SAN ANTONIO – Hospitalization for an infection within the first year following diagnosis of primary nonmetastatic breast cancer is a red flag for increased risk of subsequent development of distant metastases or breast cancer–related death, Judith S. Brand, Ph.D., reported at the San Antonio Breast Cancer Symposium.

This increased risk for future adverse breast cancer outcomes was statistically significant and clinically meaningful for women hospitalized for respiratory tract or skin infections or sepsis. Those are the patients for whom particularly close monitoring for recurrence of breast cancer is warranted in the next 5 years, said Dr. Brand of the Karolinska Institute, Stockholm.

In contrast, hospitalization for a gastrointestinal or urinary tract infection didn’t achieve significance as an independent predictor of increased risk of adverse breast cancer outcomes.

Dr. Brand presented a prospective population-based study of 8,338 women diagnosed with stage I-III breast cancer in the Stockholm area during 2001-2008. During a median 4.9 years of follow-up after diagnosis, 720 women had an infection-related hospitalization, with the great majority of these events occurring during the first year.

The incidence of hospitalization for sepsis among breast cancer patients in their first year post diagnosis was 14-fold greater than in the general Swedish female population matched for age and year. Respiratory infections resulting in hospitalization were fourfold more frequent than in the general population, skin infections were eightfold more common, and GI infections were twice as common.

Infection-related hospitalizations had a strong and independent association with breast cancer mortality during follow-up, as seen in a multivariate analysis adjusted for age at diagnosis, comorbid conditions, infectious disease history, type of breast cancer therapy, and tumor characteristics including size, grade, hormone receptor status, and lymph node involvement.

Moreover, the risk of developing distant metastases was 50%-78% greater in breast cancer patients hospitalized for respiratory infection, sepsis, or skin infection, compared with breast cancer patients who didn’t have an infection-related hospitalization.

“We think the sepsis results are the most interesting findings,” Dr. Brand said in an interview. “Sepsis could be an expression of an immunosuppressed state. And sepsis itself can induce immunosuppression for a long time, which could trigger tumor growth. Animal studies have shown that in postseptic mice, tumor grows faster.”

Infection-related hospitalizations didn’t increase the future risk of locoregional recurrences.

Independent predictors of infection-related hospitalization included older age, comorbidities, markers indicative of greater tumor aggressiveness, and treatment with chemotherapy or axillary radiotherapy.

“This shows that the risk of infection-related hospitalizations is not only due to immunosuppression caused by chemotherapy, but that the characteristics of the tumor itself play a role, as do patient characteristics. This is the first epidemiologic study to show with very extensive data that all three elements contribute to the risk,” Dr. Brand said.

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SAN ANTONIO – Hospitalization for an infection within the first year following diagnosis of primary nonmetastatic breast cancer is a red flag for increased risk of subsequent development of distant metastases or breast cancer–related death, Judith S. Brand, Ph.D., reported at the San Antonio Breast Cancer Symposium.

This increased risk for future adverse breast cancer outcomes was statistically significant and clinically meaningful for women hospitalized for respiratory tract or skin infections or sepsis. Those are the patients for whom particularly close monitoring for recurrence of breast cancer is warranted in the next 5 years, said Dr. Brand of the Karolinska Institute, Stockholm.

In contrast, hospitalization for a gastrointestinal or urinary tract infection didn’t achieve significance as an independent predictor of increased risk of adverse breast cancer outcomes.

Dr. Brand presented a prospective population-based study of 8,338 women diagnosed with stage I-III breast cancer in the Stockholm area during 2001-2008. During a median 4.9 years of follow-up after diagnosis, 720 women had an infection-related hospitalization, with the great majority of these events occurring during the first year.

The incidence of hospitalization for sepsis among breast cancer patients in their first year post diagnosis was 14-fold greater than in the general Swedish female population matched for age and year. Respiratory infections resulting in hospitalization were fourfold more frequent than in the general population, skin infections were eightfold more common, and GI infections were twice as common.

Infection-related hospitalizations had a strong and independent association with breast cancer mortality during follow-up, as seen in a multivariate analysis adjusted for age at diagnosis, comorbid conditions, infectious disease history, type of breast cancer therapy, and tumor characteristics including size, grade, hormone receptor status, and lymph node involvement.

Moreover, the risk of developing distant metastases was 50%-78% greater in breast cancer patients hospitalized for respiratory infection, sepsis, or skin infection, compared with breast cancer patients who didn’t have an infection-related hospitalization.

“We think the sepsis results are the most interesting findings,” Dr. Brand said in an interview. “Sepsis could be an expression of an immunosuppressed state. And sepsis itself can induce immunosuppression for a long time, which could trigger tumor growth. Animal studies have shown that in postseptic mice, tumor grows faster.”

Infection-related hospitalizations didn’t increase the future risk of locoregional recurrences.

Independent predictors of infection-related hospitalization included older age, comorbidities, markers indicative of greater tumor aggressiveness, and treatment with chemotherapy or axillary radiotherapy.

“This shows that the risk of infection-related hospitalizations is not only due to immunosuppression caused by chemotherapy, but that the characteristics of the tumor itself play a role, as do patient characteristics. This is the first epidemiologic study to show with very extensive data that all three elements contribute to the risk,” Dr. Brand said.

[email protected]

SAN ANTONIO – Hospitalization for an infection within the first year following diagnosis of primary nonmetastatic breast cancer is a red flag for increased risk of subsequent development of distant metastases or breast cancer–related death, Judith S. Brand, Ph.D., reported at the San Antonio Breast Cancer Symposium.

This increased risk for future adverse breast cancer outcomes was statistically significant and clinically meaningful for women hospitalized for respiratory tract or skin infections or sepsis. Those are the patients for whom particularly close monitoring for recurrence of breast cancer is warranted in the next 5 years, said Dr. Brand of the Karolinska Institute, Stockholm.

In contrast, hospitalization for a gastrointestinal or urinary tract infection didn’t achieve significance as an independent predictor of increased risk of adverse breast cancer outcomes.

Dr. Brand presented a prospective population-based study of 8,338 women diagnosed with stage I-III breast cancer in the Stockholm area during 2001-2008. During a median 4.9 years of follow-up after diagnosis, 720 women had an infection-related hospitalization, with the great majority of these events occurring during the first year.

The incidence of hospitalization for sepsis among breast cancer patients in their first year post diagnosis was 14-fold greater than in the general Swedish female population matched for age and year. Respiratory infections resulting in hospitalization were fourfold more frequent than in the general population, skin infections were eightfold more common, and GI infections were twice as common.

Infection-related hospitalizations had a strong and independent association with breast cancer mortality during follow-up, as seen in a multivariate analysis adjusted for age at diagnosis, comorbid conditions, infectious disease history, type of breast cancer therapy, and tumor characteristics including size, grade, hormone receptor status, and lymph node involvement.

Moreover, the risk of developing distant metastases was 50%-78% greater in breast cancer patients hospitalized for respiratory infection, sepsis, or skin infection, compared with breast cancer patients who didn’t have an infection-related hospitalization.

“We think the sepsis results are the most interesting findings,” Dr. Brand said in an interview. “Sepsis could be an expression of an immunosuppressed state. And sepsis itself can induce immunosuppression for a long time, which could trigger tumor growth. Animal studies have shown that in postseptic mice, tumor grows faster.”

Infection-related hospitalizations didn’t increase the future risk of locoregional recurrences.

Independent predictors of infection-related hospitalization included older age, comorbidities, markers indicative of greater tumor aggressiveness, and treatment with chemotherapy or axillary radiotherapy.

“This shows that the risk of infection-related hospitalizations is not only due to immunosuppression caused by chemotherapy, but that the characteristics of the tumor itself play a role, as do patient characteristics. This is the first epidemiologic study to show with very extensive data that all three elements contribute to the risk,” Dr. Brand said.

[email protected]

South Carolina officially became the first state to reach a “high” level of influenza activity during the 2015-2016 flu season, the Centers for Disease Control and Prevention reported Dec. 11.

Activity of influenza-like illness (ILI) in the state was at level 9 on a scale of 1-10 for the week ending Dec. 5, 2015. For the country as a whole, however, activity was down a bit, with 13 states at level 2 or higher, compared with 20 states the week before. Among those with reduced ILI activity was Oklahoma, which went from level 6 for the week ending Nov. 28 to level 3 for the week ending Dec. 5, according to the CDC report.

For the week, 1.8% of patient visits reported to the U.S. Outpatient Influenza-like Illness Surveillance Network were for ILI, which is below the national baseline of 2.1%. This measure peaked at almost 6% during last year’s flu season, with that high coming at the end of Dec. 2014. The pattern was similar for the 2013-2014 season, with a peak of about 4.5% during the same week at the end of December, the report showed.

There was one influenza-related pediatric death for the week ending Dec. 5, bringing the total to three that have been reported for the season, the CDC said.

[email protected]

South Carolina officially became the first state to reach a “high” level of influenza activity during the 2015-2016 flu season, the Centers for Disease Control and Prevention reported Dec. 11.

Activity of influenza-like illness (ILI) in the state was at level 9 on a scale of 1-10 for the week ending Dec. 5, 2015. For the country as a whole, however, activity was down a bit, with 13 states at level 2 or higher, compared with 20 states the week before. Among those with reduced ILI activity was Oklahoma, which went from level 6 for the week ending Nov. 28 to level 3 for the week ending Dec. 5, according to the CDC report.

For the week, 1.8% of patient visits reported to the U.S. Outpatient Influenza-like Illness Surveillance Network were for ILI, which is below the national baseline of 2.1%. This measure peaked at almost 6% during last year’s flu season, with that high coming at the end of Dec. 2014. The pattern was similar for the 2013-2014 season, with a peak of about 4.5% during the same week at the end of December, the report showed.

There was one influenza-related pediatric death for the week ending Dec. 5, bringing the total to three that have been reported for the season, the CDC said.

[email protected]

South Carolina officially became the first state to reach a “high” level of influenza activity during the 2015-2016 flu season, the Centers for Disease Control and Prevention reported Dec. 11.

Activity of influenza-like illness (ILI) in the state was at level 9 on a scale of 1-10 for the week ending Dec. 5, 2015. For the country as a whole, however, activity was down a bit, with 13 states at level 2 or higher, compared with 20 states the week before. Among those with reduced ILI activity was Oklahoma, which went from level 6 for the week ending Nov. 28 to level 3 for the week ending Dec. 5, according to the CDC report.

For the week, 1.8% of patient visits reported to the U.S. Outpatient Influenza-like Illness Surveillance Network were for ILI, which is below the national baseline of 2.1%. This measure peaked at almost 6% during last year’s flu season, with that high coming at the end of Dec. 2014. The pattern was similar for the 2013-2014 season, with a peak of about 4.5% during the same week at the end of December, the report showed.

There was one influenza-related pediatric death for the week ending Dec. 5, bringing the total to three that have been reported for the season, the CDC said.

[email protected]

In his December podcast for The Journal of Community and Supportive Oncology, Dr David Henry takes a look at filgrastim-sndz, the first biosimilar to be approved in United States. He also highlights two Original Reports that focus on cancer patients from racially diverse or underserved communities – one study looks at the patients’ enrollment in clinical trials; the other, at racial disparities in breast cancer diagnosis – as well as articles on the implementation of distress screening in an oncology setting and on oncology nurses’ perceptions of and practices and perceived barriers in regard to sexual health assessment and counseling among patients with cancer. The podcast rounds off with a discussion about a new era of combination therapy in cancer.

In his December podcast for The Journal of Community and Supportive Oncology, Dr David Henry takes a look at filgrastim-sndz, the first biosimilar to be approved in United States. He also highlights two Original Reports that focus on cancer patients from racially diverse or underserved communities – one study looks at the patients’ enrollment in clinical trials; the other, at racial disparities in breast cancer diagnosis – as well as articles on the implementation of distress screening in an oncology setting and on oncology nurses’ perceptions of and practices and perceived barriers in regard to sexual health assessment and counseling among patients with cancer. The podcast rounds off with a discussion about a new era of combination therapy in cancer.

In his December podcast for The Journal of Community and Supportive Oncology, Dr David Henry takes a look at filgrastim-sndz, the first biosimilar to be approved in United States. He also highlights two Original Reports that focus on cancer patients from racially diverse or underserved communities – one study looks at the patients’ enrollment in clinical trials; the other, at racial disparities in breast cancer diagnosis – as well as articles on the implementation of distress screening in an oncology setting and on oncology nurses’ perceptions of and practices and perceived barriers in regard to sexual health assessment and counseling among patients with cancer. The podcast rounds off with a discussion about a new era of combination therapy in cancer.

The past year has been an exciting one for new oncology and hematology drug approvals and the continued evolution of our oncology delivery system toward high quality and value. In all, at press time in mid-November, the US Food and Drug Administration (FDA) had approved or granted expanded indications for 24 drugs, compared with 19 in the 2 preceding years. Of those 24 approvals, 7 were accelerated and 6 were expanded approvals, and 3 alone were for the immunotherapeutic drug, nivolumab – 2 for non-small-cell lung cancer (NSCLC) and 1 for metastatic melanoma.

Click on the PDF icon at the top of this introduction to read the full article.

The past year has been an exciting one for new oncology and hematology drug approvals and the continued evolution of our oncology delivery system toward high quality and value. In all, at press time in mid-November, the US Food and Drug Administration (FDA) had approved or granted expanded indications for 24 drugs, compared with 19 in the 2 preceding years. Of those 24 approvals, 7 were accelerated and 6 were expanded approvals, and 3 alone were for the immunotherapeutic drug, nivolumab – 2 for non-small-cell lung cancer (NSCLC) and 1 for metastatic melanoma.

Click on the PDF icon at the top of this introduction to read the full article.

The past year has been an exciting one for new oncology and hematology drug approvals and the continued evolution of our oncology delivery system toward high quality and value. In all, at press time in mid-November, the US Food and Drug Administration (FDA) had approved or granted expanded indications for 24 drugs, compared with 19 in the 2 preceding years. Of those 24 approvals, 7 were accelerated and 6 were expanded approvals, and 3 alone were for the immunotherapeutic drug, nivolumab – 2 for non-small-cell lung cancer (NSCLC) and 1 for metastatic melanoma.

Click on the PDF icon at the top of this introduction to read the full article.

Clinical question: Are there patient characteristics not currently measured by the Medicare readmission program that account for differences in hospital readmission rates?

Background: The Medicare Hospital Readmissions Reduction Program (HRRP) financially penalizes hospitals with higher than expected 30-day readmission rates. During 2014, more than 2,000 U.S. hospitals were fined $480 million for high readmission rates. HRRP accounts for differences in patient age, gender, discharge diagnosis, and diagnoses identified in Medicare claims over the previous 12 months; however, the impact of other factors is uncertain.

Study design: Survey data from the Health and Retirement Study, with linked Medicare claims.

Setting: Community-dwelling U.S. adults, older than 50 years.

Synopsis: Investigators analyzed more than 33,000 admissions from 2000 to 2012. They found 22 patient characteristics not included in the HRRP calculation that were statistically significantly predictive of hospital-wide, 30-day readmission and were more likely to be present among patients cared for in hospitals in the highest quintile of readmission rates. These characteristics reduced by 48% the differences in readmission rate between the highest- and lowest-performing quintiles. Examples include patient ethnicity, education level, personal as well as household income level, presence of prescription drug plan, Medicaid enrollment, cognitive status, and numerous others.

Bottom line: Patient characteristics account for much of the difference in readmission rates between high- and low-performing hospitals, suggesting that HRRP penalties reflect who hospitals treat as much as how well they treat them.

Citation: Barnett ML, Hsu J, McWilliams JM. Patient characteristics and differences in hospital readmission rates. JAMA Intern Med. 2015;175(11):1803-1812.

Clinical question: Are there patient characteristics not currently measured by the Medicare readmission program that account for differences in hospital readmission rates?

Background: The Medicare Hospital Readmissions Reduction Program (HRRP) financially penalizes hospitals with higher than expected 30-day readmission rates. During 2014, more than 2,000 U.S. hospitals were fined $480 million for high readmission rates. HRRP accounts for differences in patient age, gender, discharge diagnosis, and diagnoses identified in Medicare claims over the previous 12 months; however, the impact of other factors is uncertain.

Study design: Survey data from the Health and Retirement Study, with linked Medicare claims.

Setting: Community-dwelling U.S. adults, older than 50 years.

Synopsis: Investigators analyzed more than 33,000 admissions from 2000 to 2012. They found 22 patient characteristics not included in the HRRP calculation that were statistically significantly predictive of hospital-wide, 30-day readmission and were more likely to be present among patients cared for in hospitals in the highest quintile of readmission rates. These characteristics reduced by 48% the differences in readmission rate between the highest- and lowest-performing quintiles. Examples include patient ethnicity, education level, personal as well as household income level, presence of prescription drug plan, Medicaid enrollment, cognitive status, and numerous others.

Bottom line: Patient characteristics account for much of the difference in readmission rates between high- and low-performing hospitals, suggesting that HRRP penalties reflect who hospitals treat as much as how well they treat them.

Citation: Barnett ML, Hsu J, McWilliams JM. Patient characteristics and differences in hospital readmission rates. JAMA Intern Med. 2015;175(11):1803-1812.

Clinical question: Are there patient characteristics not currently measured by the Medicare readmission program that account for differences in hospital readmission rates?

Background: The Medicare Hospital Readmissions Reduction Program (HRRP) financially penalizes hospitals with higher than expected 30-day readmission rates. During 2014, more than 2,000 U.S. hospitals were fined $480 million for high readmission rates. HRRP accounts for differences in patient age, gender, discharge diagnosis, and diagnoses identified in Medicare claims over the previous 12 months; however, the impact of other factors is uncertain.

Study design: Survey data from the Health and Retirement Study, with linked Medicare claims.

Setting: Community-dwelling U.S. adults, older than 50 years.

Synopsis: Investigators analyzed more than 33,000 admissions from 2000 to 2012. They found 22 patient characteristics not included in the HRRP calculation that were statistically significantly predictive of hospital-wide, 30-day readmission and were more likely to be present among patients cared for in hospitals in the highest quintile of readmission rates. These characteristics reduced by 48% the differences in readmission rate between the highest- and lowest-performing quintiles. Examples include patient ethnicity, education level, personal as well as household income level, presence of prescription drug plan, Medicaid enrollment, cognitive status, and numerous others.

Bottom line: Patient characteristics account for much of the difference in readmission rates between high- and low-performing hospitals, suggesting that HRRP penalties reflect who hospitals treat as much as how well they treat them.

Citation: Barnett ML, Hsu J, McWilliams JM. Patient characteristics and differences in hospital readmission rates. JAMA Intern Med. 2015;175(11):1803-1812.

A “broad swath” of Medicare providers wrote scripts for opioids in 2013, contradicting the idea that the overdose epidemic is mainly the work of “small groups of prolific prescribers and corrupt pill mills,” investigators wrote online in JAMA Internal Medicine.

“Contrary to the California workers’ compensation data showing a small subset of prescribers accounting for a disproportionately large percentage of opioid prescribing, Medicare opioid prescribing is distributed across many prescribers and is, if anything, less skewed than all drug prescribing,” said Dr. Jonathan H. Chen of the Veterans Affairs Palo Alto (Calif.) Health Care System, and his associates.

Their study included 808,020 prescribers and almost 1.2 billion Medicare Part D claims worth nearly $81 billion dollars. They focused on schedule II opioid prescriptions containing oxycodone, fentanyl, hydrocodone, morphine, methadone, hydromorphone, oxymorphone, meperidine, codeine, opium, or levorphanol (JAMA Intern Med. 2015 Dec 14. doi: 10.1001/jamainternmed.2015.6662).

Not surprisingly, specialists in pain management, anesthesia, and physical medicine wrote the most prescriptions per provider. But family practitioners, internists, nurse practitioners, and physician assistants wrote 35,268,234 prescriptions – more than all other specialties combined. “The trends hold up across state lines, with negligible geographic variability,” the researchers said.

The findings contradict an analysis of California workers’ compensation data, in which 1% of prescribers accounted for a third of schedule II opioid prescriptions, and 10% of prescribers accounted for 80% of prescriptions, the investigators noted. Nonetheless, 10% of Medicare prescribers in Dr. Chen’s study accounted for 78% of the total cost of opioids, possibly because they were prescribing pricier formulations or higher doses.

Overall, the findings suggest that opioid prescribing is “widespread” and “relatively indifferent to individual physicians, specialty, or region” – and that efforts to stem the tide must be equally broad, the researchers concluded.

Their study was supported by the VA Office of Academic Affiliations, the VA Health Services Research and Development Service, the National Institute of General Medical Sciences, and the Peter F. McManus Charitable Trust. The researchers had no disclosures.

A “broad swath” of Medicare providers wrote scripts for opioids in 2013, contradicting the idea that the overdose epidemic is mainly the work of “small groups of prolific prescribers and corrupt pill mills,” investigators wrote online in JAMA Internal Medicine.

“Contrary to the California workers’ compensation data showing a small subset of prescribers accounting for a disproportionately large percentage of opioid prescribing, Medicare opioid prescribing is distributed across many prescribers and is, if anything, less skewed than all drug prescribing,” said Dr. Jonathan H. Chen of the Veterans Affairs Palo Alto (Calif.) Health Care System, and his associates.

Their study included 808,020 prescribers and almost 1.2 billion Medicare Part D claims worth nearly $81 billion dollars. They focused on schedule II opioid prescriptions containing oxycodone, fentanyl, hydrocodone, morphine, methadone, hydromorphone, oxymorphone, meperidine, codeine, opium, or levorphanol (JAMA Intern Med. 2015 Dec 14. doi: 10.1001/jamainternmed.2015.6662).

Not surprisingly, specialists in pain management, anesthesia, and physical medicine wrote the most prescriptions per provider. But family practitioners, internists, nurse practitioners, and physician assistants wrote 35,268,234 prescriptions – more than all other specialties combined. “The trends hold up across state lines, with negligible geographic variability,” the researchers said.

The findings contradict an analysis of California workers’ compensation data, in which 1% of prescribers accounted for a third of schedule II opioid prescriptions, and 10% of prescribers accounted for 80% of prescriptions, the investigators noted. Nonetheless, 10% of Medicare prescribers in Dr. Chen’s study accounted for 78% of the total cost of opioids, possibly because they were prescribing pricier formulations or higher doses.

Overall, the findings suggest that opioid prescribing is “widespread” and “relatively indifferent to individual physicians, specialty, or region” – and that efforts to stem the tide must be equally broad, the researchers concluded.

Their study was supported by the VA Office of Academic Affiliations, the VA Health Services Research and Development Service, the National Institute of General Medical Sciences, and the Peter F. McManus Charitable Trust. The researchers had no disclosures.

A “broad swath” of Medicare providers wrote scripts for opioids in 2013, contradicting the idea that the overdose epidemic is mainly the work of “small groups of prolific prescribers and corrupt pill mills,” investigators wrote online in JAMA Internal Medicine.

“Contrary to the California workers’ compensation data showing a small subset of prescribers accounting for a disproportionately large percentage of opioid prescribing, Medicare opioid prescribing is distributed across many prescribers and is, if anything, less skewed than all drug prescribing,” said Dr. Jonathan H. Chen of the Veterans Affairs Palo Alto (Calif.) Health Care System, and his associates.

Their study included 808,020 prescribers and almost 1.2 billion Medicare Part D claims worth nearly $81 billion dollars. They focused on schedule II opioid prescriptions containing oxycodone, fentanyl, hydrocodone, morphine, methadone, hydromorphone, oxymorphone, meperidine, codeine, opium, or levorphanol (JAMA Intern Med. 2015 Dec 14. doi: 10.1001/jamainternmed.2015.6662).

Not surprisingly, specialists in pain management, anesthesia, and physical medicine wrote the most prescriptions per provider. But family practitioners, internists, nurse practitioners, and physician assistants wrote 35,268,234 prescriptions – more than all other specialties combined. “The trends hold up across state lines, with negligible geographic variability,” the researchers said.

The findings contradict an analysis of California workers’ compensation data, in which 1% of prescribers accounted for a third of schedule II opioid prescriptions, and 10% of prescribers accounted for 80% of prescriptions, the investigators noted. Nonetheless, 10% of Medicare prescribers in Dr. Chen’s study accounted for 78% of the total cost of opioids, possibly because they were prescribing pricier formulations or higher doses.

Overall, the findings suggest that opioid prescribing is “widespread” and “relatively indifferent to individual physicians, specialty, or region” – and that efforts to stem the tide must be equally broad, the researchers concluded.

Their study was supported by the VA Office of Academic Affiliations, the VA Health Services Research and Development Service, the National Institute of General Medical Sciences, and the Peter F. McManus Charitable Trust. The researchers had no disclosures.

Selection of oral agents for treatment of AV in adult women is dependent on multiple factors including the patient’s age, medication history, child-bearing potential, clinical presentation, and treatment preference following a discussion of the anticipated benefits versus potential risks.^1,2 In patients with the mixed inflammatory and comedonal clinical pattern of AV, oral antibiotics can be used concurrently with topical therapies when moderate to severe inflammatory lesions are noted.^3,4 However, many adult women who had AV as teenagers have already utilized oral antibiotic therapies in the past and often are interested in alternative options, express concerns regarding antibiotic resistance, report a history of antibiotic-associated yeast infections or other side effects, and/or encounter issues related to drug-drug interactions.^3,5-8 Oral hormonal therapies such as combination oral contraceptives (COCs) or spironolactone often are utilized to treat adult women with AV, sometimes in combination with each other or other agents. Combination oral contraceptives appear to be especially effective in the management of the U-shaped clinical pattern or predominantly inflammatory, late-onset AV.^1,5,9,10 Potential warnings, contraindications, adverse effects, and drug-drug interactions are important to keep in mind when considering the use of oral hormonal therapies.^8-10 Oral isotretinoin, which should be prescribed with strict adherence to the iPLEDGE™ program (https://www.ipledgeprogram.com/), remains a viable option for cases of severe nodular AV and selected cases of refractory inflammatory AV, especially when scarring and/or marked psychosocial distress are noted.^1,2,5,11 Although it is recognized that adult women with AV typically present with either a mixed inflammatory and comedonal or U-shaped clinical pattern predominantly involving the lower face and anterolateral neck, the available data do not adequately differentiate the relative responsiveness of these clinical patterns to specific therapeutic agents.

Combination Oral Contraceptives

Combination oral contraceptives are commonly used to treat AV in adult women, including those without and those with measurable androgen excess (eg, polycystic ovary syndrome [PCOS]). Combination oral contraceptives contain ethinyl estradiol and a progestational agent (eg, progestin); the latter varies in terms of its nonselective receptor interactions and the relative magnitude or absence of androgenic effects.^10,12,13 Although some COCs are approved by the US Food and Drug Administration (FDA) for AV, there is little data available to determine the comparative efficacy among these and other COCs.^10,14 When choosing a COC for treatment of AV, it is best to select an agent whose effectiveness is supported by evidence from clinical studies.^10,15

Mechanisms of Action

The reported mechanisms of action for COCs include inhibition of ovarian androgen production and ovulation through gonadotropin suppression; upregulated synthesis of sex hormone–binding globulin, which decreases free testosterone levels through receptor binding; and inhibition of 5α-reductase (by some progestins), which reduces conversion of testosterone to dihydrotestosterone, the active derivative that induces androgenic effects at peripheral target tissues.^10,13,16,17

Therapeutic Benefits

Use of COCs to treat AV in adult women who do not have measurable androgen excess is most rational in patients who also desire a method of contraception. Multiple monotherapy studies have demonstrated the efficacy of COCs in the treatment of AV on the face and trunk.^{4,10,12,15,17,18} It may take a minimum of 3 monthly cycles of use before acne lesion counts begin to appreciably decrease.^12,15,19-21 Initiating COC therapy during menstruation ensures the absence of pregnancy. Combination oral contraceptives may be used with other topical and oral therapies for AV.^2,3,9,10 Potential ancillary benefits of COCs include normalization of the menstrual cycle; reduced premenstrual dysphoric disorder symptoms; and reduced risk of endometrial cancer (approximately 50%), ovarian cancer (approximately 40%), and colorectal cancer.^22-24

Risks and Contraindications

It is important to consider the potential risks associated with the use of COCs, especially in women with AV who are not seeking a method of contraception. Side effects of COCs can include nausea, breast tenderness, breakthrough bleeding, and weight gain.^25,26 Potential adverse associations of COCs are described in the Table. The major potential vascular associations include venous thromboembolism, myocardial infarction, and cerebrovascular accident, all of which are influenced by concurrent factors such as a history of smoking, age (≥35 years), and hypertension.^27-32 It is recommended that blood pressure be measured before initiating COC therapy as part of the general examination.³³

The potential increase in breast cancer risk appears to be low, while the cervical cancer risk is reported to increase relative to the duration of use.^34-37 This latter observation may be due to the greater likelihood of unprotected sex in women using a COC and exposure to multiple sexual partners in some cases, which may increase the likelihood of oncogenic human papillomavirus infection of the cervix. If a dermatologist elects to prescribe a COC to treat AV, it has been suggested that the patient also consult with her general practitioner or gynecologist to undergo pelvic and breast examinations and a Papanicolaou test.³³ The recommendation for initial screening for cervical cancer is within 3 years of initiation of sexual intercourse or by 21 years of age, whichever is first.^33,38,39

Combination oral contraceptives are not ideal for all adult women with AV. Absolute contraindications are pregnancy and history of thromboembolic, cardiac, or hepatic disease; in women aged 35 years and older who smoke, relative contraindications include hypertension, diabetes, migraines, breastfeeding, and current breast or liver cancer.³³ In adult women with AV who have relative contra-indications but are likely to benefit from the use of a COC when other options are limited or not viable, consultation with a gynecologist is prudent. Other than rifamycin antibiotics (eg, rifampin) and griseofulvin, there is no definitive evidence that oral antibiotics (eg, tetracycline) or oral antifungal agents reduce the contraceptive efficacy of COCs, although cautions remain in print within some approved package inserts.⁸

Spironolactone

Available since 1957, spironolactone is an oral aldos-terone antagonist and potassium-sparing diuretic used to treat hypertension and congestive heart failure.⁹ Recognition of its antiandrogenic effects led to its use in dermatology to treat certain dermatologic disorders in women (eg, hirsutism, alopecia, AV).^1,4,5,9,10 Spironolactone is not approved for AV by the FDA; therefore, available data from multiple independent studies and retrospective analyses that have been collectively reviewed support its efficacy when used as both monotherapy or in combination with other agents in adult women with AV, especially those with a U-shaped pattern and/or late-onset AV.^9,40-43

Mechanism of Action

Spironolactone inhibits sebaceous gland activity through peripheral androgen receptor blockade, inhibition of 5α-reductase, decrease in androgen production, and increase in sex hormone–binding globulin.^9,10,40

Therapeutic Benefits

Good to excellent improvement of AV in women, many of whom are postadolescent, has ranged from 66% to 100% in published reports^9,40-43; however, inclusion and exclusion criteria, dosing regimens, and concomitant therapies were not usually controlled. Spironolactone has been used to treat AV in adult women as monotherapy or in combination with topical agents, oral antibiotics, and COCs.^9,40-42 Additionally, dose-ranging studies have not been completed with spironolactone for AV.^9,40 The suggested dose range is 50 mg to 200 mg daily; however, it usually is best to start at 50 mg daily and increase to 100 mg daily if clinical response is not adequate after 2 to 3 months. The gastrointestinal (GI) absorption of spironolactone is increased when ingested with a high-fat meal.^9,10

Once effective control of AV is achieved, it is optimal to use the lowest dose needed to continue reasonable suppression of new AV lesions. There is no defined end point for spironolactone use in AV, with or without concurrent PCOS, as many adult women usually continue treatment with low-dose therapy because they experience marked flaring shortly after the drug is stopped.⁹

Risks and Contraindications

Side effects associated with spironolactone are dose related and include increased diuresis, migraines, menstrual irregularities, breast tenderness, gynecomastia, fatigue, and dizziness.^9,10,40-44 Side effects (particularly menstrual irregularities and breast tenderness) are more common at doses higher than 100 mg daily, especially when used as monotherapy without concurrent use of a COC.^9,40

Spironolactone-associated hyperkalemia is most clinically relevant in patients on higher doses (eg, 100–200 mg daily), in those with renal impairment and/or congestive heart failure, and when used concurrently with certain other medications. In any patient on spironolactone, the risk of clinically relevant hyperkalemia may be increased by coingestion of potassium supplements, potassium-based salt substitutes, potassium-sparing diuretics (eg, amiloride, triamterene); aldosterone antagonists and angiotensin-converting enzyme inhibitors (eg, lisinopril, benazepril); angiotensin II receptor blockers (eg, losartan, valsartan); and tri-methoprim (with or without sulfamethoxazole).^8,9,40,45 Spironolactone may also increase serum levels of lithium or digoxin.^9,40,45,46 For management of AV, it is best that spironolactone be avoided in patients taking any of these medications.⁹

In healthy adult women with AV who are not on medications or supplements that interact adversely with spironolactone, there is no definitive recommendation regarding monitoring of serum potassium levels during treatment with spironolactone, and it has been suggested that monitoring serum potassium levels in this subgroup is not necessary.⁴⁷ However, each clinician is advised to choose whether or not they wish to obtain baseline and/or periodic serum potassium levels when prescribing spironolactone for AV based on their degree of comfort and the patient’s history. Baseline and periodic blood testing to evaluate serum electrolytes and renal function are reasonable, especially as adult women with AV are usually treated with spironolactone over a prolonged period of time.⁹

The FDA black box warning for spironolactone states that it is tumorigenic in chronic toxicity studies in rats and refers to exposures 25- to 100-fold higher than those administered to humans.^9,48 Although continued vigilance is warranted, evaluation of large populations of women treated with spironolactone do not suggest an association with increased risk of breast cancer.^49,50

Spironolactone is a category C drug and thus should be avoided during pregnancy, primarily due to animal data suggesting risks of hypospadias and feminization in male fetuses.⁹ Importantly, there is an absence of reports linking exposure during pregnancy with congenital defects in humans, including in 2 known cases of high-dose exposures for maternal Bartter syndrome.⁹

The active metabolite, canrenone, is known to be present in breast milk at 0.2% of the maternal daily dose, but breastfeeding is generally believed to be safe with spironolactone based on evidence to date.⁹

Oral Antibiotics

Oral antibiotic therapy may be used in combination with a topical regimen to treat AV in adult women, keeping in mind some important caveats.^1-7 For instance, monotherapy with oral antibiotics should be avoided, and concomitant use of benzoyl peroxide is suggested to reduce emergence of antibiotic-resistant Propionibacterium acnes strains.^3,4 A therapeutic exit plan also is suggested when prescribing oral antibiotics to limit treatment to 3 to 4 months, if possible, to help mitigate the emergence of antibiotic-resistant bacteria (eg, staphylococci and streptococci).^3-5,51

Tetracyclines, especially doxycycline and minocycline, are the most commonly prescribed agents. Doxycycline use warrants patient education on measures to limit the risks of esophageal and GI side effects and phototoxicity; enteric-coated and small tablet formulations have been shown to reduce GI side effects, especially when administered with food.^3,52-55 In addition to vestibular side effects and hyperpigmentation, minocycline may be associated with rare but potentially severe adverse reactions such as drug hypersensitivity syndrome, autoimmune hepatitis, and lupus-like syndrome, which are reported more commonly in women.^5,52,54 Vestibular side effects have been shown to decrease with use of extended-release tablets with weight-based dosing.⁵³

Oral Isotretinoin

Oral isotretinoin is well established as highly effective for treatment of severe, recalcitrant AV, including nodular acne on the face and trunk.^4,56 Currently available oral isotretinoins are branded generic formulations based on the pharmacokinetic profile of the original brand (Accutane [Roche Pharmaceuticals]) and with the use of Lidose Technology (Absorica [Cipher Pharmaceuticals]), which substantially increases GI absorption of isotretinoin in the absence of ingestion with a high-calorie, high-fat meal.⁵⁷ The short- and long-term efficacy, dosing regimens, safety considerations, and serious teratogenic risks for oral isotretinoin are well published.^4,56-58 Importantly, oral isotretinoin must be prescribed with strict adherence to the federally mandated iPLEDGE risk management program.

Low-dose oral isotretinoin therapy (<0.5 mg/kg–1 mg/kg daily) administered over several months longer than conventional regimens (ie, 16–20 weeks) has been suggested with demonstrated efficacy.⁵⁷ However, this approach is not optimal due to the lack of established sustained clearance of AV after discontinuation of therapy and the greater potential for exposure to isotretinoin during pregnancy. Recurrences of AV do occur after completion of isotretinoin therapy, especially if cumulative systemic exposure to the drug during the initial course of treatment was inadequate.^56,57

Oral isotretinoin has been shown to be effective in AV in adult women with or without PCOS with 0.5 mg/kg to 1 mg/kg daily and a total cumulative exposure of 120 mg/kg to 150 mg/kg.⁵⁹ In one study, the presence of PCOS and greater number of nodules at baseline were predictive of a higher risk of relapse during the second year posttreatment.⁵⁹

Conclusion

All oral therapies that are used to treat AV in adult women warrant individual consideration of possible benefits versus risks. Careful attention to possible side effects, patient-related risk factors, and potential drug-drug interactions is important. End points of therapy are not well established, with the exception of oral isotretinoin therapy. Clinicians must use their judgment in each case along with obtaining feedback from patients regarding the selection of therapy after a discussion of the available options.

Selection of oral agents for treatment of AV in adult women is dependent on multiple factors including the patient’s age, medication history, child-bearing potential, clinical presentation, and treatment preference following a discussion of the anticipated benefits versus potential risks.^1,2 In patients with the mixed inflammatory and comedonal clinical pattern of AV, oral antibiotics can be used concurrently with topical therapies when moderate to severe inflammatory lesions are noted.^3,4 However, many adult women who had AV as teenagers have already utilized oral antibiotic therapies in the past and often are interested in alternative options, express concerns regarding antibiotic resistance, report a history of antibiotic-associated yeast infections or other side effects, and/or encounter issues related to drug-drug interactions.^3,5-8 Oral hormonal therapies such as combination oral contraceptives (COCs) or spironolactone often are utilized to treat adult women with AV, sometimes in combination with each other or other agents. Combination oral contraceptives appear to be especially effective in the management of the U-shaped clinical pattern or predominantly inflammatory, late-onset AV.^1,5,9,10 Potential warnings, contraindications, adverse effects, and drug-drug interactions are important to keep in mind when considering the use of oral hormonal therapies.^8-10 Oral isotretinoin, which should be prescribed with strict adherence to the iPLEDGE™ program (https://www.ipledgeprogram.com/), remains a viable option for cases of severe nodular AV and selected cases of refractory inflammatory AV, especially when scarring and/or marked psychosocial distress are noted.^1,2,5,11 Although it is recognized that adult women with AV typically present with either a mixed inflammatory and comedonal or U-shaped clinical pattern predominantly involving the lower face and anterolateral neck, the available data do not adequately differentiate the relative responsiveness of these clinical patterns to specific therapeutic agents.

Combination Oral Contraceptives

Combination oral contraceptives are commonly used to treat AV in adult women, including those without and those with measurable androgen excess (eg, polycystic ovary syndrome [PCOS]). Combination oral contraceptives contain ethinyl estradiol and a progestational agent (eg, progestin); the latter varies in terms of its nonselective receptor interactions and the relative magnitude or absence of androgenic effects.^10,12,13 Although some COCs are approved by the US Food and Drug Administration (FDA) for AV, there is little data available to determine the comparative efficacy among these and other COCs.^10,14 When choosing a COC for treatment of AV, it is best to select an agent whose effectiveness is supported by evidence from clinical studies.^10,15

Mechanisms of Action

The reported mechanisms of action for COCs include inhibition of ovarian androgen production and ovulation through gonadotropin suppression; upregulated synthesis of sex hormone–binding globulin, which decreases free testosterone levels through receptor binding; and inhibition of 5α-reductase (by some progestins), which reduces conversion of testosterone to dihydrotestosterone, the active derivative that induces androgenic effects at peripheral target tissues.^10,13,16,17

Therapeutic Benefits

Use of COCs to treat AV in adult women who do not have measurable androgen excess is most rational in patients who also desire a method of contraception. Multiple monotherapy studies have demonstrated the efficacy of COCs in the treatment of AV on the face and trunk.^{4,10,12,15,17,18} It may take a minimum of 3 monthly cycles of use before acne lesion counts begin to appreciably decrease.^12,15,19-21 Initiating COC therapy during menstruation ensures the absence of pregnancy. Combination oral contraceptives may be used with other topical and oral therapies for AV.^2,3,9,10 Potential ancillary benefits of COCs include normalization of the menstrual cycle; reduced premenstrual dysphoric disorder symptoms; and reduced risk of endometrial cancer (approximately 50%), ovarian cancer (approximately 40%), and colorectal cancer.^22-24

Risks and Contraindications

It is important to consider the potential risks associated with the use of COCs, especially in women with AV who are not seeking a method of contraception. Side effects of COCs can include nausea, breast tenderness, breakthrough bleeding, and weight gain.^25,26 Potential adverse associations of COCs are described in the Table. The major potential vascular associations include venous thromboembolism, myocardial infarction, and cerebrovascular accident, all of which are influenced by concurrent factors such as a history of smoking, age (≥35 years), and hypertension.^27-32 It is recommended that blood pressure be measured before initiating COC therapy as part of the general examination.³³

The potential increase in breast cancer risk appears to be low, while the cervical cancer risk is reported to increase relative to the duration of use.^34-37 This latter observation may be due to the greater likelihood of unprotected sex in women using a COC and exposure to multiple sexual partners in some cases, which may increase the likelihood of oncogenic human papillomavirus infection of the cervix. If a dermatologist elects to prescribe a COC to treat AV, it has been suggested that the patient also consult with her general practitioner or gynecologist to undergo pelvic and breast examinations and a Papanicolaou test.³³ The recommendation for initial screening for cervical cancer is within 3 years of initiation of sexual intercourse or by 21 years of age, whichever is first.^33,38,39

Combination oral contraceptives are not ideal for all adult women with AV. Absolute contraindications are pregnancy and history of thromboembolic, cardiac, or hepatic disease; in women aged 35 years and older who smoke, relative contraindications include hypertension, diabetes, migraines, breastfeeding, and current breast or liver cancer.³³ In adult women with AV who have relative contra-indications but are likely to benefit from the use of a COC when other options are limited or not viable, consultation with a gynecologist is prudent. Other than rifamycin antibiotics (eg, rifampin) and griseofulvin, there is no definitive evidence that oral antibiotics (eg, tetracycline) or oral antifungal agents reduce the contraceptive efficacy of COCs, although cautions remain in print within some approved package inserts.⁸

Spironolactone

Available since 1957, spironolactone is an oral aldos-terone antagonist and potassium-sparing diuretic used to treat hypertension and congestive heart failure.⁹ Recognition of its antiandrogenic effects led to its use in dermatology to treat certain dermatologic disorders in women (eg, hirsutism, alopecia, AV).^1,4,5,9,10 Spironolactone is not approved for AV by the FDA; therefore, available data from multiple independent studies and retrospective analyses that have been collectively reviewed support its efficacy when used as both monotherapy or in combination with other agents in adult women with AV, especially those with a U-shaped pattern and/or late-onset AV.^9,40-43

Mechanism of Action

Spironolactone inhibits sebaceous gland activity through peripheral androgen receptor blockade, inhibition of 5α-reductase, decrease in androgen production, and increase in sex hormone–binding globulin.^9,10,40

Therapeutic Benefits

Good to excellent improvement of AV in women, many of whom are postadolescent, has ranged from 66% to 100% in published reports^9,40-43; however, inclusion and exclusion criteria, dosing regimens, and concomitant therapies were not usually controlled. Spironolactone has been used to treat AV in adult women as monotherapy or in combination with topical agents, oral antibiotics, and COCs.^9,40-42 Additionally, dose-ranging studies have not been completed with spironolactone for AV.^9,40 The suggested dose range is 50 mg to 200 mg daily; however, it usually is best to start at 50 mg daily and increase to 100 mg daily if clinical response is not adequate after 2 to 3 months. The gastrointestinal (GI) absorption of spironolactone is increased when ingested with a high-fat meal.^9,10

Once effective control of AV is achieved, it is optimal to use the lowest dose needed to continue reasonable suppression of new AV lesions. There is no defined end point for spironolactone use in AV, with or without concurrent PCOS, as many adult women usually continue treatment with low-dose therapy because they experience marked flaring shortly after the drug is stopped.⁹

Risks and Contraindications

Side effects associated with spironolactone are dose related and include increased diuresis, migraines, menstrual irregularities, breast tenderness, gynecomastia, fatigue, and dizziness.^9,10,40-44 Side effects (particularly menstrual irregularities and breast tenderness) are more common at doses higher than 100 mg daily, especially when used as monotherapy without concurrent use of a COC.^9,40

Spironolactone-associated hyperkalemia is most clinically relevant in patients on higher doses (eg, 100–200 mg daily), in those with renal impairment and/or congestive heart failure, and when used concurrently with certain other medications. In any patient on spironolactone, the risk of clinically relevant hyperkalemia may be increased by coingestion of potassium supplements, potassium-based salt substitutes, potassium-sparing diuretics (eg, amiloride, triamterene); aldosterone antagonists and angiotensin-converting enzyme inhibitors (eg, lisinopril, benazepril); angiotensin II receptor blockers (eg, losartan, valsartan); and tri-methoprim (with or without sulfamethoxazole).^8,9,40,45 Spironolactone may also increase serum levels of lithium or digoxin.^9,40,45,46 For management of AV, it is best that spironolactone be avoided in patients taking any of these medications.⁹

In healthy adult women with AV who are not on medications or supplements that interact adversely with spironolactone, there is no definitive recommendation regarding monitoring of serum potassium levels during treatment with spironolactone, and it has been suggested that monitoring serum potassium levels in this subgroup is not necessary.⁴⁷ However, each clinician is advised to choose whether or not they wish to obtain baseline and/or periodic serum potassium levels when prescribing spironolactone for AV based on their degree of comfort and the patient’s history. Baseline and periodic blood testing to evaluate serum electrolytes and renal function are reasonable, especially as adult women with AV are usually treated with spironolactone over a prolonged period of time.⁹

The FDA black box warning for spironolactone states that it is tumorigenic in chronic toxicity studies in rats and refers to exposures 25- to 100-fold higher than those administered to humans.^9,48 Although continued vigilance is warranted, evaluation of large populations of women treated with spironolactone do not suggest an association with increased risk of breast cancer.^49,50

Spironolactone is a category C drug and thus should be avoided during pregnancy, primarily due to animal data suggesting risks of hypospadias and feminization in male fetuses.⁹ Importantly, there is an absence of reports linking exposure during pregnancy with congenital defects in humans, including in 2 known cases of high-dose exposures for maternal Bartter syndrome.⁹

The active metabolite, canrenone, is known to be present in breast milk at 0.2% of the maternal daily dose, but breastfeeding is generally believed to be safe with spironolactone based on evidence to date.⁹

Oral Antibiotics

Oral antibiotic therapy may be used in combination with a topical regimen to treat AV in adult women, keeping in mind some important caveats.^1-7 For instance, monotherapy with oral antibiotics should be avoided, and concomitant use of benzoyl peroxide is suggested to reduce emergence of antibiotic-resistant Propionibacterium acnes strains.^3,4 A therapeutic exit plan also is suggested when prescribing oral antibiotics to limit treatment to 3 to 4 months, if possible, to help mitigate the emergence of antibiotic-resistant bacteria (eg, staphylococci and streptococci).^3-5,51

Tetracyclines, especially doxycycline and minocycline, are the most commonly prescribed agents. Doxycycline use warrants patient education on measures to limit the risks of esophageal and GI side effects and phototoxicity; enteric-coated and small tablet formulations have been shown to reduce GI side effects, especially when administered with food.^3,52-55 In addition to vestibular side effects and hyperpigmentation, minocycline may be associated with rare but potentially severe adverse reactions such as drug hypersensitivity syndrome, autoimmune hepatitis, and lupus-like syndrome, which are reported more commonly in women.^5,52,54 Vestibular side effects have been shown to decrease with use of extended-release tablets with weight-based dosing.⁵³

Oral Isotretinoin

Oral isotretinoin is well established as highly effective for treatment of severe, recalcitrant AV, including nodular acne on the face and trunk.^4,56 Currently available oral isotretinoins are branded generic formulations based on the pharmacokinetic profile of the original brand (Accutane [Roche Pharmaceuticals]) and with the use of Lidose Technology (Absorica [Cipher Pharmaceuticals]), which substantially increases GI absorption of isotretinoin in the absence of ingestion with a high-calorie, high-fat meal.⁵⁷ The short- and long-term efficacy, dosing regimens, safety considerations, and serious teratogenic risks for oral isotretinoin are well published.^4,56-58 Importantly, oral isotretinoin must be prescribed with strict adherence to the federally mandated iPLEDGE risk management program.

Low-dose oral isotretinoin therapy (<0.5 mg/kg–1 mg/kg daily) administered over several months longer than conventional regimens (ie, 16–20 weeks) has been suggested with demonstrated efficacy.⁵⁷ However, this approach is not optimal due to the lack of established sustained clearance of AV after discontinuation of therapy and the greater potential for exposure to isotretinoin during pregnancy. Recurrences of AV do occur after completion of isotretinoin therapy, especially if cumulative systemic exposure to the drug during the initial course of treatment was inadequate.^56,57

Oral isotretinoin has been shown to be effective in AV in adult women with or without PCOS with 0.5 mg/kg to 1 mg/kg daily and a total cumulative exposure of 120 mg/kg to 150 mg/kg.⁵⁹ In one study, the presence of PCOS and greater number of nodules at baseline were predictive of a higher risk of relapse during the second year posttreatment.⁵⁹

Conclusion

All oral therapies that are used to treat AV in adult women warrant individual consideration of possible benefits versus risks. Careful attention to possible side effects, patient-related risk factors, and potential drug-drug interactions is important. End points of therapy are not well established, with the exception of oral isotretinoin therapy. Clinicians must use their judgment in each case along with obtaining feedback from patients regarding the selection of therapy after a discussion of the available options.

Selection of oral agents for treatment of AV in adult women is dependent on multiple factors including the patient’s age, medication history, child-bearing potential, clinical presentation, and treatment preference following a discussion of the anticipated benefits versus potential risks.^1,2 In patients with the mixed inflammatory and comedonal clinical pattern of AV, oral antibiotics can be used concurrently with topical therapies when moderate to severe inflammatory lesions are noted.^3,4 However, many adult women who had AV as teenagers have already utilized oral antibiotic therapies in the past and often are interested in alternative options, express concerns regarding antibiotic resistance, report a history of antibiotic-associated yeast infections or other side effects, and/or encounter issues related to drug-drug interactions.^3,5-8 Oral hormonal therapies such as combination oral contraceptives (COCs) or spironolactone often are utilized to treat adult women with AV, sometimes in combination with each other or other agents. Combination oral contraceptives appear to be especially effective in the management of the U-shaped clinical pattern or predominantly inflammatory, late-onset AV.^1,5,9,10 Potential warnings, contraindications, adverse effects, and drug-drug interactions are important to keep in mind when considering the use of oral hormonal therapies.^8-10 Oral isotretinoin, which should be prescribed with strict adherence to the iPLEDGE™ program (https://www.ipledgeprogram.com/), remains a viable option for cases of severe nodular AV and selected cases of refractory inflammatory AV, especially when scarring and/or marked psychosocial distress are noted.^1,2,5,11 Although it is recognized that adult women with AV typically present with either a mixed inflammatory and comedonal or U-shaped clinical pattern predominantly involving the lower face and anterolateral neck, the available data do not adequately differentiate the relative responsiveness of these clinical patterns to specific therapeutic agents.

Combination Oral Contraceptives

Combination oral contraceptives are commonly used to treat AV in adult women, including those without and those with measurable androgen excess (eg, polycystic ovary syndrome [PCOS]). Combination oral contraceptives contain ethinyl estradiol and a progestational agent (eg, progestin); the latter varies in terms of its nonselective receptor interactions and the relative magnitude or absence of androgenic effects.^10,12,13 Although some COCs are approved by the US Food and Drug Administration (FDA) for AV, there is little data available to determine the comparative efficacy among these and other COCs.^10,14 When choosing a COC for treatment of AV, it is best to select an agent whose effectiveness is supported by evidence from clinical studies.^10,15

Mechanisms of Action

The reported mechanisms of action for COCs include inhibition of ovarian androgen production and ovulation through gonadotropin suppression; upregulated synthesis of sex hormone–binding globulin, which decreases free testosterone levels through receptor binding; and inhibition of 5α-reductase (by some progestins), which reduces conversion of testosterone to dihydrotestosterone, the active derivative that induces androgenic effects at peripheral target tissues.^10,13,16,17

Therapeutic Benefits

Use of COCs to treat AV in adult women who do not have measurable androgen excess is most rational in patients who also desire a method of contraception. Multiple monotherapy studies have demonstrated the efficacy of COCs in the treatment of AV on the face and trunk.^{4,10,12,15,17,18} It may take a minimum of 3 monthly cycles of use before acne lesion counts begin to appreciably decrease.^12,15,19-21 Initiating COC therapy during menstruation ensures the absence of pregnancy. Combination oral contraceptives may be used with other topical and oral therapies for AV.^2,3,9,10 Potential ancillary benefits of COCs include normalization of the menstrual cycle; reduced premenstrual dysphoric disorder symptoms; and reduced risk of endometrial cancer (approximately 50%), ovarian cancer (approximately 40%), and colorectal cancer.^22-24

Risks and Contraindications

It is important to consider the potential risks associated with the use of COCs, especially in women with AV who are not seeking a method of contraception. Side effects of COCs can include nausea, breast tenderness, breakthrough bleeding, and weight gain.^25,26 Potential adverse associations of COCs are described in the Table. The major potential vascular associations include venous thromboembolism, myocardial infarction, and cerebrovascular accident, all of which are influenced by concurrent factors such as a history of smoking, age (≥35 years), and hypertension.^27-32 It is recommended that blood pressure be measured before initiating COC therapy as part of the general examination.³³

The potential increase in breast cancer risk appears to be low, while the cervical cancer risk is reported to increase relative to the duration of use.^34-37 This latter observation may be due to the greater likelihood of unprotected sex in women using a COC and exposure to multiple sexual partners in some cases, which may increase the likelihood of oncogenic human papillomavirus infection of the cervix. If a dermatologist elects to prescribe a COC to treat AV, it has been suggested that the patient also consult with her general practitioner or gynecologist to undergo pelvic and breast examinations and a Papanicolaou test.³³ The recommendation for initial screening for cervical cancer is within 3 years of initiation of sexual intercourse or by 21 years of age, whichever is first.^33,38,39

Combination oral contraceptives are not ideal for all adult women with AV. Absolute contraindications are pregnancy and history of thromboembolic, cardiac, or hepatic disease; in women aged 35 years and older who smoke, relative contraindications include hypertension, diabetes, migraines, breastfeeding, and current breast or liver cancer.³³ In adult women with AV who have relative contra-indications but are likely to benefit from the use of a COC when other options are limited or not viable, consultation with a gynecologist is prudent. Other than rifamycin antibiotics (eg, rifampin) and griseofulvin, there is no definitive evidence that oral antibiotics (eg, tetracycline) or oral antifungal agents reduce the contraceptive efficacy of COCs, although cautions remain in print within some approved package inserts.⁸

Spironolactone

Available since 1957, spironolactone is an oral aldos-terone antagonist and potassium-sparing diuretic used to treat hypertension and congestive heart failure.⁹ Recognition of its antiandrogenic effects led to its use in dermatology to treat certain dermatologic disorders in women (eg, hirsutism, alopecia, AV).^1,4,5,9,10 Spironolactone is not approved for AV by the FDA; therefore, available data from multiple independent studies and retrospective analyses that have been collectively reviewed support its efficacy when used as both monotherapy or in combination with other agents in adult women with AV, especially those with a U-shaped pattern and/or late-onset AV.^9,40-43

Mechanism of Action

Spironolactone inhibits sebaceous gland activity through peripheral androgen receptor blockade, inhibition of 5α-reductase, decrease in androgen production, and increase in sex hormone–binding globulin.^9,10,40

Therapeutic Benefits

Good to excellent improvement of AV in women, many of whom are postadolescent, has ranged from 66% to 100% in published reports^9,40-43; however, inclusion and exclusion criteria, dosing regimens, and concomitant therapies were not usually controlled. Spironolactone has been used to treat AV in adult women as monotherapy or in combination with topical agents, oral antibiotics, and COCs.^9,40-42 Additionally, dose-ranging studies have not been completed with spironolactone for AV.^9,40 The suggested dose range is 50 mg to 200 mg daily; however, it usually is best to start at 50 mg daily and increase to 100 mg daily if clinical response is not adequate after 2 to 3 months. The gastrointestinal (GI) absorption of spironolactone is increased when ingested with a high-fat meal.^9,10

Once effective control of AV is achieved, it is optimal to use the lowest dose needed to continue reasonable suppression of new AV lesions. There is no defined end point for spironolactone use in AV, with or without concurrent PCOS, as many adult women usually continue treatment with low-dose therapy because they experience marked flaring shortly after the drug is stopped.⁹

Risks and Contraindications

Side effects associated with spironolactone are dose related and include increased diuresis, migraines, menstrual irregularities, breast tenderness, gynecomastia, fatigue, and dizziness.^9,10,40-44 Side effects (particularly menstrual irregularities and breast tenderness) are more common at doses higher than 100 mg daily, especially when used as monotherapy without concurrent use of a COC.^9,40

Spironolactone-associated hyperkalemia is most clinically relevant in patients on higher doses (eg, 100–200 mg daily), in those with renal impairment and/or congestive heart failure, and when used concurrently with certain other medications. In any patient on spironolactone, the risk of clinically relevant hyperkalemia may be increased by coingestion of potassium supplements, potassium-based salt substitutes, potassium-sparing diuretics (eg, amiloride, triamterene); aldosterone antagonists and angiotensin-converting enzyme inhibitors (eg, lisinopril, benazepril); angiotensin II receptor blockers (eg, losartan, valsartan); and tri-methoprim (with or without sulfamethoxazole).^8,9,40,45 Spironolactone may also increase serum levels of lithium or digoxin.^9,40,45,46 For management of AV, it is best that spironolactone be avoided in patients taking any of these medications.⁹

In healthy adult women with AV who are not on medications or supplements that interact adversely with spironolactone, there is no definitive recommendation regarding monitoring of serum potassium levels during treatment with spironolactone, and it has been suggested that monitoring serum potassium levels in this subgroup is not necessary.⁴⁷ However, each clinician is advised to choose whether or not they wish to obtain baseline and/or periodic serum potassium levels when prescribing spironolactone for AV based on their degree of comfort and the patient’s history. Baseline and periodic blood testing to evaluate serum electrolytes and renal function are reasonable, especially as adult women with AV are usually treated with spironolactone over a prolonged period of time.⁹

The FDA black box warning for spironolactone states that it is tumorigenic in chronic toxicity studies in rats and refers to exposures 25- to 100-fold higher than those administered to humans.^9,48 Although continued vigilance is warranted, evaluation of large populations of women treated with spironolactone do not suggest an association with increased risk of breast cancer.^49,50

Spironolactone is a category C drug and thus should be avoided during pregnancy, primarily due to animal data suggesting risks of hypospadias and feminization in male fetuses.⁹ Importantly, there is an absence of reports linking exposure during pregnancy with congenital defects in humans, including in 2 known cases of high-dose exposures for maternal Bartter syndrome.⁹

The active metabolite, canrenone, is known to be present in breast milk at 0.2% of the maternal daily dose, but breastfeeding is generally believed to be safe with spironolactone based on evidence to date.⁹

Oral Antibiotics

Oral antibiotic therapy may be used in combination with a topical regimen to treat AV in adult women, keeping in mind some important caveats.^1-7 For instance, monotherapy with oral antibiotics should be avoided, and concomitant use of benzoyl peroxide is suggested to reduce emergence of antibiotic-resistant Propionibacterium acnes strains.^3,4 A therapeutic exit plan also is suggested when prescribing oral antibiotics to limit treatment to 3 to 4 months, if possible, to help mitigate the emergence of antibiotic-resistant bacteria (eg, staphylococci and streptococci).^3-5,51

Tetracyclines, especially doxycycline and minocycline, are the most commonly prescribed agents. Doxycycline use warrants patient education on measures to limit the risks of esophageal and GI side effects and phototoxicity; enteric-coated and small tablet formulations have been shown to reduce GI side effects, especially when administered with food.^3,52-55 In addition to vestibular side effects and hyperpigmentation, minocycline may be associated with rare but potentially severe adverse reactions such as drug hypersensitivity syndrome, autoimmune hepatitis, and lupus-like syndrome, which are reported more commonly in women.^5,52,54 Vestibular side effects have been shown to decrease with use of extended-release tablets with weight-based dosing.⁵³

Oral Isotretinoin

Oral isotretinoin is well established as highly effective for treatment of severe, recalcitrant AV, including nodular acne on the face and trunk.^4,56 Currently available oral isotretinoins are branded generic formulations based on the pharmacokinetic profile of the original brand (Accutane [Roche Pharmaceuticals]) and with the use of Lidose Technology (Absorica [Cipher Pharmaceuticals]), which substantially increases GI absorption of isotretinoin in the absence of ingestion with a high-calorie, high-fat meal.⁵⁷ The short- and long-term efficacy, dosing regimens, safety considerations, and serious teratogenic risks for oral isotretinoin are well published.^4,56-58 Importantly, oral isotretinoin must be prescribed with strict adherence to the federally mandated iPLEDGE risk management program.

Low-dose oral isotretinoin therapy (<0.5 mg/kg–1 mg/kg daily) administered over several months longer than conventional regimens (ie, 16–20 weeks) has been suggested with demonstrated efficacy.⁵⁷ However, this approach is not optimal due to the lack of established sustained clearance of AV after discontinuation of therapy and the greater potential for exposure to isotretinoin during pregnancy. Recurrences of AV do occur after completion of isotretinoin therapy, especially if cumulative systemic exposure to the drug during the initial course of treatment was inadequate.^56,57

Oral isotretinoin has been shown to be effective in AV in adult women with or without PCOS with 0.5 mg/kg to 1 mg/kg daily and a total cumulative exposure of 120 mg/kg to 150 mg/kg.⁵⁹ In one study, the presence of PCOS and greater number of nodules at baseline were predictive of a higher risk of relapse during the second year posttreatment.⁵⁹

Conclusion

All oral therapies that are used to treat AV in adult women warrant individual consideration of possible benefits versus risks. Careful attention to possible side effects, patient-related risk factors, and potential drug-drug interactions is important. End points of therapy are not well established, with the exception of oral isotretinoin therapy. Clinicians must use their judgment in each case along with obtaining feedback from patients regarding the selection of therapy after a discussion of the available options.

LONDON - Researchers voiced concern on Nov. 25 about poor quality studies on the popular ADHD treatment methylphenidate, saying evidence of some benefits, but also of sleep problems and appetite loss, suggests the drug should be prescribed with caution.

Methylphenidate (brand names Ritalin, Concerta, Medikinet and Equasym) has been used to treat attention deficit hyperactivity disorder (ADHD) for more than 50 years.

The Cochrane Review researchers, who conducted a full assessment of studies on the benefits and harms of methylphenidate, said evidence on its use in children was poor.

"Our expectations of this treatment are probably greater than they should be," said Morris Zwi, a London-based consultant child and adolescent psychiatrist, who worked on the review.

"Whilst our review shows some evidence of benefit, we should bear in mind that this finding was based on very low-quality evidence. What we still need are large, well-conducted trials to clarify the risks versus the benefits."

Cochrane Reviews are conducted by international panels of independent researchers and considered as studies of the best available science on a topic.

Jonathan Green, a professor of child and adolescent psychiatry at Britain's Manchester University who was asked to comment on the Cochrane Review, said it would be "wrong to draw the conclusion... that methylphenidate is ineffective.

"In fact, clinical level evidence strongly supports the effectiveness of methylphenidate for many children with ADHD."

The Cochrane Review included data from 185 randomized controlled trials involving more than 12,000 children or adolescents. The studies were conducted mainly in the United States, Canada and Europe, and each one compared methylphenidate with either a placebo or no intervention.

In their review, the Cochrane researchers found that methylphenidate led to modest improvements in ADHD symptoms, general behavior, and quality of life, but that side-effects included a higher risk of sleep problems and loss of appetite.

The researchers added, however, that their confidence in the evidence was low since many of the trials were not conducted with sufficient rigor and results reporting was not complete.

"Clinicians prescribing methylphenidate must take account of the poor quality of the evidence, monitor treatment carefully, and weigh up the benefits and adverse effects," they said.

The analysis was published online Nov. 25 in the Cochrane Library.

LONDON - Researchers voiced concern on Nov. 25 about poor quality studies on the popular ADHD treatment methylphenidate, saying evidence of some benefits, but also of sleep problems and appetite loss, suggests the drug should be prescribed with caution.

Methylphenidate (brand names Ritalin, Concerta, Medikinet and Equasym) has been used to treat attention deficit hyperactivity disorder (ADHD) for more than 50 years.

The Cochrane Review researchers, who conducted a full assessment of studies on the benefits and harms of methylphenidate, said evidence on its use in children was poor.

"Our expectations of this treatment are probably greater than they should be," said Morris Zwi, a London-based consultant child and adolescent psychiatrist, who worked on the review.

"Whilst our review shows some evidence of benefit, we should bear in mind that this finding was based on very low-quality evidence. What we still need are large, well-conducted trials to clarify the risks versus the benefits."

Cochrane Reviews are conducted by international panels of independent researchers and considered as studies of the best available science on a topic.

Jonathan Green, a professor of child and adolescent psychiatry at Britain's Manchester University who was asked to comment on the Cochrane Review, said it would be "wrong to draw the conclusion... that methylphenidate is ineffective.

"In fact, clinical level evidence strongly supports the effectiveness of methylphenidate for many children with ADHD."

The Cochrane Review included data from 185 randomized controlled trials involving more than 12,000 children or adolescents. The studies were conducted mainly in the United States, Canada and Europe, and each one compared methylphenidate with either a placebo or no intervention.

In their review, the Cochrane researchers found that methylphenidate led to modest improvements in ADHD symptoms, general behavior, and quality of life, but that side-effects included a higher risk of sleep problems and loss of appetite.

The researchers added, however, that their confidence in the evidence was low since many of the trials were not conducted with sufficient rigor and results reporting was not complete.

"Clinicians prescribing methylphenidate must take account of the poor quality of the evidence, monitor treatment carefully, and weigh up the benefits and adverse effects," they said.

The analysis was published online Nov. 25 in the Cochrane Library.

LONDON - Researchers voiced concern on Nov. 25 about poor quality studies on the popular ADHD treatment methylphenidate, saying evidence of some benefits, but also of sleep problems and appetite loss, suggests the drug should be prescribed with caution.

Methylphenidate (brand names Ritalin, Concerta, Medikinet and Equasym) has been used to treat attention deficit hyperactivity disorder (ADHD) for more than 50 years.

The Cochrane Review researchers, who conducted a full assessment of studies on the benefits and harms of methylphenidate, said evidence on its use in children was poor.

"Our expectations of this treatment are probably greater than they should be," said Morris Zwi, a London-based consultant child and adolescent psychiatrist, who worked on the review.

"Whilst our review shows some evidence of benefit, we should bear in mind that this finding was based on very low-quality evidence. What we still need are large, well-conducted trials to clarify the risks versus the benefits."

Cochrane Reviews are conducted by international panels of independent researchers and considered as studies of the best available science on a topic.

Jonathan Green, a professor of child and adolescent psychiatry at Britain's Manchester University who was asked to comment on the Cochrane Review, said it would be "wrong to draw the conclusion... that methylphenidate is ineffective.

"In fact, clinical level evidence strongly supports the effectiveness of methylphenidate for many children with ADHD."

The Cochrane Review included data from 185 randomized controlled trials involving more than 12,000 children or adolescents. The studies were conducted mainly in the United States, Canada and Europe, and each one compared methylphenidate with either a placebo or no intervention.

In their review, the Cochrane researchers found that methylphenidate led to modest improvements in ADHD symptoms, general behavior, and quality of life, but that side-effects included a higher risk of sleep problems and loss of appetite.

The researchers added, however, that their confidence in the evidence was low since many of the trials were not conducted with sufficient rigor and results reporting was not complete.

"Clinicians prescribing methylphenidate must take account of the poor quality of the evidence, monitor treatment carefully, and weigh up the benefits and adverse effects," they said.

The analysis was published online Nov. 25 in the Cochrane Library.

Intracerebral hemorrhage related to non–vitamin-K antagonist oral anticoagulants carries a high mortality and frequently involves hematoma expansion, according to a report published online Dec. 14 in JAMA Neurology.

The characteristics and natural history of acute-phase non–vitamin-K antagonist oral anticoagulant (NOAC)-associated intracerebral hemorrhage (ICH) “are largely unknown,” and there are no prospective data concerning hematoma expansion or the effectiveness of prothrombin complex concentrate in limiting that expansion by reversing anticoagulation. Nevertheless, current recommendations suggest that clinicians consider administering prothrombin complex concentrate in this patient population, said Dr. Jan C. Purrucker of the department of neurology at Heidelberg (Germany) University and his associates (JAMA Neurol. 2015 Dec 14. doi: 10.1001/jamaneurol.2015.3682).

To characterize the clinical and radiologic course, management, and outcome of NOAC-associated intracerebral hemorrhage in routine clinical practice, Dr. Purrucker and his associates performed the ICH substudy of the Registry of Acute Stroke Under New Oral Anticoagulants (RASUNOA). This is a prospective registry involving 38 neurology departments with certified stroke units across Germany. For their substudy, the investigators focused on 61 adults with a mean age of 76 years (range, 46-97 years) who were taking NOACs (apixaban [Eliquis], dabigatran etexilate [Pradaxa], or rivaroxaban [Xarelto]) and had moderate to severe neurologic deficit and a median hematoma volume of 10.8 mL at presentation. Thirty-five of these patients (57%) were treated with prothrombin complex concentrate.

Mortality was high, at 16% (10 patients) during the acute inpatient stay and 28% (17 patients) at 3 months; 65% of the survivors had an unfavorable outcome. Substantial hematoma expansion – defined as a 33% or greater relative increase or 6 mL or greater absolute increase in ICH volume – was common, affecting 38% of patients. “This proportion was within the range reported for vitamin-K antagonist–associated intracerebral hemorrhage (36%-56%) and is higher, compared with that related to intracerebral hemorrhage in patients not receiving anticoagulation (12%-26%),” the investigators wrote.

Both larger hematoma volume at baseline (odds ratio, 2.37) and intraventricular extension at baseline (OR, 8.13) strongly correlated with adverse outcomes. In contrast, prothrombin complex concentrate failed to limit lesion expansion or avert adverse outcomes. This might be because patients given the treatment tended to have more severe initial neurologic deficits and more unfavorable hematoma location than did those who weren’t given prothrombin complex concentrate. In any case, “our study design, the limited sample size, and the potential for confounding by indication do not allow any [firm] conclusions regarding a potential association between prothrombin complex concentrate treatment and outcome,” they noted.

The RASUNOA registry was supported by the University Hospital Heidelberg. Dr. Purrucker reported receiving support from Pfizer unrelated to this study, and his associates reported ties to numerous industry sources.

Intracerebral hemorrhage related to non–vitamin-K antagonist oral anticoagulants carries a high mortality and frequently involves hematoma expansion, according to a report published online Dec. 14 in JAMA Neurology.

The characteristics and natural history of acute-phase non–vitamin-K antagonist oral anticoagulant (NOAC)-associated intracerebral hemorrhage (ICH) “are largely unknown,” and there are no prospective data concerning hematoma expansion or the effectiveness of prothrombin complex concentrate in limiting that expansion by reversing anticoagulation. Nevertheless, current recommendations suggest that clinicians consider administering prothrombin complex concentrate in this patient population, said Dr. Jan C. Purrucker of the department of neurology at Heidelberg (Germany) University and his associates (JAMA Neurol. 2015 Dec 14. doi: 10.1001/jamaneurol.2015.3682).

To characterize the clinical and radiologic course, management, and outcome of NOAC-associated intracerebral hemorrhage in routine clinical practice, Dr. Purrucker and his associates performed the ICH substudy of the Registry of Acute Stroke Under New Oral Anticoagulants (RASUNOA). This is a prospective registry involving 38 neurology departments with certified stroke units across Germany. For their substudy, the investigators focused on 61 adults with a mean age of 76 years (range, 46-97 years) who were taking NOACs (apixaban [Eliquis], dabigatran etexilate [Pradaxa], or rivaroxaban [Xarelto]) and had moderate to severe neurologic deficit and a median hematoma volume of 10.8 mL at presentation. Thirty-five of these patients (57%) were treated with prothrombin complex concentrate.

Mortality was high, at 16% (10 patients) during the acute inpatient stay and 28% (17 patients) at 3 months; 65% of the survivors had an unfavorable outcome. Substantial hematoma expansion – defined as a 33% or greater relative increase or 6 mL or greater absolute increase in ICH volume – was common, affecting 38% of patients. “This proportion was within the range reported for vitamin-K antagonist–associated intracerebral hemorrhage (36%-56%) and is higher, compared with that related to intracerebral hemorrhage in patients not receiving anticoagulation (12%-26%),” the investigators wrote.

Both larger hematoma volume at baseline (odds ratio, 2.37) and intraventricular extension at baseline (OR, 8.13) strongly correlated with adverse outcomes. In contrast, prothrombin complex concentrate failed to limit lesion expansion or avert adverse outcomes. This might be because patients given the treatment tended to have more severe initial neurologic deficits and more unfavorable hematoma location than did those who weren’t given prothrombin complex concentrate. In any case, “our study design, the limited sample size, and the potential for confounding by indication do not allow any [firm] conclusions regarding a potential association between prothrombin complex concentrate treatment and outcome,” they noted.

The RASUNOA registry was supported by the University Hospital Heidelberg. Dr. Purrucker reported receiving support from Pfizer unrelated to this study, and his associates reported ties to numerous industry sources.

Intracerebral hemorrhage related to non–vitamin-K antagonist oral anticoagulants carries a high mortality and frequently involves hematoma expansion, according to a report published online Dec. 14 in JAMA Neurology.

The characteristics and natural history of acute-phase non–vitamin-K antagonist oral anticoagulant (NOAC)-associated intracerebral hemorrhage (ICH) “are largely unknown,” and there are no prospective data concerning hematoma expansion or the effectiveness of prothrombin complex concentrate in limiting that expansion by reversing anticoagulation. Nevertheless, current recommendations suggest that clinicians consider administering prothrombin complex concentrate in this patient population, said Dr. Jan C. Purrucker of the department of neurology at Heidelberg (Germany) University and his associates (JAMA Neurol. 2015 Dec 14. doi: 10.1001/jamaneurol.2015.3682).

To characterize the clinical and radiologic course, management, and outcome of NOAC-associated intracerebral hemorrhage in routine clinical practice, Dr. Purrucker and his associates performed the ICH substudy of the Registry of Acute Stroke Under New Oral Anticoagulants (RASUNOA). This is a prospective registry involving 38 neurology departments with certified stroke units across Germany. For their substudy, the investigators focused on 61 adults with a mean age of 76 years (range, 46-97 years) who were taking NOACs (apixaban [Eliquis], dabigatran etexilate [Pradaxa], or rivaroxaban [Xarelto]) and had moderate to severe neurologic deficit and a median hematoma volume of 10.8 mL at presentation. Thirty-five of these patients (57%) were treated with prothrombin complex concentrate.

Mortality was high, at 16% (10 patients) during the acute inpatient stay and 28% (17 patients) at 3 months; 65% of the survivors had an unfavorable outcome. Substantial hematoma expansion – defined as a 33% or greater relative increase or 6 mL or greater absolute increase in ICH volume – was common, affecting 38% of patients. “This proportion was within the range reported for vitamin-K antagonist–associated intracerebral hemorrhage (36%-56%) and is higher, compared with that related to intracerebral hemorrhage in patients not receiving anticoagulation (12%-26%),” the investigators wrote.

Both larger hematoma volume at baseline (odds ratio, 2.37) and intraventricular extension at baseline (OR, 8.13) strongly correlated with adverse outcomes. In contrast, prothrombin complex concentrate failed to limit lesion expansion or avert adverse outcomes. This might be because patients given the treatment tended to have more severe initial neurologic deficits and more unfavorable hematoma location than did those who weren’t given prothrombin complex concentrate. In any case, “our study design, the limited sample size, and the potential for confounding by indication do not allow any [firm] conclusions regarding a potential association between prothrombin complex concentrate treatment and outcome,” they noted.

The RASUNOA registry was supported by the University Hospital Heidelberg. Dr. Purrucker reported receiving support from Pfizer unrelated to this study, and his associates reported ties to numerous industry sources.

Diagnosis: Urticaria pigmentosa

Urticaria pigmentosa (UP), also known as cutaneous mastocytosis, is characterized by the presence of pigmented macular and/or papular lesions associated with severe pruritis that can appear on any part of the body. With increased scratching and/or exposure to heat, the lesions become elevated. This phenomenon is known as Darier’s sign. The urticarial lesions can progress to become fluid-filled blisters. UP can rarely progress to systemic mastocytosis and present with systemic symptoms that are more common in adults, including headache, fatigue, abdominal pain, diarrhea, and tachycardia.

UP has been associated with increased inflammatory mast cells that abnormally collect in the skin. Mast cells specialize in producing histamine. In UP, the overproliferation of mast cells, secondary to point mutations in proto-oncogene c-kit binding to mast cell growth factor (MCGF), leads to an abundance of inflammatory chemicals, which produces the characteristic itching and presenting symptoms.

Although the pathophysiology of UP is known, the exact etiology is unclear. Certain medications that can cause mast-cell degranulation have been implicated, such as aspirin, NSAIDs, narcotics, alcohol, and anticholinergics. Children with allergies such as asthma are known to have an increased predisposition to UP, which typically presents in the first year of life and is self-limited by adolescence. Some cases sporadically appear, but others may be secondary to genetic inheritance as an autosomal dominant trait.

Diagnosis of UP is made by the presence of the characteristic skin lesions but can be confirmed by microscopic evaluation. A positive Darier’s sign on physical exam and lab testing for elevated histamine can aid in the diagnosis. UP is often mistaken for moles or insect bites on initial presentation; however, the persistence of the lesions for months to years is a distinguishing factor.

Given the self-limiting nature of UP, the treatment is symptomatic and supportive. Topical steroids and antihistamines can be useful to treat severe pruritis. In addition, PUVA has been shown to be an effective treatment for UP in adults.

This case and photo were submitted by Dr. Parteek Singla and Dr. Damon McClain of Naval Hospital Camp Lejeune, N.C.

Dr. Bilu Martin is in private practice at Premier Dermatology, MD, in Aventura, Fla. More diagnostic cases are available at edermatologynews.com. To submit your case for possible publication, send an email to [email protected].

Diagnosis: Urticaria pigmentosa

Urticaria pigmentosa (UP), also known as cutaneous mastocytosis, is characterized by the presence of pigmented macular and/or papular lesions associated with severe pruritis that can appear on any part of the body. With increased scratching and/or exposure to heat, the lesions become elevated. This phenomenon is known as Darier’s sign. The urticarial lesions can progress to become fluid-filled blisters. UP can rarely progress to systemic mastocytosis and present with systemic symptoms that are more common in adults, including headache, fatigue, abdominal pain, diarrhea, and tachycardia.

UP has been associated with increased inflammatory mast cells that abnormally collect in the skin. Mast cells specialize in producing histamine. In UP, the overproliferation of mast cells, secondary to point mutations in proto-oncogene c-kit binding to mast cell growth factor (MCGF), leads to an abundance of inflammatory chemicals, which produces the characteristic itching and presenting symptoms.

Although the pathophysiology of UP is known, the exact etiology is unclear. Certain medications that can cause mast-cell degranulation have been implicated, such as aspirin, NSAIDs, narcotics, alcohol, and anticholinergics. Children with allergies such as asthma are known to have an increased predisposition to UP, which typically presents in the first year of life and is self-limited by adolescence. Some cases sporadically appear, but others may be secondary to genetic inheritance as an autosomal dominant trait.

Diagnosis of UP is made by the presence of the characteristic skin lesions but can be confirmed by microscopic evaluation. A positive Darier’s sign on physical exam and lab testing for elevated histamine can aid in the diagnosis. UP is often mistaken for moles or insect bites on initial presentation; however, the persistence of the lesions for months to years is a distinguishing factor.

Given the self-limiting nature of UP, the treatment is symptomatic and supportive. Topical steroids and antihistamines can be useful to treat severe pruritis. In addition, PUVA has been shown to be an effective treatment for UP in adults.

This case and photo were submitted by Dr. Parteek Singla and Dr. Damon McClain of Naval Hospital Camp Lejeune, N.C.

Dr. Bilu Martin is in private practice at Premier Dermatology, MD, in Aventura, Fla. More diagnostic cases are available at edermatologynews.com. To submit your case for possible publication, send an email to [email protected].

Diagnosis: Urticaria pigmentosa

Urticaria pigmentosa (UP), also known as cutaneous mastocytosis, is characterized by the presence of pigmented macular and/or papular lesions associated with severe pruritis that can appear on any part of the body. With increased scratching and/or exposure to heat, the lesions become elevated. This phenomenon is known as Darier’s sign. The urticarial lesions can progress to become fluid-filled blisters. UP can rarely progress to systemic mastocytosis and present with systemic symptoms that are more common in adults, including headache, fatigue, abdominal pain, diarrhea, and tachycardia.

UP has been associated with increased inflammatory mast cells that abnormally collect in the skin. Mast cells specialize in producing histamine. In UP, the overproliferation of mast cells, secondary to point mutations in proto-oncogene c-kit binding to mast cell growth factor (MCGF), leads to an abundance of inflammatory chemicals, which produces the characteristic itching and presenting symptoms.

Although the pathophysiology of UP is known, the exact etiology is unclear. Certain medications that can cause mast-cell degranulation have been implicated, such as aspirin, NSAIDs, narcotics, alcohol, and anticholinergics. Children with allergies such as asthma are known to have an increased predisposition to UP, which typically presents in the first year of life and is self-limited by adolescence. Some cases sporadically appear, but others may be secondary to genetic inheritance as an autosomal dominant trait.

Diagnosis of UP is made by the presence of the characteristic skin lesions but can be confirmed by microscopic evaluation. A positive Darier’s sign on physical exam and lab testing for elevated histamine can aid in the diagnosis. UP is often mistaken for moles or insect bites on initial presentation; however, the persistence of the lesions for months to years is a distinguishing factor.

Given the self-limiting nature of UP, the treatment is symptomatic and supportive. Topical steroids and antihistamines can be useful to treat severe pruritis. In addition, PUVA has been shown to be an effective treatment for UP in adults.

This case and photo were submitted by Dr. Parteek Singla and Dr. Damon McClain of Naval Hospital Camp Lejeune, N.C.

Dr. Bilu Martin is in private practice at Premier Dermatology, MD, in Aventura, Fla. More diagnostic cases are available at edermatologynews.com. To submit your case for possible publication, send an email to [email protected].