduced by adding a contraindication for patients with a history of VTE and by stopping treatment if a risk situation emerges. French authorities subsequently recommended restricting use of strontium ranelate to patients younger than 80 with high fracture risk who cannot take bisphosphanates.
EMA said that it would review these and other findings on the safety profile of strontium ranelate–containing medicines and decide whether the marketing authorizations for these medicines should be changed EU-wide.
The European Medicines Agency said on Oct. 20 that it had completed a safety review seeking a possible link between angiotensin II receptor antagonists and increased cancer risk – and found none.
ARBs, which are used to treat hypertension, heart failure, diabetic nephropathy, and to reduce cardiovascular risk, have been authorized in the European Union since the 1990s.
The review was initiated at the request of the Italian Medicines Agency, the EMA said, following the June 2010 publication of a meta-analysis in the Lancet Oncology (doi:10.1016/S1470-2045(10)70106-6), which saw a 7% risk of new cancers, particularly lung cancers, among people taking ARBs. The authors of that study found the risk to be slightly lower – 6% – for people taking other types of heart medicines or no medicines.
The EMA said that it found aspects of the meta-analysis weak and noted "several problems with the quality of the data." Patients in the trials reviewed in the meta-analysis "were not followed-up for long enough to clearly establish a link between ARBs and cancer, information on the risk of cancer before start of treatment was lacking, and there was a possibility of publication bias," the EMA said in a news release.
The agency added that it had reviewed additional meta-analyses and population-based studies to confirm a lack of raised risk.
In a separate statement Oct. 20, EMA said that it had initiated a review of strontium ranelate–containing osteoporosis medicines, to better understand their risk-benefit profile.
The drugs are known to be associated with a raised risk of venous thromboembolism, and also drug rash with eosinophilia and systemic symptoms, or DRESS. Authors of a recent French study (Presse Med. 2011;40:e453-e62) concluded that the VTE risk might be reduced by adding a contraindication for patients with a history of VTE and by stopping treatment if a risk situation emerges. French authorities subsequently recommended restricting use of strontium ranelate to patients younger than 80 with high fracture risk who cannot take bisphosphanates.
EMA said that it would review these and other findings on the safety profile of strontium ranelate–containing medicines and decide whether the marketing authorizations for these medicines should be changed EU-wide.
The European Medicines Agency said on Oct. 20 that it had completed a safety review seeking a possible link between angiotensin II receptor antagonists and increased cancer risk – and found none.
ARBs, which are used to treat hypertension, heart failure, diabetic nephropathy, and to reduce cardiovascular risk, have been authorized in the European Union since the 1990s.
The review was initiated at the request of the Italian Medicines Agency, the EMA said, following the June 2010 publication of a meta-analysis in the Lancet Oncology (doi:10.1016/S1470-2045(10)70106-6), which saw a 7% risk of new cancers, particularly lung cancers, among people taking ARBs. The authors of that study found the risk to be slightly lower – 6% – for people taking other types of heart medicines or no medicines.
The EMA said that it found aspects of the meta-analysis weak and noted "several problems with the quality of the data." Patients in the trials reviewed in the meta-analysis "were not followed-up for long enough to clearly establish a link between ARBs and cancer, information on the risk of cancer before start of treatment was lacking, and there was a possibility of publication bias," the EMA said in a news release.
The agency added that it had reviewed additional meta-analyses and population-based studies to confirm a lack of raised risk.
In a separate statement Oct. 20, EMA said that it had initiated a review of strontium ranelate–containing osteoporosis medicines, to better understand their risk-benefit profile.
The drugs are known to be associated with a raised risk of venous thromboembolism, and also drug rash with eosinophilia and systemic symptoms, or DRESS. Authors of a recent French study (Presse Med. 2011;40:e453-e62) concluded that the VTE risk might be reduced by adding a contraindication for patients with a history of VTE and by stopping treatment if a risk situation emerges. French authorities subsequently recommended restricting use of strontium ranelate to patients younger than 80 with high fracture risk who cannot take bisphosphanates.
EMA said that it would review these and other findings on the safety profile of strontium ranelate–containing medicines and decide whether the marketing authorizations for these medicines should be changed EU-wide.