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Phosphodiesterase-5 inhibitors often prescribed inappropriately
While most veterans with pulmonary hypertension are treated in accordance with clinical guidelines, almost two-thirds who are prescribed therapy are being treated with pulmonary vasodilators inappropriately, an analysis of veteran prescription data reveals.
Little was known about how pulmonary vasodilators were used in practice prior to the publication of this study. While pulmonary vasodilators are considered effective for group 1 pulmonary hypertension (PH), clinical guidelines and advice from the Choosing Wisely campaign recommend against their routine use for PH patients classified into the most common types of PH – groups 2 and 3 – because of a lack of benefit, potential for harm, and high cost, the authors wrote. The report was published in Annals of the American Thoracic Society.
The new analysis shows that patients with PH are potentially being exposed to unnecessary harm, according to study author Renda Soylemez Wiener, MD, MPH, of the Center for Healthcare Organization & Implementation Research at Bedford (Mass.) Veterans Affairs Medical Center, and her colleagues. Their findings also reveal that inappropriate prescribing of pulmonary vasodilators, mostly by specialist clinicians, is contributing to the financial burden of an already stretched health system.
The research team looked at prescription data for veterans prescribed a phosphodiesterase-5 inhibitor (PDE5i), which causes pulmonary vasodilation, between 2005 and 2012 at any VA site. The primary outcome of the study was the proportion of patients who received potentially inappropriate PDE5i as classified in guideline recommendations. Patients with group 1 PH were deemed to have been treated appropriately, while those with group 2 and 3 PH were deemed to have been potentially treated inappropriately. Those with groups 4 and 5 PH were thought to have received treatment of “uncertain value.”
In a chart abstraction analysis from a randomly selected subset of PDE5i-treated patients, half (110/230, 47.8% [41.3%-54.5%]) had documented right heart catheterization to confirm the presence of PH. After factoring this into their algorithm, the investigators determined that only 11.7% [8.0%-16.8%] of these patients received clearly appropriate treatment.
Over the 8-year study period, the number of patients with PH group 2 or 3 prescribed PDE5i rose more than 14-fold, the researchers said. They speculated that this figure was likely to continue to rise with the increasing use of echocardiography and detection of PH.
According to the authors, the cost of treating one PH patient for 1 year with PDE5i therapy was between $10,000 and $13,000.
The 1,711 PH patients classified as being treated inappropriately in the study translated into a cost of over $20 million, if each patient were treated for only 1 year, but many of the patients were treated for a longer period of time.
The researchers suggested that there were several reasons why clinicians might choose to deviate from the guidelines, including lacking familiarity with them or disagreeing with them.
“While guidelines do allow trials of PDE5i in treatment for groups 2 or 3 PH on a case-by-case basis after consultation with a PH expert and a confirmatory [right heart catheterization], even PH experts disagree about whether a trial of PDE5i therapy is reasonable and appropriate for patients with group 3 PH,” they wrote.
They may also overestimate the potential benefits of treatment and/or underestimate potential harm.
Clinicians may believe that guidelines developed for a general population do not apply to the patients they are treating.
“It is understandable why clinicians may offer unproven therapies like PDE5i in hopes of providing relief to very sick patients with groups 2 or 3 PH, especially if they do not believe the recommendation applies to their individual patient or they are not convinced about the potential harms of pulmonary vasodilators,” they said.
The authors expressed concern about VA clinicians’ allowing patients to take PDE5i therapy that had been initially prescribed by clinicians outside of VA hospitals. The researchers said such drugs, which potentially had been prescribed inappropriately, “were continued by VA clinicians without much apparent scrutiny.”
The chart abstraction analysis also showed that specialists prescribed the majority of potentially inappropriate PDE5i treatment, suggesting “that other interventions to prevent inappropriate use may be required.”
The researchers concluded that “[the] time has come to develop interventions to optimize prescribing for PH in order to improve the value, quality, and safety of care.”
One potential intervention suggested by the researchers was to require patients with PH to be evaluated at a PH expert center, as recommended by treatment guidelines.
The study was funded by the Department of Veterans Affairs with resources from the Edith Nourse Rogers Memorial VA Hospital. Elizabeth S. Klings, MD, one of the study’s authors, declared receiving research support from several pharmaceutical companies.
SOURCE: Wiener RS et al. Ann Am Thorac Soc. 2018 Feb 27. doi: 10.1513/AnnalsATS.201710-762OC.
While most veterans with pulmonary hypertension are treated in accordance with clinical guidelines, almost two-thirds who are prescribed therapy are being treated with pulmonary vasodilators inappropriately, an analysis of veteran prescription data reveals.
Little was known about how pulmonary vasodilators were used in practice prior to the publication of this study. While pulmonary vasodilators are considered effective for group 1 pulmonary hypertension (PH), clinical guidelines and advice from the Choosing Wisely campaign recommend against their routine use for PH patients classified into the most common types of PH – groups 2 and 3 – because of a lack of benefit, potential for harm, and high cost, the authors wrote. The report was published in Annals of the American Thoracic Society.
The new analysis shows that patients with PH are potentially being exposed to unnecessary harm, according to study author Renda Soylemez Wiener, MD, MPH, of the Center for Healthcare Organization & Implementation Research at Bedford (Mass.) Veterans Affairs Medical Center, and her colleagues. Their findings also reveal that inappropriate prescribing of pulmonary vasodilators, mostly by specialist clinicians, is contributing to the financial burden of an already stretched health system.
The research team looked at prescription data for veterans prescribed a phosphodiesterase-5 inhibitor (PDE5i), which causes pulmonary vasodilation, between 2005 and 2012 at any VA site. The primary outcome of the study was the proportion of patients who received potentially inappropriate PDE5i as classified in guideline recommendations. Patients with group 1 PH were deemed to have been treated appropriately, while those with group 2 and 3 PH were deemed to have been potentially treated inappropriately. Those with groups 4 and 5 PH were thought to have received treatment of “uncertain value.”
In a chart abstraction analysis from a randomly selected subset of PDE5i-treated patients, half (110/230, 47.8% [41.3%-54.5%]) had documented right heart catheterization to confirm the presence of PH. After factoring this into their algorithm, the investigators determined that only 11.7% [8.0%-16.8%] of these patients received clearly appropriate treatment.
Over the 8-year study period, the number of patients with PH group 2 or 3 prescribed PDE5i rose more than 14-fold, the researchers said. They speculated that this figure was likely to continue to rise with the increasing use of echocardiography and detection of PH.
According to the authors, the cost of treating one PH patient for 1 year with PDE5i therapy was between $10,000 and $13,000.
The 1,711 PH patients classified as being treated inappropriately in the study translated into a cost of over $20 million, if each patient were treated for only 1 year, but many of the patients were treated for a longer period of time.
The researchers suggested that there were several reasons why clinicians might choose to deviate from the guidelines, including lacking familiarity with them or disagreeing with them.
“While guidelines do allow trials of PDE5i in treatment for groups 2 or 3 PH on a case-by-case basis after consultation with a PH expert and a confirmatory [right heart catheterization], even PH experts disagree about whether a trial of PDE5i therapy is reasonable and appropriate for patients with group 3 PH,” they wrote.
They may also overestimate the potential benefits of treatment and/or underestimate potential harm.
Clinicians may believe that guidelines developed for a general population do not apply to the patients they are treating.
“It is understandable why clinicians may offer unproven therapies like PDE5i in hopes of providing relief to very sick patients with groups 2 or 3 PH, especially if they do not believe the recommendation applies to their individual patient or they are not convinced about the potential harms of pulmonary vasodilators,” they said.
The authors expressed concern about VA clinicians’ allowing patients to take PDE5i therapy that had been initially prescribed by clinicians outside of VA hospitals. The researchers said such drugs, which potentially had been prescribed inappropriately, “were continued by VA clinicians without much apparent scrutiny.”
The chart abstraction analysis also showed that specialists prescribed the majority of potentially inappropriate PDE5i treatment, suggesting “that other interventions to prevent inappropriate use may be required.”
The researchers concluded that “[the] time has come to develop interventions to optimize prescribing for PH in order to improve the value, quality, and safety of care.”
One potential intervention suggested by the researchers was to require patients with PH to be evaluated at a PH expert center, as recommended by treatment guidelines.
The study was funded by the Department of Veterans Affairs with resources from the Edith Nourse Rogers Memorial VA Hospital. Elizabeth S. Klings, MD, one of the study’s authors, declared receiving research support from several pharmaceutical companies.
SOURCE: Wiener RS et al. Ann Am Thorac Soc. 2018 Feb 27. doi: 10.1513/AnnalsATS.201710-762OC.
While most veterans with pulmonary hypertension are treated in accordance with clinical guidelines, almost two-thirds who are prescribed therapy are being treated with pulmonary vasodilators inappropriately, an analysis of veteran prescription data reveals.
Little was known about how pulmonary vasodilators were used in practice prior to the publication of this study. While pulmonary vasodilators are considered effective for group 1 pulmonary hypertension (PH), clinical guidelines and advice from the Choosing Wisely campaign recommend against their routine use for PH patients classified into the most common types of PH – groups 2 and 3 – because of a lack of benefit, potential for harm, and high cost, the authors wrote. The report was published in Annals of the American Thoracic Society.
The new analysis shows that patients with PH are potentially being exposed to unnecessary harm, according to study author Renda Soylemez Wiener, MD, MPH, of the Center for Healthcare Organization & Implementation Research at Bedford (Mass.) Veterans Affairs Medical Center, and her colleagues. Their findings also reveal that inappropriate prescribing of pulmonary vasodilators, mostly by specialist clinicians, is contributing to the financial burden of an already stretched health system.
The research team looked at prescription data for veterans prescribed a phosphodiesterase-5 inhibitor (PDE5i), which causes pulmonary vasodilation, between 2005 and 2012 at any VA site. The primary outcome of the study was the proportion of patients who received potentially inappropriate PDE5i as classified in guideline recommendations. Patients with group 1 PH were deemed to have been treated appropriately, while those with group 2 and 3 PH were deemed to have been potentially treated inappropriately. Those with groups 4 and 5 PH were thought to have received treatment of “uncertain value.”
In a chart abstraction analysis from a randomly selected subset of PDE5i-treated patients, half (110/230, 47.8% [41.3%-54.5%]) had documented right heart catheterization to confirm the presence of PH. After factoring this into their algorithm, the investigators determined that only 11.7% [8.0%-16.8%] of these patients received clearly appropriate treatment.
Over the 8-year study period, the number of patients with PH group 2 or 3 prescribed PDE5i rose more than 14-fold, the researchers said. They speculated that this figure was likely to continue to rise with the increasing use of echocardiography and detection of PH.
According to the authors, the cost of treating one PH patient for 1 year with PDE5i therapy was between $10,000 and $13,000.
The 1,711 PH patients classified as being treated inappropriately in the study translated into a cost of over $20 million, if each patient were treated for only 1 year, but many of the patients were treated for a longer period of time.
The researchers suggested that there were several reasons why clinicians might choose to deviate from the guidelines, including lacking familiarity with them or disagreeing with them.
“While guidelines do allow trials of PDE5i in treatment for groups 2 or 3 PH on a case-by-case basis after consultation with a PH expert and a confirmatory [right heart catheterization], even PH experts disagree about whether a trial of PDE5i therapy is reasonable and appropriate for patients with group 3 PH,” they wrote.
They may also overestimate the potential benefits of treatment and/or underestimate potential harm.
Clinicians may believe that guidelines developed for a general population do not apply to the patients they are treating.
“It is understandable why clinicians may offer unproven therapies like PDE5i in hopes of providing relief to very sick patients with groups 2 or 3 PH, especially if they do not believe the recommendation applies to their individual patient or they are not convinced about the potential harms of pulmonary vasodilators,” they said.
The authors expressed concern about VA clinicians’ allowing patients to take PDE5i therapy that had been initially prescribed by clinicians outside of VA hospitals. The researchers said such drugs, which potentially had been prescribed inappropriately, “were continued by VA clinicians without much apparent scrutiny.”
The chart abstraction analysis also showed that specialists prescribed the majority of potentially inappropriate PDE5i treatment, suggesting “that other interventions to prevent inappropriate use may be required.”
The researchers concluded that “[the] time has come to develop interventions to optimize prescribing for PH in order to improve the value, quality, and safety of care.”
One potential intervention suggested by the researchers was to require patients with PH to be evaluated at a PH expert center, as recommended by treatment guidelines.
The study was funded by the Department of Veterans Affairs with resources from the Edith Nourse Rogers Memorial VA Hospital. Elizabeth S. Klings, MD, one of the study’s authors, declared receiving research support from several pharmaceutical companies.
SOURCE: Wiener RS et al. Ann Am Thorac Soc. 2018 Feb 27. doi: 10.1513/AnnalsATS.201710-762OC.
FROM ANNALS OF THE AMERICAN THORACIC SOCIETY
Key clinical point: Inappropriate prescribing of phosphodiesterase-5 inhibitor (PDE5i) therapy has risen 14-fold in 8 years, at a cost of $20 million per year.
Major finding:
Study details: A retrospective analysis of veterans prescribed phosphodiesterase-5 inhibitors for pulmonary hypertension between 2005 and 2012.
Disclosures: The study was funded by the Department of Veterans Affairs with resources from the Edith Nourse Rogers Memorial Veterans Hospital. Elizabeth S. Klings, MD, one of the study’s authors, declared receiving research support from several pharmaceutical companies.
Source: Wiener RS et al. Ann Am Thorac Soc. 2018 Feb 27. doi: 10.1513/AnnalsATS.201710-762OC.
Product News: 03 2018
Avène TriXera
Pierre Fabre Dermo-Cosmetique launches the Avène TriXera line consisting of 3 products. The TriXera Nutrition Nutri-fluid Cleanser gently cleanses and nourishes dry to very dry, sensitive skin. TriXera Nutrition Nutri-fluid Lotion offers 48-hour hydration for dry, sensitive skin. These nourishing effects last up to 6 hours after application. TriXera Nutrition Nutri-fluid Balm has a fluidlike texture and also offers 48-hour hydration. All 3 products contain Avène Thermal Spring Water to soothe and soften as it restores the skin’s balance, as well as evening primrose oil and soy extract to rebuild the skin barrier and prevent moisture loss. For more information, visit www.aveneusa.com.
CoolSculpting
Allergan plc announces US Food and Drug Administration clearance for the CoolSculpting treatment, a nonsurgical fat reduction technology for improved appearance of lax tissue in conjunction with submental fat. CoolSculpting works by gently cooling targeted fat cells in the body to induce natural, controlled elimination of fat cells without affecting surrounding tissue. For more information, visit www.coolsculpting.com.
Discoloration Defense
SkinCeuticals introduces Discoloration Defense, a high-potency treatment serum that prevents and corrects multiple types of discoloration. This product contains tranexamic acid and niacinamide for pigmentation, hepes for hydration, and kojic acid to brighten skin and help to reduce the amount of melanin produced. These ingredients work together to help break up existing melanin clusters, inhibit the formation of melanocytes, and deactivate inflammatory mediators. The serum provides a reduction in visible and stubborn pigmentation for a revitalized and even complexion with refined texture and clarity. For more information, visit www.skinceuticals.com.
Eskata
Aclaris Therapeutics, Inc, announces US Food and Drug Administration approval of Eskata (hydrogen peroxide) topical solution 40% for the treatment of raised seborrheic keratoses. This product is a targeted, in-office treatment applied directly to raised seborrheic keratoses using a penlike applicator. Clinical studies showed clearing of seborrheic keratoses after 2 treatments. Eskata is expected to be commercially available in the spring of 2018. For more information, visit www.eskata.com.
Ixifi
Pfizer Inc announces US Food and Drug Administration approval of Ixifi (infliximab-qbtx), a chimeric human-murine monoclonal antibody against tumor necrosis factor, as a biosimilar to Remicade (infliximab) for all eligible indications of the reference product. Ixifi has been approved in the United States as a treatment for rheumatoid arthritis, Crohn disease, ulcerative colitis, psoriatic arthritis, and plaque psoriasis. For more information, visit www.pfizer.com.
Jemdel
Ortho Dermatologics announces US Food and Drug Administration acceptance of the New Drug Application for Jemdel (halobetasol propionate 0.01%), a high-potency topical steroid for the treatment of plaque psoriasis with dosing for as long as 8 weeks. Jemdel has a Prescription Drug User Fee Act action date of October 5, 2018. For more information, visit www.ortho-dermatologics.com.
Retin-A Micro
Ortho Dermatologics announces that Retin-A Micro (tretinoin) gel microsphere 0.06%, a topical treatment for acne vulgaris, will be available commercially to health care professionals. The US Food and Drug Administration previously approved the Supplemental New Drug Application for this product in October 2017. Retin-A Micro features a microsponge delivery system technology that helps control the release of tretinoin and improves photostability, even when used in conjunction with benzoyl peroxide. This product also features a pump delivery system for controlled dispensing and consistent dosing. Caution should be exercised when prescribing to eczema patients and nursing mothers. For more information, visit www.retinamicro.com.
If you would like your product included in Product News, please email a press release to the Editorial Office at cutis@frontlinemedcom.com.
Avène TriXera
Pierre Fabre Dermo-Cosmetique launches the Avène TriXera line consisting of 3 products. The TriXera Nutrition Nutri-fluid Cleanser gently cleanses and nourishes dry to very dry, sensitive skin. TriXera Nutrition Nutri-fluid Lotion offers 48-hour hydration for dry, sensitive skin. These nourishing effects last up to 6 hours after application. TriXera Nutrition Nutri-fluid Balm has a fluidlike texture and also offers 48-hour hydration. All 3 products contain Avène Thermal Spring Water to soothe and soften as it restores the skin’s balance, as well as evening primrose oil and soy extract to rebuild the skin barrier and prevent moisture loss. For more information, visit www.aveneusa.com.
CoolSculpting
Allergan plc announces US Food and Drug Administration clearance for the CoolSculpting treatment, a nonsurgical fat reduction technology for improved appearance of lax tissue in conjunction with submental fat. CoolSculpting works by gently cooling targeted fat cells in the body to induce natural, controlled elimination of fat cells without affecting surrounding tissue. For more information, visit www.coolsculpting.com.
Discoloration Defense
SkinCeuticals introduces Discoloration Defense, a high-potency treatment serum that prevents and corrects multiple types of discoloration. This product contains tranexamic acid and niacinamide for pigmentation, hepes for hydration, and kojic acid to brighten skin and help to reduce the amount of melanin produced. These ingredients work together to help break up existing melanin clusters, inhibit the formation of melanocytes, and deactivate inflammatory mediators. The serum provides a reduction in visible and stubborn pigmentation for a revitalized and even complexion with refined texture and clarity. For more information, visit www.skinceuticals.com.
Eskata
Aclaris Therapeutics, Inc, announces US Food and Drug Administration approval of Eskata (hydrogen peroxide) topical solution 40% for the treatment of raised seborrheic keratoses. This product is a targeted, in-office treatment applied directly to raised seborrheic keratoses using a penlike applicator. Clinical studies showed clearing of seborrheic keratoses after 2 treatments. Eskata is expected to be commercially available in the spring of 2018. For more information, visit www.eskata.com.
Ixifi
Pfizer Inc announces US Food and Drug Administration approval of Ixifi (infliximab-qbtx), a chimeric human-murine monoclonal antibody against tumor necrosis factor, as a biosimilar to Remicade (infliximab) for all eligible indications of the reference product. Ixifi has been approved in the United States as a treatment for rheumatoid arthritis, Crohn disease, ulcerative colitis, psoriatic arthritis, and plaque psoriasis. For more information, visit www.pfizer.com.
Jemdel
Ortho Dermatologics announces US Food and Drug Administration acceptance of the New Drug Application for Jemdel (halobetasol propionate 0.01%), a high-potency topical steroid for the treatment of plaque psoriasis with dosing for as long as 8 weeks. Jemdel has a Prescription Drug User Fee Act action date of October 5, 2018. For more information, visit www.ortho-dermatologics.com.
Retin-A Micro
Ortho Dermatologics announces that Retin-A Micro (tretinoin) gel microsphere 0.06%, a topical treatment for acne vulgaris, will be available commercially to health care professionals. The US Food and Drug Administration previously approved the Supplemental New Drug Application for this product in October 2017. Retin-A Micro features a microsponge delivery system technology that helps control the release of tretinoin and improves photostability, even when used in conjunction with benzoyl peroxide. This product also features a pump delivery system for controlled dispensing and consistent dosing. Caution should be exercised when prescribing to eczema patients and nursing mothers. For more information, visit www.retinamicro.com.
If you would like your product included in Product News, please email a press release to the Editorial Office at cutis@frontlinemedcom.com.
Avène TriXera
Pierre Fabre Dermo-Cosmetique launches the Avène TriXera line consisting of 3 products. The TriXera Nutrition Nutri-fluid Cleanser gently cleanses and nourishes dry to very dry, sensitive skin. TriXera Nutrition Nutri-fluid Lotion offers 48-hour hydration for dry, sensitive skin. These nourishing effects last up to 6 hours after application. TriXera Nutrition Nutri-fluid Balm has a fluidlike texture and also offers 48-hour hydration. All 3 products contain Avène Thermal Spring Water to soothe and soften as it restores the skin’s balance, as well as evening primrose oil and soy extract to rebuild the skin barrier and prevent moisture loss. For more information, visit www.aveneusa.com.
CoolSculpting
Allergan plc announces US Food and Drug Administration clearance for the CoolSculpting treatment, a nonsurgical fat reduction technology for improved appearance of lax tissue in conjunction with submental fat. CoolSculpting works by gently cooling targeted fat cells in the body to induce natural, controlled elimination of fat cells without affecting surrounding tissue. For more information, visit www.coolsculpting.com.
Discoloration Defense
SkinCeuticals introduces Discoloration Defense, a high-potency treatment serum that prevents and corrects multiple types of discoloration. This product contains tranexamic acid and niacinamide for pigmentation, hepes for hydration, and kojic acid to brighten skin and help to reduce the amount of melanin produced. These ingredients work together to help break up existing melanin clusters, inhibit the formation of melanocytes, and deactivate inflammatory mediators. The serum provides a reduction in visible and stubborn pigmentation for a revitalized and even complexion with refined texture and clarity. For more information, visit www.skinceuticals.com.
Eskata
Aclaris Therapeutics, Inc, announces US Food and Drug Administration approval of Eskata (hydrogen peroxide) topical solution 40% for the treatment of raised seborrheic keratoses. This product is a targeted, in-office treatment applied directly to raised seborrheic keratoses using a penlike applicator. Clinical studies showed clearing of seborrheic keratoses after 2 treatments. Eskata is expected to be commercially available in the spring of 2018. For more information, visit www.eskata.com.
Ixifi
Pfizer Inc announces US Food and Drug Administration approval of Ixifi (infliximab-qbtx), a chimeric human-murine monoclonal antibody against tumor necrosis factor, as a biosimilar to Remicade (infliximab) for all eligible indications of the reference product. Ixifi has been approved in the United States as a treatment for rheumatoid arthritis, Crohn disease, ulcerative colitis, psoriatic arthritis, and plaque psoriasis. For more information, visit www.pfizer.com.
Jemdel
Ortho Dermatologics announces US Food and Drug Administration acceptance of the New Drug Application for Jemdel (halobetasol propionate 0.01%), a high-potency topical steroid for the treatment of plaque psoriasis with dosing for as long as 8 weeks. Jemdel has a Prescription Drug User Fee Act action date of October 5, 2018. For more information, visit www.ortho-dermatologics.com.
Retin-A Micro
Ortho Dermatologics announces that Retin-A Micro (tretinoin) gel microsphere 0.06%, a topical treatment for acne vulgaris, will be available commercially to health care professionals. The US Food and Drug Administration previously approved the Supplemental New Drug Application for this product in October 2017. Retin-A Micro features a microsponge delivery system technology that helps control the release of tretinoin and improves photostability, even when used in conjunction with benzoyl peroxide. This product also features a pump delivery system for controlled dispensing and consistent dosing. Caution should be exercised when prescribing to eczema patients and nursing mothers. For more information, visit www.retinamicro.com.
If you would like your product included in Product News, please email a press release to the Editorial Office at cutis@frontlinemedcom.com.
U.S. adolescent malignant melanoma nearly halved during 2000-2014
SAN DIEGO – based on information from a National Cancer Institute database.
The substantial drop in new cases of malignant melanoma in Americans aged 10-19 years over the most recent 15-year period with data available contrasts with a stable rate among children aged 0-9 years, and a steadily rising rate among adults during the same period, Ryan C. Kelm said at the annual meeting of the American Academy of Dermatology.
Mr. Kelm and his associates studied U.S. data compiled from 2000 to 2014 by the SEER Program, maintained by the National Cancer Institute. They identified 1,796 patients aged 0-19 years diagnosed with malignant melanoma (218 children and 1,578 adolescents). The overall incidence rate for the entire 15-year period was just over 1 case per million among children and just under 9 cases per million among adolescents. In contrast, the adult U.S. incidence rate estimates for 2018 are pegged at 260 per million among non-Hispanic whites, 40 per million among Hispanics, and 10 per million among black Americans, according to the American Cancer Society.
An additional analysis showed a notable difference in incidence rates over the 15-year period studied, depending on age. In children aged 0-9 years, the annual incidence rate held roughly steady at just under 2 cases per million throughout the 15 years. But among adolescents, the rate fell over time, from about 10-12 cases per million during 2000-2004 to about 5-7 cases per million during 2010-2014. In 2001, the rate was about 11 cases per million, and in 2013, the rate was about 6 cases per million. This contrasts with the adult rate, which has “risen rapidly over the past 30 years,” according to the American Cancer Society’s 2018 report.
The SEER data also showed that distribution of melanoma histologic types differed by age. Among adolescents the most common identified form was “superficial spreading,” in 32%, with nodular in 6%, mixed epithelioid and spindle cell in 2%, and “not otherwise specified” in 54%. In children, the most commonly identified form was mixed epithelioid and spindle cell, in 10%, followed by nodular in 9%, and superficial spreading in 9%, with 63% not otherwise specified.
SOURCE: Kelm RC et al. AAD 18, Abstract 6722.
SAN DIEGO – based on information from a National Cancer Institute database.
The substantial drop in new cases of malignant melanoma in Americans aged 10-19 years over the most recent 15-year period with data available contrasts with a stable rate among children aged 0-9 years, and a steadily rising rate among adults during the same period, Ryan C. Kelm said at the annual meeting of the American Academy of Dermatology.
Mr. Kelm and his associates studied U.S. data compiled from 2000 to 2014 by the SEER Program, maintained by the National Cancer Institute. They identified 1,796 patients aged 0-19 years diagnosed with malignant melanoma (218 children and 1,578 adolescents). The overall incidence rate for the entire 15-year period was just over 1 case per million among children and just under 9 cases per million among adolescents. In contrast, the adult U.S. incidence rate estimates for 2018 are pegged at 260 per million among non-Hispanic whites, 40 per million among Hispanics, and 10 per million among black Americans, according to the American Cancer Society.
An additional analysis showed a notable difference in incidence rates over the 15-year period studied, depending on age. In children aged 0-9 years, the annual incidence rate held roughly steady at just under 2 cases per million throughout the 15 years. But among adolescents, the rate fell over time, from about 10-12 cases per million during 2000-2004 to about 5-7 cases per million during 2010-2014. In 2001, the rate was about 11 cases per million, and in 2013, the rate was about 6 cases per million. This contrasts with the adult rate, which has “risen rapidly over the past 30 years,” according to the American Cancer Society’s 2018 report.
The SEER data also showed that distribution of melanoma histologic types differed by age. Among adolescents the most common identified form was “superficial spreading,” in 32%, with nodular in 6%, mixed epithelioid and spindle cell in 2%, and “not otherwise specified” in 54%. In children, the most commonly identified form was mixed epithelioid and spindle cell, in 10%, followed by nodular in 9%, and superficial spreading in 9%, with 63% not otherwise specified.
SOURCE: Kelm RC et al. AAD 18, Abstract 6722.
SAN DIEGO – based on information from a National Cancer Institute database.
The substantial drop in new cases of malignant melanoma in Americans aged 10-19 years over the most recent 15-year period with data available contrasts with a stable rate among children aged 0-9 years, and a steadily rising rate among adults during the same period, Ryan C. Kelm said at the annual meeting of the American Academy of Dermatology.
Mr. Kelm and his associates studied U.S. data compiled from 2000 to 2014 by the SEER Program, maintained by the National Cancer Institute. They identified 1,796 patients aged 0-19 years diagnosed with malignant melanoma (218 children and 1,578 adolescents). The overall incidence rate for the entire 15-year period was just over 1 case per million among children and just under 9 cases per million among adolescents. In contrast, the adult U.S. incidence rate estimates for 2018 are pegged at 260 per million among non-Hispanic whites, 40 per million among Hispanics, and 10 per million among black Americans, according to the American Cancer Society.
An additional analysis showed a notable difference in incidence rates over the 15-year period studied, depending on age. In children aged 0-9 years, the annual incidence rate held roughly steady at just under 2 cases per million throughout the 15 years. But among adolescents, the rate fell over time, from about 10-12 cases per million during 2000-2004 to about 5-7 cases per million during 2010-2014. In 2001, the rate was about 11 cases per million, and in 2013, the rate was about 6 cases per million. This contrasts with the adult rate, which has “risen rapidly over the past 30 years,” according to the American Cancer Society’s 2018 report.
The SEER data also showed that distribution of melanoma histologic types differed by age. Among adolescents the most common identified form was “superficial spreading,” in 32%, with nodular in 6%, mixed epithelioid and spindle cell in 2%, and “not otherwise specified” in 54%. In children, the most commonly identified form was mixed epithelioid and spindle cell, in 10%, followed by nodular in 9%, and superficial spreading in 9%, with 63% not otherwise specified.
SOURCE: Kelm RC et al. AAD 18, Abstract 6722.
REPORTING FROM AAD 18
Key clinical point: U.S. incident malignant melanoma in adolescents dropped by nearly 50% during 2000-2014.
Major finding: Malignant melanoma occurred in about 11 adolescents per million in 2001 and about 6 per million in 2013.
Study details: Review of data collected in the SEER database of the National Cancer Institute.
Disclosures: Mr. Kelm had no disclosures.
Source: Kelm RC et al. AAD 18, Abstract 6722.
MDedge Daily News: Time to raise the bar on diabetes blood sugar levels
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
Is it time to raise the bar on diabetes blood sugar levels? Sudden cardiac death menaces young diabetes patients. There’s room for improvement in treating psoriatic arthritis. And the FDA chief chastises payers over high drug prices.
Listen to the MDedge Daily News podcast for all the details on today’s top news.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
Is it time to raise the bar on diabetes blood sugar levels? Sudden cardiac death menaces young diabetes patients. There’s room for improvement in treating psoriatic arthritis. And the FDA chief chastises payers over high drug prices.
Listen to the MDedge Daily News podcast for all the details on today’s top news.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
Is it time to raise the bar on diabetes blood sugar levels? Sudden cardiac death menaces young diabetes patients. There’s room for improvement in treating psoriatic arthritis. And the FDA chief chastises payers over high drug prices.
Listen to the MDedge Daily News podcast for all the details on today’s top news.
Windows to the Brain
“We were kind of astounded by this—it’s a very unrecognized phenomenon,” said Richard Leigh, MD, assistant clinical investigator at the National Institute of Neurological Disorders and Stroke (NINDS). Dr. Leigh and his co-researchers had discovered that gadolinium, used in brain scans for stroke patients, sometimes leaks into eyes—literally highlighting abnormalities. The finding could lead to more accurate stroke treatment.
The researchers performed MRI scans on 167 stroke patients on admission to the hospital without administering gadolinium and compared those scans to scans taken using gadolinium 2 hours and 24 hours later.
They found that the gadolinium made some eyes glow brightly, marking the location of brain damage. It appeared that the stroke could compromise the blood-ocular barrier. “It looks like the stroke is influencing the eye, and so the eye is reflective of what is going on in the brain,” said Dr. Leigh.
In about three-fourths of patients, gadolinium leaked into the eyes on 1 of the scans: 66% in the 2-hour scan (typically leaking in the aqueous chamber, in the front of the eye) and 75% in the 24-hour scan (typically in in the vitreous chamber, in the back of the eye).
Older patients, those with hypertension and those with brighter spots on their brain scans (associated with brain aging) were more likely to show gadolinium in the vitreous chamber at 24 hours. In a minority of patients, both eye chambers showed gadolinium at 2 hours. In those patients, stroke tended to affect a larger portion of the brain and cause more damage to the blood-brain barrier than did strokes in patients with a slower pattern of gadolinium leakage or no leakage. The researchers observed the phenomenon in both untreated patients and in those who received tPA.
The findings raise the possibility that clinicians could administer a substance to patients that would collect in the eye, like gadolinium, and quickly yield information about the stroke without the need for an MRI, the researchers say. “It’s much easier for us to look inside somebody’s eye than to look into somebody’s brain,” Dr. Leigh said. “So if the eye truly is a window to the brain, we can use one to learn about the other.”
“We were kind of astounded by this—it’s a very unrecognized phenomenon,” said Richard Leigh, MD, assistant clinical investigator at the National Institute of Neurological Disorders and Stroke (NINDS). Dr. Leigh and his co-researchers had discovered that gadolinium, used in brain scans for stroke patients, sometimes leaks into eyes—literally highlighting abnormalities. The finding could lead to more accurate stroke treatment.
The researchers performed MRI scans on 167 stroke patients on admission to the hospital without administering gadolinium and compared those scans to scans taken using gadolinium 2 hours and 24 hours later.
They found that the gadolinium made some eyes glow brightly, marking the location of brain damage. It appeared that the stroke could compromise the blood-ocular barrier. “It looks like the stroke is influencing the eye, and so the eye is reflective of what is going on in the brain,” said Dr. Leigh.
In about three-fourths of patients, gadolinium leaked into the eyes on 1 of the scans: 66% in the 2-hour scan (typically leaking in the aqueous chamber, in the front of the eye) and 75% in the 24-hour scan (typically in in the vitreous chamber, in the back of the eye).
Older patients, those with hypertension and those with brighter spots on their brain scans (associated with brain aging) were more likely to show gadolinium in the vitreous chamber at 24 hours. In a minority of patients, both eye chambers showed gadolinium at 2 hours. In those patients, stroke tended to affect a larger portion of the brain and cause more damage to the blood-brain barrier than did strokes in patients with a slower pattern of gadolinium leakage or no leakage. The researchers observed the phenomenon in both untreated patients and in those who received tPA.
The findings raise the possibility that clinicians could administer a substance to patients that would collect in the eye, like gadolinium, and quickly yield information about the stroke without the need for an MRI, the researchers say. “It’s much easier for us to look inside somebody’s eye than to look into somebody’s brain,” Dr. Leigh said. “So if the eye truly is a window to the brain, we can use one to learn about the other.”
“We were kind of astounded by this—it’s a very unrecognized phenomenon,” said Richard Leigh, MD, assistant clinical investigator at the National Institute of Neurological Disorders and Stroke (NINDS). Dr. Leigh and his co-researchers had discovered that gadolinium, used in brain scans for stroke patients, sometimes leaks into eyes—literally highlighting abnormalities. The finding could lead to more accurate stroke treatment.
The researchers performed MRI scans on 167 stroke patients on admission to the hospital without administering gadolinium and compared those scans to scans taken using gadolinium 2 hours and 24 hours later.
They found that the gadolinium made some eyes glow brightly, marking the location of brain damage. It appeared that the stroke could compromise the blood-ocular barrier. “It looks like the stroke is influencing the eye, and so the eye is reflective of what is going on in the brain,” said Dr. Leigh.
In about three-fourths of patients, gadolinium leaked into the eyes on 1 of the scans: 66% in the 2-hour scan (typically leaking in the aqueous chamber, in the front of the eye) and 75% in the 24-hour scan (typically in in the vitreous chamber, in the back of the eye).
Older patients, those with hypertension and those with brighter spots on their brain scans (associated with brain aging) were more likely to show gadolinium in the vitreous chamber at 24 hours. In a minority of patients, both eye chambers showed gadolinium at 2 hours. In those patients, stroke tended to affect a larger portion of the brain and cause more damage to the blood-brain barrier than did strokes in patients with a slower pattern of gadolinium leakage or no leakage. The researchers observed the phenomenon in both untreated patients and in those who received tPA.
The findings raise the possibility that clinicians could administer a substance to patients that would collect in the eye, like gadolinium, and quickly yield information about the stroke without the need for an MRI, the researchers say. “It’s much easier for us to look inside somebody’s eye than to look into somebody’s brain,” Dr. Leigh said. “So if the eye truly is a window to the brain, we can use one to learn about the other.”
CCSs have greater risk of cardiovascular disease
Childhood cancer survivors (CCSs) have an increased risk of premature cardiovascular disease in adulthood, according to a new study.
Researchers found a nearly 2-fold increased risk of cardiovascular diseases in CCSs compared to the general population.
Cardiovascular disease was identified in 4.5% of CCSs and occurred in most before they reached the age of 40, nearly 8 years earlier than in the general population.
“Our results show that these survivors of childhood cancer have a substantially elevated burden of prematurely occurring traditional cardiovascular risk factors and cardiovascular diseases,” said study author Joerg Faber, MD, PhD, of the Johannes Gutenberg University Mainz in Germany.
Dr Faber and his colleagues reported these results in the European Heart Journal.
The researchers evaluated 951 adult CCSs (ages 23 to 48), referred to as the CVSS cohort (Cardiac and Vascular Late Sequelae in Long-Term Survivors of Childhood Cancer Study).
The patients had been diagnosed with cancer between 1980 and 1990. The most common diagnoses were leukemia (43.5%), central nervous system tumors (12.8%), and lymphoma (9.9%).
For this study, the patients underwent standardized clinical and laboratory cardiovascular screening. The mean time from cancer diagnosis to cardiovascular screening was 28.4 years (range, 23–36).
The researchers compared the incidence of cardiovascular risk factors and cardiovascular disease in the CVSS cohort and subjects from the Gutenberg Health Study (GHS), a population-based study including more than 15,000 subjects.
Risk factors
The CVSS cohort had a greater risk of 2 cardiovascular risk factors—arterial hypertension and dyslipidemia—than the GHS cohort. In the CVSS cohort, the incidence of dyslipidemia was 28.3%, and the incidence of hypertension was 23.0%.
CVSS subjects had an age-adjusted 38% increase in risk for hypertension (relative risk [RR]=1.38) and a 26% increase in risk for dyslipidemia (RR=1.26).
Hypertension occurred about 6 years earlier in CVSS subjects than GHS subjects (rate advancement period estimator [RAP]=5.75). And dyslipidemia occurred about 8 years earlier in the CVSS cohort (RAP=8.16).
“[T]he premature onset of high blood pressure and blood lipid disorders may play an important role in the development of severe cardiovascular conditions, such as heart disease and stroke, in the long-term,” said study author Philipp S. Wild, MD, of the German Center for Cardiovascular Research (DZHK) in Mainz, Germany.
“We also found that a remarkable number [of CVSS subjects] attended their clinical examination for this study with previously unidentified cardiovascular risk factors and cardiovascular disease. For example, only 62 out of 269 were aware of having dyslipidemia. Consequently, 207, approximately 80%, were only diagnosed at that point.”
Disease
In the CVSS cohort, 4.5% of patients had at least 1 type of cardiovascular disease. This included venous thromboembolism (2.0%), congestive heart failure (1.2%), stroke (0.5%), peripheral artery disease (0.5%), atrial fibrillation (0.4%), and coronary heart disease (0.3%).
CVSS subjects had nearly twice the risk of cardiovascular disease as GHS subjects. The age-adjusted RR was 1.89. And CVSS subjects developed cardiovascular disease roughly 8 years earlier than GHS subjects (RAP=7.9).
In the CVSS cohort, the probability of developing cardiovascular disease was estimated as 2.9% at age 30 and 9.6% at age 45.
The researchers said these findings show that CCSs have a greater risk of cardiovascular disease that continues to increase with age. This, in turn, means CCSs may be more likely to die earlier. However, this might be preventable, according to Dr Wild.
“Early systematic screening, particularly focusing on blood pressure and lipid measurements, might be suggested in all childhood cancer survivors irrespective of the type of cancer or treatment they had had,” Dr Wild said. “This might help to prevent long-term cardiovascular diseases by intervening early—for instance, by modifying lifestyles and having treatment for high blood pressure.”
“Usually, survivors are followed for only 5 to 10 years after completion of therapy, and this is focused on the risk of the cancer returning and the acute adverse effects of their treatment, rather than on other conditions,” added Dr Faber.
“Current guidelines recommend cardiovascular assessments only for subgroups known to be at risk, such as for patients who were treated with anthracycline therapy and/or radiation therapy. However, further investigations are needed to answer questions about the best follow-up care.”
Childhood cancer survivors (CCSs) have an increased risk of premature cardiovascular disease in adulthood, according to a new study.
Researchers found a nearly 2-fold increased risk of cardiovascular diseases in CCSs compared to the general population.
Cardiovascular disease was identified in 4.5% of CCSs and occurred in most before they reached the age of 40, nearly 8 years earlier than in the general population.
“Our results show that these survivors of childhood cancer have a substantially elevated burden of prematurely occurring traditional cardiovascular risk factors and cardiovascular diseases,” said study author Joerg Faber, MD, PhD, of the Johannes Gutenberg University Mainz in Germany.
Dr Faber and his colleagues reported these results in the European Heart Journal.
The researchers evaluated 951 adult CCSs (ages 23 to 48), referred to as the CVSS cohort (Cardiac and Vascular Late Sequelae in Long-Term Survivors of Childhood Cancer Study).
The patients had been diagnosed with cancer between 1980 and 1990. The most common diagnoses were leukemia (43.5%), central nervous system tumors (12.8%), and lymphoma (9.9%).
For this study, the patients underwent standardized clinical and laboratory cardiovascular screening. The mean time from cancer diagnosis to cardiovascular screening was 28.4 years (range, 23–36).
The researchers compared the incidence of cardiovascular risk factors and cardiovascular disease in the CVSS cohort and subjects from the Gutenberg Health Study (GHS), a population-based study including more than 15,000 subjects.
Risk factors
The CVSS cohort had a greater risk of 2 cardiovascular risk factors—arterial hypertension and dyslipidemia—than the GHS cohort. In the CVSS cohort, the incidence of dyslipidemia was 28.3%, and the incidence of hypertension was 23.0%.
CVSS subjects had an age-adjusted 38% increase in risk for hypertension (relative risk [RR]=1.38) and a 26% increase in risk for dyslipidemia (RR=1.26).
Hypertension occurred about 6 years earlier in CVSS subjects than GHS subjects (rate advancement period estimator [RAP]=5.75). And dyslipidemia occurred about 8 years earlier in the CVSS cohort (RAP=8.16).
“[T]he premature onset of high blood pressure and blood lipid disorders may play an important role in the development of severe cardiovascular conditions, such as heart disease and stroke, in the long-term,” said study author Philipp S. Wild, MD, of the German Center for Cardiovascular Research (DZHK) in Mainz, Germany.
“We also found that a remarkable number [of CVSS subjects] attended their clinical examination for this study with previously unidentified cardiovascular risk factors and cardiovascular disease. For example, only 62 out of 269 were aware of having dyslipidemia. Consequently, 207, approximately 80%, were only diagnosed at that point.”
Disease
In the CVSS cohort, 4.5% of patients had at least 1 type of cardiovascular disease. This included venous thromboembolism (2.0%), congestive heart failure (1.2%), stroke (0.5%), peripheral artery disease (0.5%), atrial fibrillation (0.4%), and coronary heart disease (0.3%).
CVSS subjects had nearly twice the risk of cardiovascular disease as GHS subjects. The age-adjusted RR was 1.89. And CVSS subjects developed cardiovascular disease roughly 8 years earlier than GHS subjects (RAP=7.9).
In the CVSS cohort, the probability of developing cardiovascular disease was estimated as 2.9% at age 30 and 9.6% at age 45.
The researchers said these findings show that CCSs have a greater risk of cardiovascular disease that continues to increase with age. This, in turn, means CCSs may be more likely to die earlier. However, this might be preventable, according to Dr Wild.
“Early systematic screening, particularly focusing on blood pressure and lipid measurements, might be suggested in all childhood cancer survivors irrespective of the type of cancer or treatment they had had,” Dr Wild said. “This might help to prevent long-term cardiovascular diseases by intervening early—for instance, by modifying lifestyles and having treatment for high blood pressure.”
“Usually, survivors are followed for only 5 to 10 years after completion of therapy, and this is focused on the risk of the cancer returning and the acute adverse effects of their treatment, rather than on other conditions,” added Dr Faber.
“Current guidelines recommend cardiovascular assessments only for subgroups known to be at risk, such as for patients who were treated with anthracycline therapy and/or radiation therapy. However, further investigations are needed to answer questions about the best follow-up care.”
Childhood cancer survivors (CCSs) have an increased risk of premature cardiovascular disease in adulthood, according to a new study.
Researchers found a nearly 2-fold increased risk of cardiovascular diseases in CCSs compared to the general population.
Cardiovascular disease was identified in 4.5% of CCSs and occurred in most before they reached the age of 40, nearly 8 years earlier than in the general population.
“Our results show that these survivors of childhood cancer have a substantially elevated burden of prematurely occurring traditional cardiovascular risk factors and cardiovascular diseases,” said study author Joerg Faber, MD, PhD, of the Johannes Gutenberg University Mainz in Germany.
Dr Faber and his colleagues reported these results in the European Heart Journal.
The researchers evaluated 951 adult CCSs (ages 23 to 48), referred to as the CVSS cohort (Cardiac and Vascular Late Sequelae in Long-Term Survivors of Childhood Cancer Study).
The patients had been diagnosed with cancer between 1980 and 1990. The most common diagnoses were leukemia (43.5%), central nervous system tumors (12.8%), and lymphoma (9.9%).
For this study, the patients underwent standardized clinical and laboratory cardiovascular screening. The mean time from cancer diagnosis to cardiovascular screening was 28.4 years (range, 23–36).
The researchers compared the incidence of cardiovascular risk factors and cardiovascular disease in the CVSS cohort and subjects from the Gutenberg Health Study (GHS), a population-based study including more than 15,000 subjects.
Risk factors
The CVSS cohort had a greater risk of 2 cardiovascular risk factors—arterial hypertension and dyslipidemia—than the GHS cohort. In the CVSS cohort, the incidence of dyslipidemia was 28.3%, and the incidence of hypertension was 23.0%.
CVSS subjects had an age-adjusted 38% increase in risk for hypertension (relative risk [RR]=1.38) and a 26% increase in risk for dyslipidemia (RR=1.26).
Hypertension occurred about 6 years earlier in CVSS subjects than GHS subjects (rate advancement period estimator [RAP]=5.75). And dyslipidemia occurred about 8 years earlier in the CVSS cohort (RAP=8.16).
“[T]he premature onset of high blood pressure and blood lipid disorders may play an important role in the development of severe cardiovascular conditions, such as heart disease and stroke, in the long-term,” said study author Philipp S. Wild, MD, of the German Center for Cardiovascular Research (DZHK) in Mainz, Germany.
“We also found that a remarkable number [of CVSS subjects] attended their clinical examination for this study with previously unidentified cardiovascular risk factors and cardiovascular disease. For example, only 62 out of 269 were aware of having dyslipidemia. Consequently, 207, approximately 80%, were only diagnosed at that point.”
Disease
In the CVSS cohort, 4.5% of patients had at least 1 type of cardiovascular disease. This included venous thromboembolism (2.0%), congestive heart failure (1.2%), stroke (0.5%), peripheral artery disease (0.5%), atrial fibrillation (0.4%), and coronary heart disease (0.3%).
CVSS subjects had nearly twice the risk of cardiovascular disease as GHS subjects. The age-adjusted RR was 1.89. And CVSS subjects developed cardiovascular disease roughly 8 years earlier than GHS subjects (RAP=7.9).
In the CVSS cohort, the probability of developing cardiovascular disease was estimated as 2.9% at age 30 and 9.6% at age 45.
The researchers said these findings show that CCSs have a greater risk of cardiovascular disease that continues to increase with age. This, in turn, means CCSs may be more likely to die earlier. However, this might be preventable, according to Dr Wild.
“Early systematic screening, particularly focusing on blood pressure and lipid measurements, might be suggested in all childhood cancer survivors irrespective of the type of cancer or treatment they had had,” Dr Wild said. “This might help to prevent long-term cardiovascular diseases by intervening early—for instance, by modifying lifestyles and having treatment for high blood pressure.”
“Usually, survivors are followed for only 5 to 10 years after completion of therapy, and this is focused on the risk of the cancer returning and the acute adverse effects of their treatment, rather than on other conditions,” added Dr Faber.
“Current guidelines recommend cardiovascular assessments only for subgroups known to be at risk, such as for patients who were treated with anthracycline therapy and/or radiation therapy. However, further investigations are needed to answer questions about the best follow-up care.”
Team targets transcription factor in AML
Researchers say they have discovered a way to target the transcription factor MEF2C in acute myeloid leukemia (AML).
The team found they could stop the growth of MEF2C-driven AML cells by blocking either LKB1 or the salt-inducible kinases SIK3 and SIK2.
Christopher Vakoc, MD, PhD, of Cold Spring Harbor Laboratory in Cold Spring Harbor, New York, and his colleagues described this research in Molecular Cell.
The current discoveries are the result of a broad search for potential therapeutic strategies against AML that began several years ago in Dr Vakoc’s lab.
In 2013, his team devised a system based on CRISPR gene editing tools. They used this system to screen large numbers of genes, seeking to discover their impact on cancer cell survival.
Now, the system has revealed that LKB1 and SIK are critical for the survival of certain AML cells. These enzymes had not previously been linked to AML, but the researchers learned that LKB1 and SIK help control MEF2C.
The team observed overlapping LKB1, SIK, and MEF2C dependencies in AML cell lines, particularly MLL fusion lines (MOLM-13, MV4-11, NOMO-1, and THP-1). And the researchers found the transcriptional output of MEF2C could be suppressed by inhibition of LKB1 or SIK.
“At the end of project, we realized we’d actually discovered a way to control a transcription factor,” Dr Vakoc said.
He and his colleagues found that SIK3 inactivation had the strongest effect on MEF2C. Two hours of exposure to the SIK inhibitor HG-9-91-01 (100 nM) was enough to suppress the MEF2C signature.
The researchers also noted that the effect of SIK3 targeting on transcription was attenuated if it was performed in cells deficient in HDAC4. This and related findings suggested that LKB1-SIK3 signaling supports the transcriptional output of MEF2C through inhibition of HDAC4.
Dr Vakoc and his colleagues said the “potency and selectivity of AML growth arrest” they observed after targeting LKB1 or SIK2 and SIK3 resembles the effects of targeting other validated kinase oncogenes in AML, such as FLT3.
The team also said the sensitivity of AML cell lines to HG-9-91-01 “compares favorably” to the sensitivity of cancer cell lines to kinase inhibitors already approved for oncology indications. However, “additional optimization” of HG-9-91-01 is needed.
Researchers say they have discovered a way to target the transcription factor MEF2C in acute myeloid leukemia (AML).
The team found they could stop the growth of MEF2C-driven AML cells by blocking either LKB1 or the salt-inducible kinases SIK3 and SIK2.
Christopher Vakoc, MD, PhD, of Cold Spring Harbor Laboratory in Cold Spring Harbor, New York, and his colleagues described this research in Molecular Cell.
The current discoveries are the result of a broad search for potential therapeutic strategies against AML that began several years ago in Dr Vakoc’s lab.
In 2013, his team devised a system based on CRISPR gene editing tools. They used this system to screen large numbers of genes, seeking to discover their impact on cancer cell survival.
Now, the system has revealed that LKB1 and SIK are critical for the survival of certain AML cells. These enzymes had not previously been linked to AML, but the researchers learned that LKB1 and SIK help control MEF2C.
The team observed overlapping LKB1, SIK, and MEF2C dependencies in AML cell lines, particularly MLL fusion lines (MOLM-13, MV4-11, NOMO-1, and THP-1). And the researchers found the transcriptional output of MEF2C could be suppressed by inhibition of LKB1 or SIK.
“At the end of project, we realized we’d actually discovered a way to control a transcription factor,” Dr Vakoc said.
He and his colleagues found that SIK3 inactivation had the strongest effect on MEF2C. Two hours of exposure to the SIK inhibitor HG-9-91-01 (100 nM) was enough to suppress the MEF2C signature.
The researchers also noted that the effect of SIK3 targeting on transcription was attenuated if it was performed in cells deficient in HDAC4. This and related findings suggested that LKB1-SIK3 signaling supports the transcriptional output of MEF2C through inhibition of HDAC4.
Dr Vakoc and his colleagues said the “potency and selectivity of AML growth arrest” they observed after targeting LKB1 or SIK2 and SIK3 resembles the effects of targeting other validated kinase oncogenes in AML, such as FLT3.
The team also said the sensitivity of AML cell lines to HG-9-91-01 “compares favorably” to the sensitivity of cancer cell lines to kinase inhibitors already approved for oncology indications. However, “additional optimization” of HG-9-91-01 is needed.
Researchers say they have discovered a way to target the transcription factor MEF2C in acute myeloid leukemia (AML).
The team found they could stop the growth of MEF2C-driven AML cells by blocking either LKB1 or the salt-inducible kinases SIK3 and SIK2.
Christopher Vakoc, MD, PhD, of Cold Spring Harbor Laboratory in Cold Spring Harbor, New York, and his colleagues described this research in Molecular Cell.
The current discoveries are the result of a broad search for potential therapeutic strategies against AML that began several years ago in Dr Vakoc’s lab.
In 2013, his team devised a system based on CRISPR gene editing tools. They used this system to screen large numbers of genes, seeking to discover their impact on cancer cell survival.
Now, the system has revealed that LKB1 and SIK are critical for the survival of certain AML cells. These enzymes had not previously been linked to AML, but the researchers learned that LKB1 and SIK help control MEF2C.
The team observed overlapping LKB1, SIK, and MEF2C dependencies in AML cell lines, particularly MLL fusion lines (MOLM-13, MV4-11, NOMO-1, and THP-1). And the researchers found the transcriptional output of MEF2C could be suppressed by inhibition of LKB1 or SIK.
“At the end of project, we realized we’d actually discovered a way to control a transcription factor,” Dr Vakoc said.
He and his colleagues found that SIK3 inactivation had the strongest effect on MEF2C. Two hours of exposure to the SIK inhibitor HG-9-91-01 (100 nM) was enough to suppress the MEF2C signature.
The researchers also noted that the effect of SIK3 targeting on transcription was attenuated if it was performed in cells deficient in HDAC4. This and related findings suggested that LKB1-SIK3 signaling supports the transcriptional output of MEF2C through inhibition of HDAC4.
Dr Vakoc and his colleagues said the “potency and selectivity of AML growth arrest” they observed after targeting LKB1 or SIK2 and SIK3 resembles the effects of targeting other validated kinase oncogenes in AML, such as FLT3.
The team also said the sensitivity of AML cell lines to HG-9-91-01 “compares favorably” to the sensitivity of cancer cell lines to kinase inhibitors already approved for oncology indications. However, “additional optimization” of HG-9-91-01 is needed.
Clinical trial registries don’t match up
A new study has revealed discrepancies in completion status for trials listed on ClinicalTrials.gov and the EU Clinical Trials Register (EUCTR).
Researchers evaluated nearly 10,500 trials listed on both registries and found that roughly 16% of them were marked as “completed” on one registry and “ongoing” on the other.
Most of these (91%) were listed as “ongoing” on EUCTR but “completed” on ClinicalTrials.gov.
“Trial registries are important public documents,” said Ben Goldacre, of the University of Oxford in the UK.
“Doctors, researchers, and patients rely on the information that trialists post about their clinical trial. Concerningly, we now show that this data is commonly inaccurate.”
Goldacre and his colleague, Jessica Fleminger, also from the University of Oxford, reported these findings in PLOS ONE.
The researchers looked at 10,492 clinical trials that were registered on both ClinicalTrials.gov and EUCTR.
For most of these trials (83.8%, n=8794), completion status was the same on both registries. But there were 1698 trials (16.2%) that were listed as “completed” on one registry and “ongoing” on another.
A majority of the discrepant trials (90.5%, n=1536) were “ongoing” on EUCTR and “complete” on ClinicalTrials.gov.
Overall, 43.1% (4530/10,492) of dual-registered trials were listed as “ongoing” on EUCTR, and 33.9% of these (1536/4530) were listed as “completed” on ClinicalTrials.gov.
Thirty percent (3156/10,492) of dual-registered trials were marked as “ongoing” on ClinicalTrials.gov, and 5.1% (162/3156) of these were marked as “completed” on EUCTR.
Goldacre and Fleminger said it is unclear whether researchers, registry owners, or both are responsible for these errors. Regardless, researchers identifying discrepancies should request clarifications from the trialists, and registry owners should undertake simple cross-checks of data to ensure that completion status is accurate.
A new study has revealed discrepancies in completion status for trials listed on ClinicalTrials.gov and the EU Clinical Trials Register (EUCTR).
Researchers evaluated nearly 10,500 trials listed on both registries and found that roughly 16% of them were marked as “completed” on one registry and “ongoing” on the other.
Most of these (91%) were listed as “ongoing” on EUCTR but “completed” on ClinicalTrials.gov.
“Trial registries are important public documents,” said Ben Goldacre, of the University of Oxford in the UK.
“Doctors, researchers, and patients rely on the information that trialists post about their clinical trial. Concerningly, we now show that this data is commonly inaccurate.”
Goldacre and his colleague, Jessica Fleminger, also from the University of Oxford, reported these findings in PLOS ONE.
The researchers looked at 10,492 clinical trials that were registered on both ClinicalTrials.gov and EUCTR.
For most of these trials (83.8%, n=8794), completion status was the same on both registries. But there were 1698 trials (16.2%) that were listed as “completed” on one registry and “ongoing” on another.
A majority of the discrepant trials (90.5%, n=1536) were “ongoing” on EUCTR and “complete” on ClinicalTrials.gov.
Overall, 43.1% (4530/10,492) of dual-registered trials were listed as “ongoing” on EUCTR, and 33.9% of these (1536/4530) were listed as “completed” on ClinicalTrials.gov.
Thirty percent (3156/10,492) of dual-registered trials were marked as “ongoing” on ClinicalTrials.gov, and 5.1% (162/3156) of these were marked as “completed” on EUCTR.
Goldacre and Fleminger said it is unclear whether researchers, registry owners, or both are responsible for these errors. Regardless, researchers identifying discrepancies should request clarifications from the trialists, and registry owners should undertake simple cross-checks of data to ensure that completion status is accurate.
A new study has revealed discrepancies in completion status for trials listed on ClinicalTrials.gov and the EU Clinical Trials Register (EUCTR).
Researchers evaluated nearly 10,500 trials listed on both registries and found that roughly 16% of them were marked as “completed” on one registry and “ongoing” on the other.
Most of these (91%) were listed as “ongoing” on EUCTR but “completed” on ClinicalTrials.gov.
“Trial registries are important public documents,” said Ben Goldacre, of the University of Oxford in the UK.
“Doctors, researchers, and patients rely on the information that trialists post about their clinical trial. Concerningly, we now show that this data is commonly inaccurate.”
Goldacre and his colleague, Jessica Fleminger, also from the University of Oxford, reported these findings in PLOS ONE.
The researchers looked at 10,492 clinical trials that were registered on both ClinicalTrials.gov and EUCTR.
For most of these trials (83.8%, n=8794), completion status was the same on both registries. But there were 1698 trials (16.2%) that were listed as “completed” on one registry and “ongoing” on another.
A majority of the discrepant trials (90.5%, n=1536) were “ongoing” on EUCTR and “complete” on ClinicalTrials.gov.
Overall, 43.1% (4530/10,492) of dual-registered trials were listed as “ongoing” on EUCTR, and 33.9% of these (1536/4530) were listed as “completed” on ClinicalTrials.gov.
Thirty percent (3156/10,492) of dual-registered trials were marked as “ongoing” on ClinicalTrials.gov, and 5.1% (162/3156) of these were marked as “completed” on EUCTR.
Goldacre and Fleminger said it is unclear whether researchers, registry owners, or both are responsible for these errors. Regardless, researchers identifying discrepancies should request clarifications from the trialists, and registry owners should undertake simple cross-checks of data to ensure that completion status is accurate.
A Test in Context: Lipid Profile, Fasting Versus Nonfasting
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
Nordestgaard, B.G., J Am Coll Cardiol 70(13):1637, September 26, 2017
This Danish author reviews the impact of a fasting versus nonfasting state on lipid profile testing. He addresses the pros and cons of fasting or nonfasting lipid profiles, the impact on individual lipid parameters, and the implications for diagnosing and treating cardiovascular disease (CVD). Testing lipid profiles in the nonfasting state is increasingly common, in part because it is simpler, given that (typically) 16 hours per day are nonfasting. In addition, a nonfasting lipid profile is more accurate for measuring total atherogenic lipoproteins in plasma because it includes those of hepatic origin in the fasting state and those of intestinal origin in the nonfasting state. Maximum mean differences in lipid parameters measured in nonfasting versus fasting patients are +26mg/dL for triglycerides, -8mg/dL for total cholesterol, -8mg/dL for LDL cholesterol, +8mg/dL for remnant cholesterol, and -8mg/dL for non-HDL cholesterol. The reductions in total, LDL and non-HDL cholesterol are mainly due to fluid intake and not food consumption. A nonfasting condition has no appreciable effect on HDL cholesterol, lipoprotein(a), or apolipoproteins A1 and B. Nonfasting lipid profiles have equal predictive ability for CVD and should not affect treatment decisions (e.g., statin use) for most patients. Testing of nonfasting samples is simpler for all parties (patients, clinicians and laboratories), safer for patients who cannot fast, increases efficiency, and saves money. International guidelines since 2009 are increasingly recommending nonfasting lipid profiles. The author notes that testing of fasting lipid profiles continues largely because “we have always done it this way.” He recommends that nonfasting blood samples be routinely tested, except in selected patients who require fasting samples. 55 references (boerge.nordestgaard@regionh.dk – no reprints)
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
Nordestgaard, B.G., J Am Coll Cardiol 70(13):1637, September 26, 2017
This Danish author reviews the impact of a fasting versus nonfasting state on lipid profile testing. He addresses the pros and cons of fasting or nonfasting lipid profiles, the impact on individual lipid parameters, and the implications for diagnosing and treating cardiovascular disease (CVD). Testing lipid profiles in the nonfasting state is increasingly common, in part because it is simpler, given that (typically) 16 hours per day are nonfasting. In addition, a nonfasting lipid profile is more accurate for measuring total atherogenic lipoproteins in plasma because it includes those of hepatic origin in the fasting state and those of intestinal origin in the nonfasting state. Maximum mean differences in lipid parameters measured in nonfasting versus fasting patients are +26mg/dL for triglycerides, -8mg/dL for total cholesterol, -8mg/dL for LDL cholesterol, +8mg/dL for remnant cholesterol, and -8mg/dL for non-HDL cholesterol. The reductions in total, LDL and non-HDL cholesterol are mainly due to fluid intake and not food consumption. A nonfasting condition has no appreciable effect on HDL cholesterol, lipoprotein(a), or apolipoproteins A1 and B. Nonfasting lipid profiles have equal predictive ability for CVD and should not affect treatment decisions (e.g., statin use) for most patients. Testing of nonfasting samples is simpler for all parties (patients, clinicians and laboratories), safer for patients who cannot fast, increases efficiency, and saves money. International guidelines since 2009 are increasingly recommending nonfasting lipid profiles. The author notes that testing of fasting lipid profiles continues largely because “we have always done it this way.” He recommends that nonfasting blood samples be routinely tested, except in selected patients who require fasting samples. 55 references (boerge.nordestgaard@regionh.dk – no reprints)
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
Nordestgaard, B.G., J Am Coll Cardiol 70(13):1637, September 26, 2017
This Danish author reviews the impact of a fasting versus nonfasting state on lipid profile testing. He addresses the pros and cons of fasting or nonfasting lipid profiles, the impact on individual lipid parameters, and the implications for diagnosing and treating cardiovascular disease (CVD). Testing lipid profiles in the nonfasting state is increasingly common, in part because it is simpler, given that (typically) 16 hours per day are nonfasting. In addition, a nonfasting lipid profile is more accurate for measuring total atherogenic lipoproteins in plasma because it includes those of hepatic origin in the fasting state and those of intestinal origin in the nonfasting state. Maximum mean differences in lipid parameters measured in nonfasting versus fasting patients are +26mg/dL for triglycerides, -8mg/dL for total cholesterol, -8mg/dL for LDL cholesterol, +8mg/dL for remnant cholesterol, and -8mg/dL for non-HDL cholesterol. The reductions in total, LDL and non-HDL cholesterol are mainly due to fluid intake and not food consumption. A nonfasting condition has no appreciable effect on HDL cholesterol, lipoprotein(a), or apolipoproteins A1 and B. Nonfasting lipid profiles have equal predictive ability for CVD and should not affect treatment decisions (e.g., statin use) for most patients. Testing of nonfasting samples is simpler for all parties (patients, clinicians and laboratories), safer for patients who cannot fast, increases efficiency, and saves money. International guidelines since 2009 are increasingly recommending nonfasting lipid profiles. The author notes that testing of fasting lipid profiles continues largely because “we have always done it this way.” He recommends that nonfasting blood samples be routinely tested, except in selected patients who require fasting samples. 55 references (boerge.nordestgaard@regionh.dk – no reprints)
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Monitoring for Infection in MS Patients
Q) How do you monitor for infection in patients with multiple sclerosis who take disease-modifying therapies?
The answer to this question is “it depends”—on several factors, including current and previous use of disease-modifying therapies (DMTs), concomitant medications, comorbidities, vaccination history, presence of John Cunningham virus (JCV) antibodies (in the case of natalizumab use), and prior or current use of immunosuppressive therapies.
There are many FDA-approved DMTs for multiple sclerosis (MS). Each has a different rate of infection occurring in clinical trials and varying requirements and/or recommendations for safety monitoring. The package inserts for each DMT offer some guidance for clinicians.
Injectable therapies. For two interferon therapies—interferon ß-1b SC and interferon ß-1a—it is recommended to order a complete blood count (CBC), blood chemistry, and liver function tests (LFTs) at baseline, then again at one, three, and six months, and then at clinician discretion thereafter.1,2 For peginterferon ß-1a, ordering a CBC, basic chemistry, and LFTs, at the clinician’s discretion, is advised.3 The package insert for interferon ß-1a IM does not offer specific recommendations for routine safety monitoring.4
The package insert for glatiramer acetate offers no recommendations for routine safety monitoring.5
In patients for whom two or more DMTs have failed to work, the monoclonal antibody daclizumab may be indicated. Compared to placebo and active comparator, this drug was associated with a higher risk for infection in clinical trials. The most commonly observed types were upper respiratory, urinary tract, and viral infections. There are no recommendations for CBC monitoring with daclizumab, but monthly LFTs are required due to increased risk for hepatic injury.6
Oral DMTs. Patients taking fingolimod, teriflunomide, and dimethyl fumarate have increased risk for infection; as a result, there are more safety monitoring recommendations for these medications.7-9
Prior to starting therapy with fingolimod, baseline CBC, blood chemistries, and varicella antibody testing should be done. During therapy, routine CBC testing and LFTs are advised at the clinician’s discretion or if the patient exhibits signs and symptoms of infection (see Table). In clinical trials, fingolimod use was interrupted if the lymphocyte count was sustained at < 200. In rare cases, progressive multifocal leukoencephalopathy (PML) has occurred—so the patient’s age, JCV antibody status, prior use of immunosuppressant therapy, and length of fingolimod treatment should be taken into consideration.7
Patients starting teriflunomide should have baseline LFTs and CBC and tuberculosis (TB) testing (either skin or serum), with subsequent monthly LFTs for the first six months on treatment. Some patients may experience neutropenia, thrombocytopenia, and lymphopenia. As a result, patients may have an increased risk for infection. Safety monitoring is at the clinician’s discretion.8
For patients initiating dimethyl fumarate, a baseline CBC is recommended, to be repeated every six to 12 months thereafter, and/or as clinically indicated. Since lymphopenia may occur, consider interruption of dimethyl fumarate in patients with lymphocyte counts < 0.5 persisting for more than six months. Rare cases of PML have also occurred; at the first suggestive sign or symptom, dimethyl fumarate should be withheld and appropriate diagnostic testing should be completed.9
Infusion therapies. There are four infusion therapies available for MS treatment. Mitoxantrone, though not commonly used, is still available for relapsing and secondary progressive forms of MS. Common infections seen in clinical trials include upper respiratory, urinary tract, and sinus infections. A CBC, including platelets, should be obtained prior to each course of mitoxantrone and again if signs and symptoms of infection develop.10
Natalizumab is an integrin receptor antagonist administered in monthly IV infusions. Patients receiving natalizumab may have increased risk for urinary tract infections, lower respiratory infections, gastroenteritis, vaginitis, and herpes infections. These risks should be monitored at the clinician’s discretion. There have been several cases of PML associated with natalizumab; risk factors include duration of therapy, prior use of immunosuppressants, and presence of JCV antibodies.11
Alemtuzumab is a CD52-directed monoclonal antibody indicated in patients with relapsing forms of MS who have had an inadequate response to at least two DMTs. In clinical trials, subjects had a higher risk for nasopharyngitis, urinary tract infections, upper respiratory infections, sinusitis, herpetic infections, influenza, and bronchitis. Due to the increased risk for infection and secondary autoimmunities, patients are required to have monthly CBC testing, LFTs, and urinalysis for up to 48 months after their last infusion.12
Lastly, ocrelizumab is a CD20-directed cytolytic antibody for the treatment of relapsing and progressive forms of MS. In clinical trials, there was a higher incidence of upper and lower respiratory infections, skin infections, and herpes-related infections. Prior to initiating ocrelizumab, hepatitis B virus screening should be completed. There are no specific recommendations for routine monitoring during therapy, although providers should monitor patients clinically for any signs and symptoms of infection.13
A word of caution: The common signs and symptoms of infection are listed in the Table. If these symptoms are present in your patient, consider ordering diagnostic testing to evaluate for infection.
Symptoms of PML include progressive unilateral weakness, clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes. At the first sign or symptom suggestive of PML, the DMT should be discontinued and diagnostic testing performed.
Providers may contact the manufacturer directly for further guidance on DMT surveillance and treatment protocols. —CK
Christen Kutz, PhD, PA-C
Colorado Springs Neurological Associates
1. Betaseron (interferon [b]-1b) [package insert]. Whippany, NJ: Bayer HealthCare Pharmaceuticals; 1993.
2. Rebif (interferon [b]-1a) [package insert]. Rockland, MA: EMD Serono; revised 2015.
3. Plegridy (peginterferon [b]-1a) [package insert]. Cambridge, MA: Biogen Idec; 2013.
4. Avonex (interferon [b] -1a) [package insert]. Cambridge, MA: Biogen Inc.; 1996.
5. Copaxone (glatiramer acetate) [package insert]. Overland Park, KS: Teva Neuroscience; revised 2016.
6. Zinbryta (daclizumab) [package insert]. Cambridge, MA: Biogen Idec; 2016.
7. Gilenya (fingolimod) [package insert]. Hanover, NJ: Novartis; revised 2016.
8. Aubagio (teriflunomide) [package insert]. Cambridge, MA: Genzyme Corporation; revised 2016.
9. Tecfidera (dimethyl fumarate) [package insert]. Cambridge, MA: Biogen Idec; revised 2017.
10. Novantrone (mitoxantrone) [package insert]. Rockland, MA: EMD Serono; 2008.
11. Tysabri (natalizumab) [package insert]. Cambridge, MA: Biogen Idec; revised 2017.
12. Lemtrada (alemtuzumab) [package insert]. Cambridge, MA: Genzyme Corporation; revised 2017.
13. Ocrevus (ocrelizumab) [package insert]. San Francisco, CA: Genentech; 2017.
Clinician Reviews in partnership with
MS Consult is edited by Colleen J. Harris, MN, NP, MSCN, Nurse Practitioner/Manager of the Multiple Sclerosis Clinic at Foothills Medical Centre in Calgary, Alberta, Canada, and Bryan Walker, MHS, PA-C, who is in the Department of Neurology, Division of MS and Neuroimmunology, at Duke University Medical Center in Durham, North Carolina. This month's responses were authored by Christen Kutz, PhD, PA-C, who practices at Colorado Springs Neurological Associates, and Amy L. Dix, MPAS, PA-C, MSCS, who practices in the Department of Neurology at Kansas City Multiple Sclerosis Center in Overland Park, Kansas.
Clinician Reviews in partnership with
MS Consult is edited by Colleen J. Harris, MN, NP, MSCN, Nurse Practitioner/Manager of the Multiple Sclerosis Clinic at Foothills Medical Centre in Calgary, Alberta, Canada, and Bryan Walker, MHS, PA-C, who is in the Department of Neurology, Division of MS and Neuroimmunology, at Duke University Medical Center in Durham, North Carolina. This month's responses were authored by Christen Kutz, PhD, PA-C, who practices at Colorado Springs Neurological Associates, and Amy L. Dix, MPAS, PA-C, MSCS, who practices in the Department of Neurology at Kansas City Multiple Sclerosis Center in Overland Park, Kansas.
Clinician Reviews in partnership with
MS Consult is edited by Colleen J. Harris, MN, NP, MSCN, Nurse Practitioner/Manager of the Multiple Sclerosis Clinic at Foothills Medical Centre in Calgary, Alberta, Canada, and Bryan Walker, MHS, PA-C, who is in the Department of Neurology, Division of MS and Neuroimmunology, at Duke University Medical Center in Durham, North Carolina. This month's responses were authored by Christen Kutz, PhD, PA-C, who practices at Colorado Springs Neurological Associates, and Amy L. Dix, MPAS, PA-C, MSCS, who practices in the Department of Neurology at Kansas City Multiple Sclerosis Center in Overland Park, Kansas.
Q) How do you monitor for infection in patients with multiple sclerosis who take disease-modifying therapies?
The answer to this question is “it depends”—on several factors, including current and previous use of disease-modifying therapies (DMTs), concomitant medications, comorbidities, vaccination history, presence of John Cunningham virus (JCV) antibodies (in the case of natalizumab use), and prior or current use of immunosuppressive therapies.
There are many FDA-approved DMTs for multiple sclerosis (MS). Each has a different rate of infection occurring in clinical trials and varying requirements and/or recommendations for safety monitoring. The package inserts for each DMT offer some guidance for clinicians.
Injectable therapies. For two interferon therapies—interferon ß-1b SC and interferon ß-1a—it is recommended to order a complete blood count (CBC), blood chemistry, and liver function tests (LFTs) at baseline, then again at one, three, and six months, and then at clinician discretion thereafter.1,2 For peginterferon ß-1a, ordering a CBC, basic chemistry, and LFTs, at the clinician’s discretion, is advised.3 The package insert for interferon ß-1a IM does not offer specific recommendations for routine safety monitoring.4
The package insert for glatiramer acetate offers no recommendations for routine safety monitoring.5
In patients for whom two or more DMTs have failed to work, the monoclonal antibody daclizumab may be indicated. Compared to placebo and active comparator, this drug was associated with a higher risk for infection in clinical trials. The most commonly observed types were upper respiratory, urinary tract, and viral infections. There are no recommendations for CBC monitoring with daclizumab, but monthly LFTs are required due to increased risk for hepatic injury.6
Oral DMTs. Patients taking fingolimod, teriflunomide, and dimethyl fumarate have increased risk for infection; as a result, there are more safety monitoring recommendations for these medications.7-9
Prior to starting therapy with fingolimod, baseline CBC, blood chemistries, and varicella antibody testing should be done. During therapy, routine CBC testing and LFTs are advised at the clinician’s discretion or if the patient exhibits signs and symptoms of infection (see Table). In clinical trials, fingolimod use was interrupted if the lymphocyte count was sustained at < 200. In rare cases, progressive multifocal leukoencephalopathy (PML) has occurred—so the patient’s age, JCV antibody status, prior use of immunosuppressant therapy, and length of fingolimod treatment should be taken into consideration.7
Patients starting teriflunomide should have baseline LFTs and CBC and tuberculosis (TB) testing (either skin or serum), with subsequent monthly LFTs for the first six months on treatment. Some patients may experience neutropenia, thrombocytopenia, and lymphopenia. As a result, patients may have an increased risk for infection. Safety monitoring is at the clinician’s discretion.8
For patients initiating dimethyl fumarate, a baseline CBC is recommended, to be repeated every six to 12 months thereafter, and/or as clinically indicated. Since lymphopenia may occur, consider interruption of dimethyl fumarate in patients with lymphocyte counts < 0.5 persisting for more than six months. Rare cases of PML have also occurred; at the first suggestive sign or symptom, dimethyl fumarate should be withheld and appropriate diagnostic testing should be completed.9
Infusion therapies. There are four infusion therapies available for MS treatment. Mitoxantrone, though not commonly used, is still available for relapsing and secondary progressive forms of MS. Common infections seen in clinical trials include upper respiratory, urinary tract, and sinus infections. A CBC, including platelets, should be obtained prior to each course of mitoxantrone and again if signs and symptoms of infection develop.10
Natalizumab is an integrin receptor antagonist administered in monthly IV infusions. Patients receiving natalizumab may have increased risk for urinary tract infections, lower respiratory infections, gastroenteritis, vaginitis, and herpes infections. These risks should be monitored at the clinician’s discretion. There have been several cases of PML associated with natalizumab; risk factors include duration of therapy, prior use of immunosuppressants, and presence of JCV antibodies.11
Alemtuzumab is a CD52-directed monoclonal antibody indicated in patients with relapsing forms of MS who have had an inadequate response to at least two DMTs. In clinical trials, subjects had a higher risk for nasopharyngitis, urinary tract infections, upper respiratory infections, sinusitis, herpetic infections, influenza, and bronchitis. Due to the increased risk for infection and secondary autoimmunities, patients are required to have monthly CBC testing, LFTs, and urinalysis for up to 48 months after their last infusion.12
Lastly, ocrelizumab is a CD20-directed cytolytic antibody for the treatment of relapsing and progressive forms of MS. In clinical trials, there was a higher incidence of upper and lower respiratory infections, skin infections, and herpes-related infections. Prior to initiating ocrelizumab, hepatitis B virus screening should be completed. There are no specific recommendations for routine monitoring during therapy, although providers should monitor patients clinically for any signs and symptoms of infection.13
A word of caution: The common signs and symptoms of infection are listed in the Table. If these symptoms are present in your patient, consider ordering diagnostic testing to evaluate for infection.
Symptoms of PML include progressive unilateral weakness, clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes. At the first sign or symptom suggestive of PML, the DMT should be discontinued and diagnostic testing performed.
Providers may contact the manufacturer directly for further guidance on DMT surveillance and treatment protocols. —CK
Christen Kutz, PhD, PA-C
Colorado Springs Neurological Associates
Q) How do you monitor for infection in patients with multiple sclerosis who take disease-modifying therapies?
The answer to this question is “it depends”—on several factors, including current and previous use of disease-modifying therapies (DMTs), concomitant medications, comorbidities, vaccination history, presence of John Cunningham virus (JCV) antibodies (in the case of natalizumab use), and prior or current use of immunosuppressive therapies.
There are many FDA-approved DMTs for multiple sclerosis (MS). Each has a different rate of infection occurring in clinical trials and varying requirements and/or recommendations for safety monitoring. The package inserts for each DMT offer some guidance for clinicians.
Injectable therapies. For two interferon therapies—interferon ß-1b SC and interferon ß-1a—it is recommended to order a complete blood count (CBC), blood chemistry, and liver function tests (LFTs) at baseline, then again at one, three, and six months, and then at clinician discretion thereafter.1,2 For peginterferon ß-1a, ordering a CBC, basic chemistry, and LFTs, at the clinician’s discretion, is advised.3 The package insert for interferon ß-1a IM does not offer specific recommendations for routine safety monitoring.4
The package insert for glatiramer acetate offers no recommendations for routine safety monitoring.5
In patients for whom two or more DMTs have failed to work, the monoclonal antibody daclizumab may be indicated. Compared to placebo and active comparator, this drug was associated with a higher risk for infection in clinical trials. The most commonly observed types were upper respiratory, urinary tract, and viral infections. There are no recommendations for CBC monitoring with daclizumab, but monthly LFTs are required due to increased risk for hepatic injury.6
Oral DMTs. Patients taking fingolimod, teriflunomide, and dimethyl fumarate have increased risk for infection; as a result, there are more safety monitoring recommendations for these medications.7-9
Prior to starting therapy with fingolimod, baseline CBC, blood chemistries, and varicella antibody testing should be done. During therapy, routine CBC testing and LFTs are advised at the clinician’s discretion or if the patient exhibits signs and symptoms of infection (see Table). In clinical trials, fingolimod use was interrupted if the lymphocyte count was sustained at < 200. In rare cases, progressive multifocal leukoencephalopathy (PML) has occurred—so the patient’s age, JCV antibody status, prior use of immunosuppressant therapy, and length of fingolimod treatment should be taken into consideration.7
Patients starting teriflunomide should have baseline LFTs and CBC and tuberculosis (TB) testing (either skin or serum), with subsequent monthly LFTs for the first six months on treatment. Some patients may experience neutropenia, thrombocytopenia, and lymphopenia. As a result, patients may have an increased risk for infection. Safety monitoring is at the clinician’s discretion.8
For patients initiating dimethyl fumarate, a baseline CBC is recommended, to be repeated every six to 12 months thereafter, and/or as clinically indicated. Since lymphopenia may occur, consider interruption of dimethyl fumarate in patients with lymphocyte counts < 0.5 persisting for more than six months. Rare cases of PML have also occurred; at the first suggestive sign or symptom, dimethyl fumarate should be withheld and appropriate diagnostic testing should be completed.9
Infusion therapies. There are four infusion therapies available for MS treatment. Mitoxantrone, though not commonly used, is still available for relapsing and secondary progressive forms of MS. Common infections seen in clinical trials include upper respiratory, urinary tract, and sinus infections. A CBC, including platelets, should be obtained prior to each course of mitoxantrone and again if signs and symptoms of infection develop.10
Natalizumab is an integrin receptor antagonist administered in monthly IV infusions. Patients receiving natalizumab may have increased risk for urinary tract infections, lower respiratory infections, gastroenteritis, vaginitis, and herpes infections. These risks should be monitored at the clinician’s discretion. There have been several cases of PML associated with natalizumab; risk factors include duration of therapy, prior use of immunosuppressants, and presence of JCV antibodies.11
Alemtuzumab is a CD52-directed monoclonal antibody indicated in patients with relapsing forms of MS who have had an inadequate response to at least two DMTs. In clinical trials, subjects had a higher risk for nasopharyngitis, urinary tract infections, upper respiratory infections, sinusitis, herpetic infections, influenza, and bronchitis. Due to the increased risk for infection and secondary autoimmunities, patients are required to have monthly CBC testing, LFTs, and urinalysis for up to 48 months after their last infusion.12
Lastly, ocrelizumab is a CD20-directed cytolytic antibody for the treatment of relapsing and progressive forms of MS. In clinical trials, there was a higher incidence of upper and lower respiratory infections, skin infections, and herpes-related infections. Prior to initiating ocrelizumab, hepatitis B virus screening should be completed. There are no specific recommendations for routine monitoring during therapy, although providers should monitor patients clinically for any signs and symptoms of infection.13
A word of caution: The common signs and symptoms of infection are listed in the Table. If these symptoms are present in your patient, consider ordering diagnostic testing to evaluate for infection.
Symptoms of PML include progressive unilateral weakness, clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes. At the first sign or symptom suggestive of PML, the DMT should be discontinued and diagnostic testing performed.
Providers may contact the manufacturer directly for further guidance on DMT surveillance and treatment protocols. —CK
Christen Kutz, PhD, PA-C
Colorado Springs Neurological Associates
1. Betaseron (interferon [b]-1b) [package insert]. Whippany, NJ: Bayer HealthCare Pharmaceuticals; 1993.
2. Rebif (interferon [b]-1a) [package insert]. Rockland, MA: EMD Serono; revised 2015.
3. Plegridy (peginterferon [b]-1a) [package insert]. Cambridge, MA: Biogen Idec; 2013.
4. Avonex (interferon [b] -1a) [package insert]. Cambridge, MA: Biogen Inc.; 1996.
5. Copaxone (glatiramer acetate) [package insert]. Overland Park, KS: Teva Neuroscience; revised 2016.
6. Zinbryta (daclizumab) [package insert]. Cambridge, MA: Biogen Idec; 2016.
7. Gilenya (fingolimod) [package insert]. Hanover, NJ: Novartis; revised 2016.
8. Aubagio (teriflunomide) [package insert]. Cambridge, MA: Genzyme Corporation; revised 2016.
9. Tecfidera (dimethyl fumarate) [package insert]. Cambridge, MA: Biogen Idec; revised 2017.
10. Novantrone (mitoxantrone) [package insert]. Rockland, MA: EMD Serono; 2008.
11. Tysabri (natalizumab) [package insert]. Cambridge, MA: Biogen Idec; revised 2017.
12. Lemtrada (alemtuzumab) [package insert]. Cambridge, MA: Genzyme Corporation; revised 2017.
13. Ocrevus (ocrelizumab) [package insert]. San Francisco, CA: Genentech; 2017.
1. Betaseron (interferon [b]-1b) [package insert]. Whippany, NJ: Bayer HealthCare Pharmaceuticals; 1993.
2. Rebif (interferon [b]-1a) [package insert]. Rockland, MA: EMD Serono; revised 2015.
3. Plegridy (peginterferon [b]-1a) [package insert]. Cambridge, MA: Biogen Idec; 2013.
4. Avonex (interferon [b] -1a) [package insert]. Cambridge, MA: Biogen Inc.; 1996.
5. Copaxone (glatiramer acetate) [package insert]. Overland Park, KS: Teva Neuroscience; revised 2016.
6. Zinbryta (daclizumab) [package insert]. Cambridge, MA: Biogen Idec; 2016.
7. Gilenya (fingolimod) [package insert]. Hanover, NJ: Novartis; revised 2016.
8. Aubagio (teriflunomide) [package insert]. Cambridge, MA: Genzyme Corporation; revised 2016.
9. Tecfidera (dimethyl fumarate) [package insert]. Cambridge, MA: Biogen Idec; revised 2017.
10. Novantrone (mitoxantrone) [package insert]. Rockland, MA: EMD Serono; 2008.
11. Tysabri (natalizumab) [package insert]. Cambridge, MA: Biogen Idec; revised 2017.
12. Lemtrada (alemtuzumab) [package insert]. Cambridge, MA: Genzyme Corporation; revised 2017.
13. Ocrevus (ocrelizumab) [package insert]. San Francisco, CA: Genentech; 2017.
