Commentary

Recently, two studies were published addressing the potential association of childhood cancer and assisted reproductive technology. For more than a decade and a half, it has been acknowledged that ART is associated with increased concern both with structural birth defects, as well as imprinting disorders. As both of these issues have been linked to greater cancer risk in children, it is important to decipher the impact of ART on childhood cancer risk.

Published online April 1 in JAMA Pediatrics, the study, “Association of in vitro fertilization [IVF] with childhood cancer in the United States,”¹ by LG Spector et al. looked retrospectively at birth and cancer registries in 14 states with 8 years of data on 275,686 children were conceived via ART through 2013, who were compared with 2,266,847 children selected randomly.

The overall cancer rate per 1,000,000 person-years was low in both groups: 252 for the IVF group and 193 for the control group, for an overall hazard risk of 1.17. Of note, the rate of hepatic tumors was higher among the IVF group than the non-IVF group (18 vs. 5.7; hazard ratio, 2.46). There appeared to be no association with specific IVF treatments, whether children were conceived by donor egg vs. autologous egg; frozen embryos vs. fresh embryos; use of intracytoplasmic sperm injection (ICSI) vs. none; assisted hatching vs. none; and day-3 vs. day-5 transfer. The researchers concluded that the “increased rate of embryonal cancers, particularly hepatic tumors, that could not be attributed to IVF rather than to underlying infertility.”

This first and largest cohort study of association between IVF and the risk of childhood cancer ever published showed little evidence of excess risk of most cancers, including more common cancers such as leukemia.

The authors did note limitations in their study. Mothers who conceived via IVF were more likely to be white, non-Hispanic, more educated, and older. Could this patient population undergoing ART be at greater risk of producing offspring with cancer concerns? If that were the case – and not great risk of childhood cancer in ART, per se – one therefore would extrapolate that couples undergoing ART vs. alternative infertility treatment should not show a treatment-biased risk (i.e., ART vs. non-ART).

This was demonstrated recently in the study, “Risk of cancer in children and young adults conceived by assisted reproductive technology.”² This Dutch historical cohort study with prospective follow-up of a median 21 years evaluated 47,690 live-born children, of which 24,269 were ART conceived, 13,761 naturally conceived, and 9,660 conceived naturally or with fertility drugs but not by ART.

Overall, cancer risk was not increased in ART-conceived children, compared with naturally conceived subfertile women or even the general population. A nonsignificant increased risk was observed in children conceived by ICSI or cryopreservation.

On the basis of these two studies, there appears to be no significant increased risk of cancer in children conceived through fertility treatment, including ART.

Although these studies do not support the conclusion reached by a 2013 meta-analysis of 9 studies that specifically looked at ART and 16 other studies that looked at other types of medically assisted reproduction (such medically assisted reproduction as reproduction achieved through ovulation induction; controlled ovarian stimulation; ovulation triggering; intrauterine, intracervical, or intravaginal insemination) which reported a significant increased risk of overall cancers (1.33), including leukemia, CNS cancer, and neuroblastoma,³ they do agree more closely with two prospective studies conducted in the United Kingdom and Nordic countries.

In the U.K. study,⁴ there was no overall increased risk of cancer associated with ART, but two types of cancer were noted to be higher in the ART-conceived group – hepatoblastoma (3.27 risk) and rhabdomyosarcoma (2.62 risk) – but the absolute risk of these two types of cancer was small in this 17-year study of 106,013 children. This, of course, would be consistent with the JAMA Pediatrics study. In the Nordic study,⁵ similar to the Dutch Study, IVF was not associated with a significant increased risk of cancer (1.08). The Nordic study included 91,796 children born of ART-assisted pregnancies, compared with 358,419 children born after spontaneous conceptions.

The evidence so far shows that there appears to be no significant increased risk of cancer overall associated with fertility treatments, including IVF.
 

Dr. Miller is a clinical associate professor at the University of Illinois in Chicago and past president of the AAGL. He is a reproductive endocrinologist and minimally invasive gynecologic surgeon in metropolitan Chicago and the director of minimally invasive gynecologic surgery at Advocate Lutheran General Hospital, Park Ridge, Ill. He also is a member of Ob.Gyn. News editorial advisory board. Dr. Miller disclosed that he is president of the Advanced IVF Institute in Park Ridge and Naperville, Ill.

References

1. JAMA Pediatr. 2019 Apr 1. doi: 10.1001/jamapediatrics.2019.0392.

2. Hum Reprod. 2019 Apr 1;34(4):740-50.

3. Fertil Steril. 2013 Jul. doi: 10.1016/j.fertnstert.2013.03.017.

4. N Engl J Med. 2013 Nov 7;369(19):1819-27.

5. Hum Reprod. 2014 Sep;29(9):2050-7.

Recently, two studies were published addressing the potential association of childhood cancer and assisted reproductive technology. For more than a decade and a half, it has been acknowledged that ART is associated with increased concern both with structural birth defects, as well as imprinting disorders. As both of these issues have been linked to greater cancer risk in children, it is important to decipher the impact of ART on childhood cancer risk.

Published online April 1 in JAMA Pediatrics, the study, “Association of in vitro fertilization [IVF] with childhood cancer in the United States,”¹ by LG Spector et al. looked retrospectively at birth and cancer registries in 14 states with 8 years of data on 275,686 children were conceived via ART through 2013, who were compared with 2,266,847 children selected randomly.

The overall cancer rate per 1,000,000 person-years was low in both groups: 252 for the IVF group and 193 for the control group, for an overall hazard risk of 1.17. Of note, the rate of hepatic tumors was higher among the IVF group than the non-IVF group (18 vs. 5.7; hazard ratio, 2.46). There appeared to be no association with specific IVF treatments, whether children were conceived by donor egg vs. autologous egg; frozen embryos vs. fresh embryos; use of intracytoplasmic sperm injection (ICSI) vs. none; assisted hatching vs. none; and day-3 vs. day-5 transfer. The researchers concluded that the “increased rate of embryonal cancers, particularly hepatic tumors, that could not be attributed to IVF rather than to underlying infertility.”

This first and largest cohort study of association between IVF and the risk of childhood cancer ever published showed little evidence of excess risk of most cancers, including more common cancers such as leukemia.

The authors did note limitations in their study. Mothers who conceived via IVF were more likely to be white, non-Hispanic, more educated, and older. Could this patient population undergoing ART be at greater risk of producing offspring with cancer concerns? If that were the case – and not great risk of childhood cancer in ART, per se – one therefore would extrapolate that couples undergoing ART vs. alternative infertility treatment should not show a treatment-biased risk (i.e., ART vs. non-ART).

This was demonstrated recently in the study, “Risk of cancer in children and young adults conceived by assisted reproductive technology.”² This Dutch historical cohort study with prospective follow-up of a median 21 years evaluated 47,690 live-born children, of which 24,269 were ART conceived, 13,761 naturally conceived, and 9,660 conceived naturally or with fertility drugs but not by ART.

Overall, cancer risk was not increased in ART-conceived children, compared with naturally conceived subfertile women or even the general population. A nonsignificant increased risk was observed in children conceived by ICSI or cryopreservation.

On the basis of these two studies, there appears to be no significant increased risk of cancer in children conceived through fertility treatment, including ART.

Although these studies do not support the conclusion reached by a 2013 meta-analysis of 9 studies that specifically looked at ART and 16 other studies that looked at other types of medically assisted reproduction (such medically assisted reproduction as reproduction achieved through ovulation induction; controlled ovarian stimulation; ovulation triggering; intrauterine, intracervical, or intravaginal insemination) which reported a significant increased risk of overall cancers (1.33), including leukemia, CNS cancer, and neuroblastoma,³ they do agree more closely with two prospective studies conducted in the United Kingdom and Nordic countries.

In the U.K. study,⁴ there was no overall increased risk of cancer associated with ART, but two types of cancer were noted to be higher in the ART-conceived group – hepatoblastoma (3.27 risk) and rhabdomyosarcoma (2.62 risk) – but the absolute risk of these two types of cancer was small in this 17-year study of 106,013 children. This, of course, would be consistent with the JAMA Pediatrics study. In the Nordic study,⁵ similar to the Dutch Study, IVF was not associated with a significant increased risk of cancer (1.08). The Nordic study included 91,796 children born of ART-assisted pregnancies, compared with 358,419 children born after spontaneous conceptions.

The evidence so far shows that there appears to be no significant increased risk of cancer overall associated with fertility treatments, including IVF.
 

Dr. Miller is a clinical associate professor at the University of Illinois in Chicago and past president of the AAGL. He is a reproductive endocrinologist and minimally invasive gynecologic surgeon in metropolitan Chicago and the director of minimally invasive gynecologic surgery at Advocate Lutheran General Hospital, Park Ridge, Ill. He also is a member of Ob.Gyn. News editorial advisory board. Dr. Miller disclosed that he is president of the Advanced IVF Institute in Park Ridge and Naperville, Ill.

References

1. JAMA Pediatr. 2019 Apr 1. doi: 10.1001/jamapediatrics.2019.0392.

2. Hum Reprod. 2019 Apr 1;34(4):740-50.

3. Fertil Steril. 2013 Jul. doi: 10.1016/j.fertnstert.2013.03.017.

4. N Engl J Med. 2013 Nov 7;369(19):1819-27.

5. Hum Reprod. 2014 Sep;29(9):2050-7.

Recently, two studies were published addressing the potential association of childhood cancer and assisted reproductive technology. For more than a decade and a half, it has been acknowledged that ART is associated with increased concern both with structural birth defects, as well as imprinting disorders. As both of these issues have been linked to greater cancer risk in children, it is important to decipher the impact of ART on childhood cancer risk.

Published online April 1 in JAMA Pediatrics, the study, “Association of in vitro fertilization [IVF] with childhood cancer in the United States,”¹ by LG Spector et al. looked retrospectively at birth and cancer registries in 14 states with 8 years of data on 275,686 children were conceived via ART through 2013, who were compared with 2,266,847 children selected randomly.

The overall cancer rate per 1,000,000 person-years was low in both groups: 252 for the IVF group and 193 for the control group, for an overall hazard risk of 1.17. Of note, the rate of hepatic tumors was higher among the IVF group than the non-IVF group (18 vs. 5.7; hazard ratio, 2.46). There appeared to be no association with specific IVF treatments, whether children were conceived by donor egg vs. autologous egg; frozen embryos vs. fresh embryos; use of intracytoplasmic sperm injection (ICSI) vs. none; assisted hatching vs. none; and day-3 vs. day-5 transfer. The researchers concluded that the “increased rate of embryonal cancers, particularly hepatic tumors, that could not be attributed to IVF rather than to underlying infertility.”

This first and largest cohort study of association between IVF and the risk of childhood cancer ever published showed little evidence of excess risk of most cancers, including more common cancers such as leukemia.

The authors did note limitations in their study. Mothers who conceived via IVF were more likely to be white, non-Hispanic, more educated, and older. Could this patient population undergoing ART be at greater risk of producing offspring with cancer concerns? If that were the case – and not great risk of childhood cancer in ART, per se – one therefore would extrapolate that couples undergoing ART vs. alternative infertility treatment should not show a treatment-biased risk (i.e., ART vs. non-ART).

This was demonstrated recently in the study, “Risk of cancer in children and young adults conceived by assisted reproductive technology.”² This Dutch historical cohort study with prospective follow-up of a median 21 years evaluated 47,690 live-born children, of which 24,269 were ART conceived, 13,761 naturally conceived, and 9,660 conceived naturally or with fertility drugs but not by ART.

Overall, cancer risk was not increased in ART-conceived children, compared with naturally conceived subfertile women or even the general population. A nonsignificant increased risk was observed in children conceived by ICSI or cryopreservation.

On the basis of these two studies, there appears to be no significant increased risk of cancer in children conceived through fertility treatment, including ART.

Although these studies do not support the conclusion reached by a 2013 meta-analysis of 9 studies that specifically looked at ART and 16 other studies that looked at other types of medically assisted reproduction (such medically assisted reproduction as reproduction achieved through ovulation induction; controlled ovarian stimulation; ovulation triggering; intrauterine, intracervical, or intravaginal insemination) which reported a significant increased risk of overall cancers (1.33), including leukemia, CNS cancer, and neuroblastoma,³ they do agree more closely with two prospective studies conducted in the United Kingdom and Nordic countries.

In the U.K. study,⁴ there was no overall increased risk of cancer associated with ART, but two types of cancer were noted to be higher in the ART-conceived group – hepatoblastoma (3.27 risk) and rhabdomyosarcoma (2.62 risk) – but the absolute risk of these two types of cancer was small in this 17-year study of 106,013 children. This, of course, would be consistent with the JAMA Pediatrics study. In the Nordic study,⁵ similar to the Dutch Study, IVF was not associated with a significant increased risk of cancer (1.08). The Nordic study included 91,796 children born of ART-assisted pregnancies, compared with 358,419 children born after spontaneous conceptions.

The evidence so far shows that there appears to be no significant increased risk of cancer overall associated with fertility treatments, including IVF.
 

Dr. Miller is a clinical associate professor at the University of Illinois in Chicago and past president of the AAGL. He is a reproductive endocrinologist and minimally invasive gynecologic surgeon in metropolitan Chicago and the director of minimally invasive gynecologic surgery at Advocate Lutheran General Hospital, Park Ridge, Ill. He also is a member of Ob.Gyn. News editorial advisory board. Dr. Miller disclosed that he is president of the Advanced IVF Institute in Park Ridge and Naperville, Ill.

References

1. JAMA Pediatr. 2019 Apr 1. doi: 10.1001/jamapediatrics.2019.0392.

2. Hum Reprod. 2019 Apr 1;34(4):740-50.

3. Fertil Steril. 2013 Jul. doi: 10.1016/j.fertnstert.2013.03.017.

4. N Engl J Med. 2013 Nov 7;369(19):1819-27.

5. Hum Reprod. 2014 Sep;29(9):2050-7.

The Red Lake Indian Health Service (IHS) health care facility is in north-central Minnesota within the Red Lake Nation. The facility supports primary care, emergency, urgent care, pharmacy, inpatient, optometry, dental, radiology, laboratory, physical therapy, and behavioral health services to about 10,000 Red Lake Band of Chippewa Indian patients. The Red Lake pharmacy provides inpatient and outpatient medication services and pharmacist-managed clinical patient care.

In 2013, the Red Lake IHS medical staff endorsed the implementation of comprehensive clinical pharmacy services to increase health care access and optimize clinical outcomes for patients. During the evolution of pharmacy-based patient-centric care, the clinical programs offered by Red Lake IHS pharmacy expanded from 1 anticoagulation clinic to multiple advanced-practice clinical pharmacy services. This included pharmacy primary care, medication-assisted therapy, naloxone, hepatitis C, and behavioral health medication management clinics.

The immense clinical growth of the pharmacy department demonstrated a need to assess and monitor pharmacist competency to ensure the delivery of quality patient care. Essential quality improvement processes were lacking. To fill these quality improvement gaps, a robust pharmacist credentialing and privileging program was implemented in 2015.

Patient Care

As efforts within health care establishments across the US focus on the delivery of efficient, high-quality, affordable health care, pharmacists have become increasingly instrumental in providing patient care within expanded clinical roles.^1-8 Many clinical pharmacy models have evolved into interdisciplinary approaches to care.⁹ Within these models, abiding by state and federal laws, pharmacists practice under the indirect supervision of licensed independent practitioners (LIPs), such as physicians, nurse practitioners, and physician assistants.⁸ Under collaborative practice agreements (CPAs), patients are initially diagnosed by LIPs, then referred to clinical pharmacists for therapeutic management.^5,7

Clinical pharmacist functions encompass comprehensive medication management (ie, prescribing, monitoring, and adjustment of medications), nonpharmacologic guidance, and coordination of care. Interdisciplinary collaboration allows pharmacists opportunities to provide direct patient care or consultations by telecommunication in many different clinical environments, including disease management, primary care, or specialty care. Pharmacists may manage chronic or acute illnesses associated with endocrine, cardiovascular, respiratory, gastrointestinal, or other systems.

Pharmacist Credentialing

With the advancement of modern clinical pharmacy practice, many pharmacists have undertaken responsibilities to fulfill the complex duties of clinical care and diverse patient situations, but with few or no requirements to prove initial or ongoing clinical competency.² Traditionally, pharmacist credentialing is limited to a onetime or periodic review of education and licensure, with little to no involvement in privileging and ongoing monitoring of clinical proficiency.¹⁰ These quality assurance disparities can be met and satisfied through credentialing and privileging processes. Credentialing and privileging are systematic, evidence-based processes that provide validation to HCPs, employers, and patients that pharmacists are qualified to practice clinically. ^2,9 According to the Council on Credentialing in Pharmacy, clinical pharmacists should be held accountable for demonstrating competency and providing quality care through credentialing and privileging, as required for other HCPs.^2,12

Credentialing and recredentialing is a primary source verification process. These processes ensure that there are no license restrictions or revocations; certifications are current; mandatory courses, certificates, and continuing education are complete; training and orientation are satisfactory; and any disciplinary action, malpractice claims, or history of impairment is reported. Privileging is the review of credentials and evaluation of clinical training and competence by the Clinical Director and Medical Executive Committee to determine whether a clinical pharmacist is competent to practice within requested privileges.¹¹

Credentialing and privileging processes are designed not only to initially confirm that a pharmacist is competent to practice clinically, but also monitor ongoing performance.^2,13 Participation in professional practice evaluations, which includes peer reviews, ongoing professional practice evaluations, and focused professional practice evaluations, is required for all credentialed and privileged practitioners. These evaluations are used to identify, assess, and correct unsatisfactory trends. Individual practices, documentation, and processes are evaluated against existing department standards (eg, CPAs, policies, processes)^11,13 The results of individual professional practice evaluations are reviewed with practitioners on a regular basis and performance improvement plans implemented as needed.

Since 2015, 17 pharmacists at the Red Lake IHS health care facility have been granted membership to the medical staff as credentialed and privileged practitioners. In a retrospective review of professional practice evaluations by the Red Lake IHS pharmacy clinical coordinator, 971 outpatient clinical peer reviews, including the evaluation of 21,526 peer-review elements were completed by pharmacists from fiscal year 2015 through 2018. Peer-review elements assessed visit documentation, patient care, and other clinic processes defined by department standards. Beginning in 2016, peer-review feedback was implemented and completed on a quarterly basis with each pharmacist. In fiscal years 2015, 2016, 2017, and 2018, the percentage of peer-review elements found as noncompliant with department standards were 18.0%, 11.6%, 3.7%, and 3.4%, respectively. Compared with the 2015 year baseline, these data correlate with a decrease of peer-review concerns by 35.5% in 2016, 79.4% in 2017, and 81.1% in 2018.

Conclusion

Pharmacists have become increasingly instrumental in providing effective, cost-efficient, and accessible clinical services by continuing to move toward expanding and evolving roles within comprehensive, patient-centered clinical pharmacy practice settings.^5,6 Multifaceted clinical responsibilities associated with health care delivery necessitate assessment and monitoring of pharmacist performance. Credentialing and privileging is an established and trusted systematic process that assures HCPs, employers, and patients that pharmacists are qualified and competent to practice clinically.^2,4,12 Implementation of professional practice evaluations suggest improved staff compliance with visit documentation, patient care standards, and clinic processes required by CPAs, policies, and department standards to ensure the delivery of safe, high-quality patient care.

The Red Lake Indian Health Service (IHS) health care facility is in north-central Minnesota within the Red Lake Nation. The facility supports primary care, emergency, urgent care, pharmacy, inpatient, optometry, dental, radiology, laboratory, physical therapy, and behavioral health services to about 10,000 Red Lake Band of Chippewa Indian patients. The Red Lake pharmacy provides inpatient and outpatient medication services and pharmacist-managed clinical patient care.

In 2013, the Red Lake IHS medical staff endorsed the implementation of comprehensive clinical pharmacy services to increase health care access and optimize clinical outcomes for patients. During the evolution of pharmacy-based patient-centric care, the clinical programs offered by Red Lake IHS pharmacy expanded from 1 anticoagulation clinic to multiple advanced-practice clinical pharmacy services. This included pharmacy primary care, medication-assisted therapy, naloxone, hepatitis C, and behavioral health medication management clinics.

The immense clinical growth of the pharmacy department demonstrated a need to assess and monitor pharmacist competency to ensure the delivery of quality patient care. Essential quality improvement processes were lacking. To fill these quality improvement gaps, a robust pharmacist credentialing and privileging program was implemented in 2015.

Patient Care

As efforts within health care establishments across the US focus on the delivery of efficient, high-quality, affordable health care, pharmacists have become increasingly instrumental in providing patient care within expanded clinical roles.^1-8 Many clinical pharmacy models have evolved into interdisciplinary approaches to care.⁹ Within these models, abiding by state and federal laws, pharmacists practice under the indirect supervision of licensed independent practitioners (LIPs), such as physicians, nurse practitioners, and physician assistants.⁸ Under collaborative practice agreements (CPAs), patients are initially diagnosed by LIPs, then referred to clinical pharmacists for therapeutic management.^5,7

Clinical pharmacist functions encompass comprehensive medication management (ie, prescribing, monitoring, and adjustment of medications), nonpharmacologic guidance, and coordination of care. Interdisciplinary collaboration allows pharmacists opportunities to provide direct patient care or consultations by telecommunication in many different clinical environments, including disease management, primary care, or specialty care. Pharmacists may manage chronic or acute illnesses associated with endocrine, cardiovascular, respiratory, gastrointestinal, or other systems.

Pharmacist Credentialing

With the advancement of modern clinical pharmacy practice, many pharmacists have undertaken responsibilities to fulfill the complex duties of clinical care and diverse patient situations, but with few or no requirements to prove initial or ongoing clinical competency.² Traditionally, pharmacist credentialing is limited to a onetime or periodic review of education and licensure, with little to no involvement in privileging and ongoing monitoring of clinical proficiency.¹⁰ These quality assurance disparities can be met and satisfied through credentialing and privileging processes. Credentialing and privileging are systematic, evidence-based processes that provide validation to HCPs, employers, and patients that pharmacists are qualified to practice clinically. ^2,9 According to the Council on Credentialing in Pharmacy, clinical pharmacists should be held accountable for demonstrating competency and providing quality care through credentialing and privileging, as required for other HCPs.^2,12

Credentialing and recredentialing is a primary source verification process. These processes ensure that there are no license restrictions or revocations; certifications are current; mandatory courses, certificates, and continuing education are complete; training and orientation are satisfactory; and any disciplinary action, malpractice claims, or history of impairment is reported. Privileging is the review of credentials and evaluation of clinical training and competence by the Clinical Director and Medical Executive Committee to determine whether a clinical pharmacist is competent to practice within requested privileges.¹¹

Credentialing and privileging processes are designed not only to initially confirm that a pharmacist is competent to practice clinically, but also monitor ongoing performance.^2,13 Participation in professional practice evaluations, which includes peer reviews, ongoing professional practice evaluations, and focused professional practice evaluations, is required for all credentialed and privileged practitioners. These evaluations are used to identify, assess, and correct unsatisfactory trends. Individual practices, documentation, and processes are evaluated against existing department standards (eg, CPAs, policies, processes)^11,13 The results of individual professional practice evaluations are reviewed with practitioners on a regular basis and performance improvement plans implemented as needed.

Since 2015, 17 pharmacists at the Red Lake IHS health care facility have been granted membership to the medical staff as credentialed and privileged practitioners. In a retrospective review of professional practice evaluations by the Red Lake IHS pharmacy clinical coordinator, 971 outpatient clinical peer reviews, including the evaluation of 21,526 peer-review elements were completed by pharmacists from fiscal year 2015 through 2018. Peer-review elements assessed visit documentation, patient care, and other clinic processes defined by department standards. Beginning in 2016, peer-review feedback was implemented and completed on a quarterly basis with each pharmacist. In fiscal years 2015, 2016, 2017, and 2018, the percentage of peer-review elements found as noncompliant with department standards were 18.0%, 11.6%, 3.7%, and 3.4%, respectively. Compared with the 2015 year baseline, these data correlate with a decrease of peer-review concerns by 35.5% in 2016, 79.4% in 2017, and 81.1% in 2018.

Conclusion

Pharmacists have become increasingly instrumental in providing effective, cost-efficient, and accessible clinical services by continuing to move toward expanding and evolving roles within comprehensive, patient-centered clinical pharmacy practice settings.^5,6 Multifaceted clinical responsibilities associated with health care delivery necessitate assessment and monitoring of pharmacist performance. Credentialing and privileging is an established and trusted systematic process that assures HCPs, employers, and patients that pharmacists are qualified and competent to practice clinically.^2,4,12 Implementation of professional practice evaluations suggest improved staff compliance with visit documentation, patient care standards, and clinic processes required by CPAs, policies, and department standards to ensure the delivery of safe, high-quality patient care.

The Red Lake Indian Health Service (IHS) health care facility is in north-central Minnesota within the Red Lake Nation. The facility supports primary care, emergency, urgent care, pharmacy, inpatient, optometry, dental, radiology, laboratory, physical therapy, and behavioral health services to about 10,000 Red Lake Band of Chippewa Indian patients. The Red Lake pharmacy provides inpatient and outpatient medication services and pharmacist-managed clinical patient care.

In 2013, the Red Lake IHS medical staff endorsed the implementation of comprehensive clinical pharmacy services to increase health care access and optimize clinical outcomes for patients. During the evolution of pharmacy-based patient-centric care, the clinical programs offered by Red Lake IHS pharmacy expanded from 1 anticoagulation clinic to multiple advanced-practice clinical pharmacy services. This included pharmacy primary care, medication-assisted therapy, naloxone, hepatitis C, and behavioral health medication management clinics.

The immense clinical growth of the pharmacy department demonstrated a need to assess and monitor pharmacist competency to ensure the delivery of quality patient care. Essential quality improvement processes were lacking. To fill these quality improvement gaps, a robust pharmacist credentialing and privileging program was implemented in 2015.

Patient Care

As efforts within health care establishments across the US focus on the delivery of efficient, high-quality, affordable health care, pharmacists have become increasingly instrumental in providing patient care within expanded clinical roles.^1-8 Many clinical pharmacy models have evolved into interdisciplinary approaches to care.⁹ Within these models, abiding by state and federal laws, pharmacists practice under the indirect supervision of licensed independent practitioners (LIPs), such as physicians, nurse practitioners, and physician assistants.⁸ Under collaborative practice agreements (CPAs), patients are initially diagnosed by LIPs, then referred to clinical pharmacists for therapeutic management.^5,7

Clinical pharmacist functions encompass comprehensive medication management (ie, prescribing, monitoring, and adjustment of medications), nonpharmacologic guidance, and coordination of care. Interdisciplinary collaboration allows pharmacists opportunities to provide direct patient care or consultations by telecommunication in many different clinical environments, including disease management, primary care, or specialty care. Pharmacists may manage chronic or acute illnesses associated with endocrine, cardiovascular, respiratory, gastrointestinal, or other systems.

Pharmacist Credentialing

With the advancement of modern clinical pharmacy practice, many pharmacists have undertaken responsibilities to fulfill the complex duties of clinical care and diverse patient situations, but with few or no requirements to prove initial or ongoing clinical competency.² Traditionally, pharmacist credentialing is limited to a onetime or periodic review of education and licensure, with little to no involvement in privileging and ongoing monitoring of clinical proficiency.¹⁰ These quality assurance disparities can be met and satisfied through credentialing and privileging processes. Credentialing and privileging are systematic, evidence-based processes that provide validation to HCPs, employers, and patients that pharmacists are qualified to practice clinically. ^2,9 According to the Council on Credentialing in Pharmacy, clinical pharmacists should be held accountable for demonstrating competency and providing quality care through credentialing and privileging, as required for other HCPs.^2,12

Credentialing and recredentialing is a primary source verification process. These processes ensure that there are no license restrictions or revocations; certifications are current; mandatory courses, certificates, and continuing education are complete; training and orientation are satisfactory; and any disciplinary action, malpractice claims, or history of impairment is reported. Privileging is the review of credentials and evaluation of clinical training and competence by the Clinical Director and Medical Executive Committee to determine whether a clinical pharmacist is competent to practice within requested privileges.¹¹

Credentialing and privileging processes are designed not only to initially confirm that a pharmacist is competent to practice clinically, but also monitor ongoing performance.^2,13 Participation in professional practice evaluations, which includes peer reviews, ongoing professional practice evaluations, and focused professional practice evaluations, is required for all credentialed and privileged practitioners. These evaluations are used to identify, assess, and correct unsatisfactory trends. Individual practices, documentation, and processes are evaluated against existing department standards (eg, CPAs, policies, processes)^11,13 The results of individual professional practice evaluations are reviewed with practitioners on a regular basis and performance improvement plans implemented as needed.

Since 2015, 17 pharmacists at the Red Lake IHS health care facility have been granted membership to the medical staff as credentialed and privileged practitioners. In a retrospective review of professional practice evaluations by the Red Lake IHS pharmacy clinical coordinator, 971 outpatient clinical peer reviews, including the evaluation of 21,526 peer-review elements were completed by pharmacists from fiscal year 2015 through 2018. Peer-review elements assessed visit documentation, patient care, and other clinic processes defined by department standards. Beginning in 2016, peer-review feedback was implemented and completed on a quarterly basis with each pharmacist. In fiscal years 2015, 2016, 2017, and 2018, the percentage of peer-review elements found as noncompliant with department standards were 18.0%, 11.6%, 3.7%, and 3.4%, respectively. Compared with the 2015 year baseline, these data correlate with a decrease of peer-review concerns by 35.5% in 2016, 79.4% in 2017, and 81.1% in 2018.

Conclusion

Pharmacists have become increasingly instrumental in providing effective, cost-efficient, and accessible clinical services by continuing to move toward expanding and evolving roles within comprehensive, patient-centered clinical pharmacy practice settings.^5,6 Multifaceted clinical responsibilities associated with health care delivery necessitate assessment and monitoring of pharmacist performance. Credentialing and privileging is an established and trusted systematic process that assures HCPs, employers, and patients that pharmacists are qualified and competent to practice clinically.^2,4,12 Implementation of professional practice evaluations suggest improved staff compliance with visit documentation, patient care standards, and clinic processes required by CPAs, policies, and department standards to ensure the delivery of safe, high-quality patient care.

As nurses who are often the first face that a veteran sees, members of NOVA (Nurses Organization of Veterans Affairs) are committed to enhancing access, coordinating care, and improving health care at the US Department of Veterans Affairs (VA). NOVA also is the voice of VA nurses on Capitol Hill. Every year, the leadership and legislative committee members provide a list of critical issues identified in their Legislative Priority Goals. For 2019, the goals are divided into 3 areas of concern that either require legislation, funding, or implementation at the regulatory level within the VA.

At the top of the list is implementation of the VA Mission Act and its community care network. The 2018 VA Mission Act (Section 101 of Public Law 115-182) mandated the VA to consolidate existing community care programs and rewrite eligibility rules. Currently, the VA has at least 7 separate community care programs, including the Veterans Choice Program, which gives veterans who live ≥ 40 miles from a VA facility or have a wait time of ≥ 30 days an option to receive care in the local community with VA picking up the bill. Proposed access standards for the new program—Veterans Community Care Program (VCCP)—were made public in January 2019 and would allow veterans with ≥ 30-minute drive time and/or a wait time of ≥ 20 days for primary care or mental health appointments at a VA facility to use outside care. For specialty care eligibility, the drive time would increase to ≥ 60 minutes and ≥ 28 days for an appointment at a VA facility.

NOVA understands the need for community care partners: They are a crucial part of an integrated network designed to provide care for services that are not readily available within the Veterans Health Administration (VHA), but care that veterans receive in the community must be equal to VHA care. Equal care will require training and strict quality measures and standards verified for the VCCP providers. The VA also must remain the primary provider of care and the coordinator of care for all enrolled veterans.

NOVA identified 6 goals for VA Mission Act implementation. These include the following:

• Require that training, competency, and quality standards for VCCP providers are equal to those of VHA providers;
• Request third-party administrator to verify that providers meet those standards before assigning to VCCP panel;
• Simplify eligibility/access rules for community care without depleting VA funds;
• Ensure that VHA continues to be the first point of access and coordinator of all health care for enrolled veterans;
• Implement a care coordination system allowing veterans to return with ease to the VA when resources are available; and
• Employ mandatory training for VHA personnel and all community providers to improve the coordination of care, understanding of military culture, and health care needs across networks.

Other priorities include staffing/recruitment and retention—a longstanding issue within many VA facilities. Currently, the VHA has > 40,000 unfilled positions. It is no secret that the VA has had difficulty hiring essential staff at many levels. Complexities of job site databases and excessive time required to complete on-boarding, shortages in human resources personnel, and less than competitive salaries all add to the growing backlog. The inability for the VA to hire and train providers negatively impacts the access to VHA care and spurs increases in veterans using private sector care.

The VA modernization must include an electronic health record designed to support VHA’s model of health care delivery. It is crucial that Congress ensure proper IT funding to improve patient safety, software usability, and standardization of patient health care records across VHA.

VA nurses are the largest sector of employees within VHA with > 90,000 currently taking care of veterans. As VA continues its modernization, NOVA asks that nursing leadership be at the forefront of all strategic decision making.

In March, NOVA nurses shared their thoughts and views with members of Congress. They also continued discussions with the administration and VA leadership about how we can work together toward common goals—whether that be educating the next generation of nurses, providing innovative health care solutions, or engaging veterans in how they envision their health care in the future. Visit www.vanurse.org for more information about NOVA, the Legislative Priority Goals, or to become a member.

As nurses who are often the first face that a veteran sees, members of NOVA (Nurses Organization of Veterans Affairs) are committed to enhancing access, coordinating care, and improving health care at the US Department of Veterans Affairs (VA). NOVA also is the voice of VA nurses on Capitol Hill. Every year, the leadership and legislative committee members provide a list of critical issues identified in their Legislative Priority Goals. For 2019, the goals are divided into 3 areas of concern that either require legislation, funding, or implementation at the regulatory level within the VA.

At the top of the list is implementation of the VA Mission Act and its community care network. The 2018 VA Mission Act (Section 101 of Public Law 115-182) mandated the VA to consolidate existing community care programs and rewrite eligibility rules. Currently, the VA has at least 7 separate community care programs, including the Veterans Choice Program, which gives veterans who live ≥ 40 miles from a VA facility or have a wait time of ≥ 30 days an option to receive care in the local community with VA picking up the bill. Proposed access standards for the new program—Veterans Community Care Program (VCCP)—were made public in January 2019 and would allow veterans with ≥ 30-minute drive time and/or a wait time of ≥ 20 days for primary care or mental health appointments at a VA facility to use outside care. For specialty care eligibility, the drive time would increase to ≥ 60 minutes and ≥ 28 days for an appointment at a VA facility.

NOVA understands the need for community care partners: They are a crucial part of an integrated network designed to provide care for services that are not readily available within the Veterans Health Administration (VHA), but care that veterans receive in the community must be equal to VHA care. Equal care will require training and strict quality measures and standards verified for the VCCP providers. The VA also must remain the primary provider of care and the coordinator of care for all enrolled veterans.

NOVA identified 6 goals for VA Mission Act implementation. These include the following:

• Require that training, competency, and quality standards for VCCP providers are equal to those of VHA providers;
• Request third-party administrator to verify that providers meet those standards before assigning to VCCP panel;
• Simplify eligibility/access rules for community care without depleting VA funds;
• Ensure that VHA continues to be the first point of access and coordinator of all health care for enrolled veterans;
• Implement a care coordination system allowing veterans to return with ease to the VA when resources are available; and
• Employ mandatory training for VHA personnel and all community providers to improve the coordination of care, understanding of military culture, and health care needs across networks.

Other priorities include staffing/recruitment and retention—a longstanding issue within many VA facilities. Currently, the VHA has > 40,000 unfilled positions. It is no secret that the VA has had difficulty hiring essential staff at many levels. Complexities of job site databases and excessive time required to complete on-boarding, shortages in human resources personnel, and less than competitive salaries all add to the growing backlog. The inability for the VA to hire and train providers negatively impacts the access to VHA care and spurs increases in veterans using private sector care.

The VA modernization must include an electronic health record designed to support VHA’s model of health care delivery. It is crucial that Congress ensure proper IT funding to improve patient safety, software usability, and standardization of patient health care records across VHA.

VA nurses are the largest sector of employees within VHA with > 90,000 currently taking care of veterans. As VA continues its modernization, NOVA asks that nursing leadership be at the forefront of all strategic decision making.

In March, NOVA nurses shared their thoughts and views with members of Congress. They also continued discussions with the administration and VA leadership about how we can work together toward common goals—whether that be educating the next generation of nurses, providing innovative health care solutions, or engaging veterans in how they envision their health care in the future. Visit www.vanurse.org for more information about NOVA, the Legislative Priority Goals, or to become a member.

As nurses who are often the first face that a veteran sees, members of NOVA (Nurses Organization of Veterans Affairs) are committed to enhancing access, coordinating care, and improving health care at the US Department of Veterans Affairs (VA). NOVA also is the voice of VA nurses on Capitol Hill. Every year, the leadership and legislative committee members provide a list of critical issues identified in their Legislative Priority Goals. For 2019, the goals are divided into 3 areas of concern that either require legislation, funding, or implementation at the regulatory level within the VA.

At the top of the list is implementation of the VA Mission Act and its community care network. The 2018 VA Mission Act (Section 101 of Public Law 115-182) mandated the VA to consolidate existing community care programs and rewrite eligibility rules. Currently, the VA has at least 7 separate community care programs, including the Veterans Choice Program, which gives veterans who live ≥ 40 miles from a VA facility or have a wait time of ≥ 30 days an option to receive care in the local community with VA picking up the bill. Proposed access standards for the new program—Veterans Community Care Program (VCCP)—were made public in January 2019 and would allow veterans with ≥ 30-minute drive time and/or a wait time of ≥ 20 days for primary care or mental health appointments at a VA facility to use outside care. For specialty care eligibility, the drive time would increase to ≥ 60 minutes and ≥ 28 days for an appointment at a VA facility.

NOVA understands the need for community care partners: They are a crucial part of an integrated network designed to provide care for services that are not readily available within the Veterans Health Administration (VHA), but care that veterans receive in the community must be equal to VHA care. Equal care will require training and strict quality measures and standards verified for the VCCP providers. The VA also must remain the primary provider of care and the coordinator of care for all enrolled veterans.

NOVA identified 6 goals for VA Mission Act implementation. These include the following:

• Require that training, competency, and quality standards for VCCP providers are equal to those of VHA providers;
• Request third-party administrator to verify that providers meet those standards before assigning to VCCP panel;
• Simplify eligibility/access rules for community care without depleting VA funds;
• Ensure that VHA continues to be the first point of access and coordinator of all health care for enrolled veterans;
• Implement a care coordination system allowing veterans to return with ease to the VA when resources are available; and
• Employ mandatory training for VHA personnel and all community providers to improve the coordination of care, understanding of military culture, and health care needs across networks.

Other priorities include staffing/recruitment and retention—a longstanding issue within many VA facilities. Currently, the VHA has > 40,000 unfilled positions. It is no secret that the VA has had difficulty hiring essential staff at many levels. Complexities of job site databases and excessive time required to complete on-boarding, shortages in human resources personnel, and less than competitive salaries all add to the growing backlog. The inability for the VA to hire and train providers negatively impacts the access to VHA care and spurs increases in veterans using private sector care.

The VA modernization must include an electronic health record designed to support VHA’s model of health care delivery. It is crucial that Congress ensure proper IT funding to improve patient safety, software usability, and standardization of patient health care records across VHA.

VA nurses are the largest sector of employees within VHA with > 90,000 currently taking care of veterans. As VA continues its modernization, NOVA asks that nursing leadership be at the forefront of all strategic decision making.

In March, NOVA nurses shared their thoughts and views with members of Congress. They also continued discussions with the administration and VA leadership about how we can work together toward common goals—whether that be educating the next generation of nurses, providing innovative health care solutions, or engaging veterans in how they envision their health care in the future. Visit www.vanurse.org for more information about NOVA, the Legislative Priority Goals, or to become a member.

In March 2019, the Food and Drug Administration approved a novel medication, Zulresso (brexanolone), for the treatment of postpartum depression. Brexanolone is the first FDA-approved medication for the treatment of postpartum depression, a serious illness that affects nearly one in nine women soon after giving birth.¹

Mothers with postpartum depression experience feelings of sadness, irritability, and anxiety, as well as isolation from their loved ones (including their new baby) and exhaustion. The feelings of sadness and anxiety can be extreme, and can interfere with a woman’s ability to care for herself or her family. In some cases, these symptoms can be life threatening. Indeed, the most common cause of maternal death after childbirth in the developed world is suicide.² Because of the severity of the symptoms and their impact on the family, postpartum depression usually requires treatment.

Until now, there have been no drugs specifically approved to treat postpartum depression. Commonly, postpartum depression is treated with medications that previously were approved for the treatment of major depressive disorder, despite limited evidence documenting their efficacy for postpartum depression. Other putative treatment alternatives include psychotherapy, estrogen therapy, and neuromodulation, such as electroconvulsive therapy and repetitive transcranial magnetic stimulation. Each of these treatments can take weeks or longer to take effect, time that is of elevated importance given the rapidly developing mother-infant relationship in the early postpartum period. Brexanolone addresses both the issue of efficacy and speed of onset, representing a major step forward in the care of women suffering from postpartum depression.

Importantly, the approval of brexanolone marks an important milestone for the psychiatric research community in general and the National Institute of Mental Health in particular, as it represents a compelling example of successful bench-to-bedside translation of basic neuroscience findings to benefit patients. As we have noted elsewhere,³ the research underlying the discovery of endogenous neurosteroids and their role in modulating GABA receptors laid the foundation for the development of brexanolone, an intravenous formulation of the neurosteroid allopregnanolone. The recognition that allopregnanolone was a protective factor induced by stress, that it derived from progesterone, and that its peripheral blood levels were dramatically reduced in the early postpartum period led to the hypothesis that it might be useful as a treatment for postpartum depression.

Sage Therapeutics took on the task of testing this hypothesis, designing a program, in consultation with the FDA, to test the efficacy of allopregnanolone in women with postpartum depression in a series of randomized, placebo-controlled studies assessing brexanolone. The results showed that, not only did brexanolone rapidly reduce depressive symptoms in these women, with symptom relief as early as within 2 days, but the improvement lasted up to 30 days after the treatment was stopped.^4,5 It is a significant accomplishment of Sage Therapeutics to not only successfully complete the therapeutic program of studies (given past experience with difficulties recruiting these women for placebo-controlled treatment trials) but as well to demonstrate a robust therapeutic effect.

Although the FDA’s approval of a new and novel treatment is exciting for many women, there are still limitations to the broader use of brexanolone. It is delivered intravenously, requires an overnight stay in a certified medical center, and is likely to be considerably expensive, according to early reports – potentially limiting the access to the treatment. There also are potentially serious side effects, such as sedation, dizziness, or sudden loss of consciousness. Nonetheless, this is a promising first step and hopefully will spur further efforts to identify and optimize additional strategies to treat postpartum depression. In fact, other formulations of allopregnanolone and novel analogs to treat postpartum depression already are under study, including some that are orally bioavailable.^6,7,8

Several important questions remain to be answered about both brexanolone and postpartum depression: What is the underlying mechanism through which allopregnanolone acts in the brain and reduces depressive symptoms? Is the mechanism unique to postpartum women, or might brexanolone also be effective in nonreproductive depressions in women and men? What causes postpartum depression, and what are the risk factors involved for women who develop this serious condition? Future work will focus on these and other important questions to the benefit of women who have suffered with this condition.

The FDA approval of brexanolone represents the second approval in a month of a new antidepressant treatment targeting different molecules in the brain. In early March 2019, the agency approved Spravato (esketamine) nasal spray as a therapy for treatment-resistant depression. Like brexanolone, esketamine is a fast-acting antidepressant that works through a novel mechanism, completely different from other antidepressants. These new treatment approvals are encouraging, as there has been a paucity for many years in approving new effective treatments for mood disorders.

However, treatment development in psychiatry still has a long way to go and the full underlying neurobiology of mood disorders, including postpartum depression, remains poorly understood. Many challenges are ahead of us in our efforts to develop new treatments and increase our understanding of mental illnesses. Nevertheless, the approval of brexanolone is an important milestone, giving hope to the many women who suffer from postpartum depression, and paving the way for the development of additional novel and effective medications to treat this serious and sometimes life-threatening condition.

Dr. Gordon is the director of the National Institute of Mental Health (NIMH), the lead federal agency for research on mental disorders. He oversees an extensive research portfolio of basic and clinical research that seeks to transform the understanding and treatment of mental illnesses, paving the way for prevention, recovery, and cure. Dr. Hillefors works at the NIMH and oversees the Translational Therapeutics Program in the division of translational research, focusing on the development of novel treatments and biomarkers and early phase clinical trials. She received her MD and PhD in neuroscience at the Karolinska Institute, Sweden. Dr. Schmidt joined the NIMH in 1986 after completing his psychiatric residency at the University of Toronto. He is the chief of the Section on Behavioral Endocrinology, within the Intramural Research Program at the NIMH, where his laboratory studies the relationship between hormones, stress, and mood – particularly in the areas of postpartum depression, severe premenstrual dysphoria, and perimenopausal depression.

References

1. J Psychiatric Res. 2018 Sep;104:235-48.

2. Br J Psychiatry. 2003 Oct;183:279-81.

3. NIMH Director’s Messages. 2019 Mar 20.

4. Lancet. 2017 Jul 29;390(10093):480-9.

5. Lancet. 2018 Sep 22; 392(10152):1058-70.

6. Sage Therapeutics News. 2019 Jan 7.

7. Marinus Pharmaceuticals. 2017 Jun 27.

8. ClinicalTrials.gov Identifier: NCT03460756. 2019 Mar.

In March 2019, the Food and Drug Administration approved a novel medication, Zulresso (brexanolone), for the treatment of postpartum depression. Brexanolone is the first FDA-approved medication for the treatment of postpartum depression, a serious illness that affects nearly one in nine women soon after giving birth.¹

Mothers with postpartum depression experience feelings of sadness, irritability, and anxiety, as well as isolation from their loved ones (including their new baby) and exhaustion. The feelings of sadness and anxiety can be extreme, and can interfere with a woman’s ability to care for herself or her family. In some cases, these symptoms can be life threatening. Indeed, the most common cause of maternal death after childbirth in the developed world is suicide.² Because of the severity of the symptoms and their impact on the family, postpartum depression usually requires treatment.

Until now, there have been no drugs specifically approved to treat postpartum depression. Commonly, postpartum depression is treated with medications that previously were approved for the treatment of major depressive disorder, despite limited evidence documenting their efficacy for postpartum depression. Other putative treatment alternatives include psychotherapy, estrogen therapy, and neuromodulation, such as electroconvulsive therapy and repetitive transcranial magnetic stimulation. Each of these treatments can take weeks or longer to take effect, time that is of elevated importance given the rapidly developing mother-infant relationship in the early postpartum period. Brexanolone addresses both the issue of efficacy and speed of onset, representing a major step forward in the care of women suffering from postpartum depression.

Importantly, the approval of brexanolone marks an important milestone for the psychiatric research community in general and the National Institute of Mental Health in particular, as it represents a compelling example of successful bench-to-bedside translation of basic neuroscience findings to benefit patients. As we have noted elsewhere,³ the research underlying the discovery of endogenous neurosteroids and their role in modulating GABA receptors laid the foundation for the development of brexanolone, an intravenous formulation of the neurosteroid allopregnanolone. The recognition that allopregnanolone was a protective factor induced by stress, that it derived from progesterone, and that its peripheral blood levels were dramatically reduced in the early postpartum period led to the hypothesis that it might be useful as a treatment for postpartum depression.

Sage Therapeutics took on the task of testing this hypothesis, designing a program, in consultation with the FDA, to test the efficacy of allopregnanolone in women with postpartum depression in a series of randomized, placebo-controlled studies assessing brexanolone. The results showed that, not only did brexanolone rapidly reduce depressive symptoms in these women, with symptom relief as early as within 2 days, but the improvement lasted up to 30 days after the treatment was stopped.^4,5 It is a significant accomplishment of Sage Therapeutics to not only successfully complete the therapeutic program of studies (given past experience with difficulties recruiting these women for placebo-controlled treatment trials) but as well to demonstrate a robust therapeutic effect.

Although the FDA’s approval of a new and novel treatment is exciting for many women, there are still limitations to the broader use of brexanolone. It is delivered intravenously, requires an overnight stay in a certified medical center, and is likely to be considerably expensive, according to early reports – potentially limiting the access to the treatment. There also are potentially serious side effects, such as sedation, dizziness, or sudden loss of consciousness. Nonetheless, this is a promising first step and hopefully will spur further efforts to identify and optimize additional strategies to treat postpartum depression. In fact, other formulations of allopregnanolone and novel analogs to treat postpartum depression already are under study, including some that are orally bioavailable.^6,7,8

Several important questions remain to be answered about both brexanolone and postpartum depression: What is the underlying mechanism through which allopregnanolone acts in the brain and reduces depressive symptoms? Is the mechanism unique to postpartum women, or might brexanolone also be effective in nonreproductive depressions in women and men? What causes postpartum depression, and what are the risk factors involved for women who develop this serious condition? Future work will focus on these and other important questions to the benefit of women who have suffered with this condition.

The FDA approval of brexanolone represents the second approval in a month of a new antidepressant treatment targeting different molecules in the brain. In early March 2019, the agency approved Spravato (esketamine) nasal spray as a therapy for treatment-resistant depression. Like brexanolone, esketamine is a fast-acting antidepressant that works through a novel mechanism, completely different from other antidepressants. These new treatment approvals are encouraging, as there has been a paucity for many years in approving new effective treatments for mood disorders.

However, treatment development in psychiatry still has a long way to go and the full underlying neurobiology of mood disorders, including postpartum depression, remains poorly understood. Many challenges are ahead of us in our efforts to develop new treatments and increase our understanding of mental illnesses. Nevertheless, the approval of brexanolone is an important milestone, giving hope to the many women who suffer from postpartum depression, and paving the way for the development of additional novel and effective medications to treat this serious and sometimes life-threatening condition.

Dr. Gordon is the director of the National Institute of Mental Health (NIMH), the lead federal agency for research on mental disorders. He oversees an extensive research portfolio of basic and clinical research that seeks to transform the understanding and treatment of mental illnesses, paving the way for prevention, recovery, and cure. Dr. Hillefors works at the NIMH and oversees the Translational Therapeutics Program in the division of translational research, focusing on the development of novel treatments and biomarkers and early phase clinical trials. She received her MD and PhD in neuroscience at the Karolinska Institute, Sweden. Dr. Schmidt joined the NIMH in 1986 after completing his psychiatric residency at the University of Toronto. He is the chief of the Section on Behavioral Endocrinology, within the Intramural Research Program at the NIMH, where his laboratory studies the relationship between hormones, stress, and mood – particularly in the areas of postpartum depression, severe premenstrual dysphoria, and perimenopausal depression.

References

1. J Psychiatric Res. 2018 Sep;104:235-48.

2. Br J Psychiatry. 2003 Oct;183:279-81.

3. NIMH Director’s Messages. 2019 Mar 20.

4. Lancet. 2017 Jul 29;390(10093):480-9.

5. Lancet. 2018 Sep 22; 392(10152):1058-70.

6. Sage Therapeutics News. 2019 Jan 7.

7. Marinus Pharmaceuticals. 2017 Jun 27.

8. ClinicalTrials.gov Identifier: NCT03460756. 2019 Mar.

In March 2019, the Food and Drug Administration approved a novel medication, Zulresso (brexanolone), for the treatment of postpartum depression. Brexanolone is the first FDA-approved medication for the treatment of postpartum depression, a serious illness that affects nearly one in nine women soon after giving birth.¹

Mothers with postpartum depression experience feelings of sadness, irritability, and anxiety, as well as isolation from their loved ones (including their new baby) and exhaustion. The feelings of sadness and anxiety can be extreme, and can interfere with a woman’s ability to care for herself or her family. In some cases, these symptoms can be life threatening. Indeed, the most common cause of maternal death after childbirth in the developed world is suicide.² Because of the severity of the symptoms and their impact on the family, postpartum depression usually requires treatment.

Until now, there have been no drugs specifically approved to treat postpartum depression. Commonly, postpartum depression is treated with medications that previously were approved for the treatment of major depressive disorder, despite limited evidence documenting their efficacy for postpartum depression. Other putative treatment alternatives include psychotherapy, estrogen therapy, and neuromodulation, such as electroconvulsive therapy and repetitive transcranial magnetic stimulation. Each of these treatments can take weeks or longer to take effect, time that is of elevated importance given the rapidly developing mother-infant relationship in the early postpartum period. Brexanolone addresses both the issue of efficacy and speed of onset, representing a major step forward in the care of women suffering from postpartum depression.

Importantly, the approval of brexanolone marks an important milestone for the psychiatric research community in general and the National Institute of Mental Health in particular, as it represents a compelling example of successful bench-to-bedside translation of basic neuroscience findings to benefit patients. As we have noted elsewhere,³ the research underlying the discovery of endogenous neurosteroids and their role in modulating GABA receptors laid the foundation for the development of brexanolone, an intravenous formulation of the neurosteroid allopregnanolone. The recognition that allopregnanolone was a protective factor induced by stress, that it derived from progesterone, and that its peripheral blood levels were dramatically reduced in the early postpartum period led to the hypothesis that it might be useful as a treatment for postpartum depression.

Sage Therapeutics took on the task of testing this hypothesis, designing a program, in consultation with the FDA, to test the efficacy of allopregnanolone in women with postpartum depression in a series of randomized, placebo-controlled studies assessing brexanolone. The results showed that, not only did brexanolone rapidly reduce depressive symptoms in these women, with symptom relief as early as within 2 days, but the improvement lasted up to 30 days after the treatment was stopped.^4,5 It is a significant accomplishment of Sage Therapeutics to not only successfully complete the therapeutic program of studies (given past experience with difficulties recruiting these women for placebo-controlled treatment trials) but as well to demonstrate a robust therapeutic effect.

Although the FDA’s approval of a new and novel treatment is exciting for many women, there are still limitations to the broader use of brexanolone. It is delivered intravenously, requires an overnight stay in a certified medical center, and is likely to be considerably expensive, according to early reports – potentially limiting the access to the treatment. There also are potentially serious side effects, such as sedation, dizziness, or sudden loss of consciousness. Nonetheless, this is a promising first step and hopefully will spur further efforts to identify and optimize additional strategies to treat postpartum depression. In fact, other formulations of allopregnanolone and novel analogs to treat postpartum depression already are under study, including some that are orally bioavailable.^6,7,8

Several important questions remain to be answered about both brexanolone and postpartum depression: What is the underlying mechanism through which allopregnanolone acts in the brain and reduces depressive symptoms? Is the mechanism unique to postpartum women, or might brexanolone also be effective in nonreproductive depressions in women and men? What causes postpartum depression, and what are the risk factors involved for women who develop this serious condition? Future work will focus on these and other important questions to the benefit of women who have suffered with this condition.

The FDA approval of brexanolone represents the second approval in a month of a new antidepressant treatment targeting different molecules in the brain. In early March 2019, the agency approved Spravato (esketamine) nasal spray as a therapy for treatment-resistant depression. Like brexanolone, esketamine is a fast-acting antidepressant that works through a novel mechanism, completely different from other antidepressants. These new treatment approvals are encouraging, as there has been a paucity for many years in approving new effective treatments for mood disorders.

However, treatment development in psychiatry still has a long way to go and the full underlying neurobiology of mood disorders, including postpartum depression, remains poorly understood. Many challenges are ahead of us in our efforts to develop new treatments and increase our understanding of mental illnesses. Nevertheless, the approval of brexanolone is an important milestone, giving hope to the many women who suffer from postpartum depression, and paving the way for the development of additional novel and effective medications to treat this serious and sometimes life-threatening condition.

Dr. Gordon is the director of the National Institute of Mental Health (NIMH), the lead federal agency for research on mental disorders. He oversees an extensive research portfolio of basic and clinical research that seeks to transform the understanding and treatment of mental illnesses, paving the way for prevention, recovery, and cure. Dr. Hillefors works at the NIMH and oversees the Translational Therapeutics Program in the division of translational research, focusing on the development of novel treatments and biomarkers and early phase clinical trials. She received her MD and PhD in neuroscience at the Karolinska Institute, Sweden. Dr. Schmidt joined the NIMH in 1986 after completing his psychiatric residency at the University of Toronto. He is the chief of the Section on Behavioral Endocrinology, within the Intramural Research Program at the NIMH, where his laboratory studies the relationship between hormones, stress, and mood – particularly in the areas of postpartum depression, severe premenstrual dysphoria, and perimenopausal depression.

References

1. J Psychiatric Res. 2018 Sep;104:235-48.

2. Br J Psychiatry. 2003 Oct;183:279-81.

3. NIMH Director’s Messages. 2019 Mar 20.

4. Lancet. 2017 Jul 29;390(10093):480-9.

5. Lancet. 2018 Sep 22; 392(10152):1058-70.

6. Sage Therapeutics News. 2019 Jan 7.

7. Marinus Pharmaceuticals. 2017 Jun 27.

8. ClinicalTrials.gov Identifier: NCT03460756. 2019 Mar.

To the Editor:

We read with interest the case report of nephrogenic systemic fibrosis (NSF) by Chuang, Kaneshiro, and Betancourt in the June 2018 issue of Federal Practitioner.¹ It was reported that a 61-year-old Hispanic male patient with a history of IV heroin abuse with end-stage renal disease (ESRD) secondary to membranous glomerulonephritis on hemodialysis and chronic hepatitis C infection received 15 mL gadoversetamide, a linear gadolinium-based contrast agent (GBCA) during magnetic resonance imaging (MRI) of the brain. Hemodialysis was performed 18 hours after the contrast administration.

Eight weeks after his initial presentation, the patient developed pyoderma gangrenosum on his right forearm, which was treated with high-dose steroids. He then developed thickening and induration of his bilateral forearm skin with peau d’orange appearance. NSF was confirmed by a skin biopsy. The patient developed contractures of his upper and lower extremities and was finally wheelchair bound.

This case is very concerning since no NSF cases in patients receiving GBCA have been published since 2009. Unfortunately, the authors give no information on the occurrence of this particular case. Thus, it is unclear whether this case was observed before or after the switch to macrocyclic agents in patients with reduced renal function. The reported patient with ESRD was on hemodialysis and received 15 mL gadoversetamide during MRI of the brain. In 2007 the ESUR (European Society of Urogenital Radiology) published guidelines indicating linear GBCA (gadodiamide, gadoversetamide, gadopentetate dimeglumine) as high-risk agents that may not be used in patients with eGFR < 30 mL/min/1.73 m².^2,3

Consequently in 2007, the European Medicines Agency contraindicated these linear GBCA in patients with chronic kidney disease grades 4 and 5. Also in 2007 the US Food and Drug Administration (FDA) requested a revision of the prescribing information for all 5 GBCA approved in the US.⁴ In response to accumulating more informative data, in 2010 the FDA again used this class labeling approach to more explicitly describe differences in NSF risks among the agents.⁴ FDA regulation and contraindication of the use of low-stability GBCA in patients with advanced renal impairment and robust local policies on the safe use of these agents have resulted in marked reduction in the prevalence of NSF in the US. This case report needs to clarify why a high-risk linear agent was administered to a patient with ESRD.

In 2006 Grobner and Marckmann and colleagues reported their observations of a previously unrecognized link between exposure to gadodiamide and the development of NSF.^5,6 It soon became clear that NSF is a delayed adverse contrast reaction that may cause severe disability and even death. Advanced renal disease and high-risk linear GBCA are the main factors in the pathogenesis of NSF. Additionally, the dose of the agent may play a role. NSF can occur from hours to years after exposure to GBCA. Not all patients with severe kidney disease exposed to high-risk agents developed NSF. Thus, additional factors were proposed to play a role in the pathogenesis of NSF. Among those factors were erythropoietin, metabolic acidosis, anion gap, iron, increased phosphate, zinc loss, proinflammatory conditions/inflammation and angiotensin-converting enzyme (ACE) inhibitors.⁷ Although there is little proof with these assumptions, special care must be taken as shown by this reported patient with multiple inflammatory disorders.

- Gertraud Heinz, MD, MBA; Aart van der Molen, MD; and Giles Roditi, MD; on behalf of the ESUR Contrast Media Safety Committee

Author affiliations: Gertraud Heinz is former President ESUR and Head of the Department of Radiology, Diagnostics and Intervention University Hospital St. Pölten Karl Landsteiner University of Health Sciences.

Correspondence: Gertraud Heinz (gertraud.heinz@stpoelten .lknoe.at)

Disclosures: The authors report no conflict of interest with regard to this article.

References
1. Chuang K, Kaneshiro C, Betancourt J. Nephrogenic systemic fibrosis in a patient with multiple inflammatory disorders. Fed Pract. 2018;35(6):40-43.
2. Thomsen HS; European Society of Urogenital Radiology (ESUR). ESUR guideline: gadolinium based contrast media and nephrogenic systemic fibrosis. Eur Radiol. 2007;17(10):2692-2696.
3. Thomsen HS, Morcos SK, Almén T, et al; ESUR Contrast Medium Safety Committee. Nephrogenic systemic fibrosis and gadolinium-based contrast media: updated ESUR Contrast Media Safety Committee guidelines. Eur Radiol. 2013;23(2):307-318
4. Yang L, Krefting I, Gorovets A, et al. Nephrogenic systemic fibrosis and class labeling of gadolinium-based agents by the Food and Drug Administration. Radiology. 2012;265(1):248-253.
5. Grobner T. Gadolinium—a specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic systemic fibrosis? Nephrol Dial Transplant. 2006;21(4):1104-1108.
6. Marckmann P, Skov L, Rossen K, et al. Nephrogenic systemic fibrosis: suspected causative role of gadodiamide used for contrast-enhanced magnetic resonance imaging. J Am Soc Nephrol. 2006;17(9):2359-2362.
7. Thomsen HS, Bennett CL. Six years after. Acta Radiol. 2012;53(8):827-829.

To the Editor:

With great interest, I read the case report by Chuang, Kaneshiro, and Betancourt.¹ Patients with nephrogenic systemic fibrosis (NSF) are of special interest because the disease is still unclear as mentioned by the authors. Although new cases may occur,² this case raises some concerns that I would like to address.

First, it would be of great interest to know the date when the patient received the high-risk gadolinium-based contrast agent (GBCA) gadoversetamide. Unfortunately, the authors did not mention the date of the injection of the GBCA that probably caused NSF. Due to the obvious association between the applications of special GBCAs in 2006, the US Food and Drug Administration (FDA) warned physicians not to inject these contrast agents in patients with compromised kidney function.³ Moreover, in 2007 the American College of Radiology (ACR) published guidelines for the safe use of GBCAs in patients with renal failure.⁴ Also, the European Medicines Agency (EMA) demanded that companies provide warning in product inserts about the acquisition of NSF in patients with severe kidney injury.⁵

Second, the clinical illustration of the case is inadequate. In the manuscript, we read that the patient acquired NSF-characteristic lesions like peau d’orange skin lesions and contractures of his extremities, but unfortunately, Chuang, Kaneshiro, and Betancourt did not provide figures that show them. On the other hand, Figure 1 shows an uncharacteristic dermal induration around inflammatory and ulcerated skin lesion (pyoderma gangrenosum).¹ Such clinical signs are well known and occur perilesional of different conditions independently of NSF.^6-8

Third, the histological features described as presence of fibrotic tissue in the deep dermis in Figure 2, and dermal fibrosis with thick collagen deposition in Figure 3¹ do not confirm the existence of NSF.

Taken together, the case presented by Chuang, Kaneshiro, and Betancourt contains some unclear aspects; therefore, it is questionable whether the published case describes a patient with NSF or not. In the current presentation, the diagnosis NSF seems to be an overestimation.

NSF still is a poorly understood disorder. Therefore, exactly documented new cases could be of clinical value when providing interesting information. Even single cases could shed some light in the darkness of the pathological mechanisms of this entity. On the other hand, we should not mix the existing cohort of published NSF cases with other scleroderma-like diseases, because this will lead to a confusion. Moreover, such a practice could inhibit the discovery of the pathophysiology of NSF.

- Ingrid Böhm, MD

Author affiliations: Ingrid Böhm is a Physician in the Department of Diagnostics, Interventional and Pediatric Radiology at the University Hospital of Bern, Inselspital, University of Bern in Bern, Switzerland.

Correspondence: Ingrid Böhm ([email protected])

Disclosures: The author reports no conflict of interest with regard to this article.

References
1. Chuang K, Kaneshiro C, Betancourt J. Nephrogenic systemic fibrosis in a patient with multiple inflammatory disorders. Fed Pract . 2018;35(6):40-43.
2. Larson KN, Gagnon AL, Darling MD, Patterson JW, Cropley TG. Nephrogenic systemic fibrosis manifesting a decade after exposure to gadolinium. JAMA Dermatol. 2015;151(10):1117-1120.
3. US Food and Drug Administration. A Public Health Advisory. Gadolinium-containing contrast agents for magnetic resonance imaging (MRI). http://wayback.archive-it.org/7993/20170112033022/http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformation forPatientsandProviders/ucm053112.htm. Published June 8, 2006. Accessed March 15, 2019.
4. Kanal E, Barkovich AJ, Bell C, et al; ACR Blue Ribbon Panel on MR Safety. ACR guidance document for safe MR practices: 2007. AJR Am J Roentgenol. 2007;188(6):1447-1474.
5. European Medicines Agency. Public statement: Vasovist and nephrogenic systemic fibrosis (NSF). https://www.ema.europa.eu/en/news/public-statement-vasovist-nephrogenic-systemic-fibrosis-nsf. Published February 7, 2007. Accessed March 15, 2019.
6. Luke JC. The etiology and modern treatment of varicose ulcer. Can Med Assoc J. 1940;43(3):217-221.
7. Paulsen E, Bygum A. Keratin gel as an adjuvant in the treatment of recalcitrant pyoderma gangrenosum ulcers: a case report. Acta Derm Venereol. 2019;99(2):234-235.
8. Boehm I, Bauer R. Low-dose methotrexate controls a severe form of polyarteritis nodosa. Arch Dermatol. 2000; 136(2):167-169.

Response:

We thank Drs. Heinz, van der Molen, and Roditi for their valuable response. The following is the opinion of the authors and is not representative of the views or policies of our institution. The patient in this case received a gadolinium-based contrast agent (GBCA) in 2015 and was diagnosed with nephrogenic systemic fibrosis (NSF) 8 weeks later. We agree with the correspondents that linear GBCAs should not be used in patients with eGFR < 30 mL/min/1.73 m². To date, a few cases of patients who received GBCA and developed NSF since 2009 have unfortunately continued to be reported in the literature.^1-3 Our intention in publishing this case was to provide ongoing education to the medical community regarding this serious condition to ensure prevention of future cases.

We thank Dr. Böhm for her important inquiry. The patient received a histopathologic diagnosis of NSF. The report from the patient’s left dorsal forearm skin punch biopsy was read by our pathologist as “fibrosis and inflammation consistent with nephrogenic systemic fibrosis,” a diagnosis agreed upon by our colleagues in the dermatology and rheumatology departments based on the rapidity of his symptom onset and progression. While we acknowledge that this patient had other inflammatory disorders of the skin that may have coexisted with the diagnosis, after weighing the preponderance of clinical evidence in support of the biopsy results, we believe that this represents a case of NSF, which is associated with high morbidity and mortality. Thankfully, the patient in this case engaged extensively in physical and occupational therapy and is still alive nearly 4 years later. We would like to thank all the letter writers for their correspondence.

Author Affiliations: Kelley Chuang and Casey Kaneshiro are Hospitalists and Jaime Betancourt is a Pulmonologist, all in the Department of Medicine at the VA Greater Los Angeles Healthcare System in California.

Correspondence: Kelley Chuang ([email protected])

Disclosures: The authors report no conflict of interest with regard to this article.

References
1. Aggarwal A, Froehlich AA, Essah P, Brinster N, High WA, Downs RW. Complications of nephrogenic systemic fibrosis following repeated exposure to gadolinium in a man with hypothyroidism: a case report. J Med Case Rep. 2011;5:566.
2. Fuah KW, Lim CT. Erythema nodosum masking nephrogenic systemic fibrosis as initial skin manifestation. BMC Nephrol. 2017;18(1):249.
3. Koratala A, Bhatti V. Nephrogenic systemic fibrosis. Clin Case Rep. 2017;5(7):1184-1185.

To the Editor:

We read with interest the case report of nephrogenic systemic fibrosis (NSF) by Chuang, Kaneshiro, and Betancourt in the June 2018 issue of Federal Practitioner.¹ It was reported that a 61-year-old Hispanic male patient with a history of IV heroin abuse with end-stage renal disease (ESRD) secondary to membranous glomerulonephritis on hemodialysis and chronic hepatitis C infection received 15 mL gadoversetamide, a linear gadolinium-based contrast agent (GBCA) during magnetic resonance imaging (MRI) of the brain. Hemodialysis was performed 18 hours after the contrast administration.

Eight weeks after his initial presentation, the patient developed pyoderma gangrenosum on his right forearm, which was treated with high-dose steroids. He then developed thickening and induration of his bilateral forearm skin with peau d’orange appearance. NSF was confirmed by a skin biopsy. The patient developed contractures of his upper and lower extremities and was finally wheelchair bound.

This case is very concerning since no NSF cases in patients receiving GBCA have been published since 2009. Unfortunately, the authors give no information on the occurrence of this particular case. Thus, it is unclear whether this case was observed before or after the switch to macrocyclic agents in patients with reduced renal function. The reported patient with ESRD was on hemodialysis and received 15 mL gadoversetamide during MRI of the brain. In 2007 the ESUR (European Society of Urogenital Radiology) published guidelines indicating linear GBCA (gadodiamide, gadoversetamide, gadopentetate dimeglumine) as high-risk agents that may not be used in patients with eGFR < 30 mL/min/1.73 m².^2,3

Consequently in 2007, the European Medicines Agency contraindicated these linear GBCA in patients with chronic kidney disease grades 4 and 5. Also in 2007 the US Food and Drug Administration (FDA) requested a revision of the prescribing information for all 5 GBCA approved in the US.⁴ In response to accumulating more informative data, in 2010 the FDA again used this class labeling approach to more explicitly describe differences in NSF risks among the agents.⁴ FDA regulation and contraindication of the use of low-stability GBCA in patients with advanced renal impairment and robust local policies on the safe use of these agents have resulted in marked reduction in the prevalence of NSF in the US. This case report needs to clarify why a high-risk linear agent was administered to a patient with ESRD.

In 2006 Grobner and Marckmann and colleagues reported their observations of a previously unrecognized link between exposure to gadodiamide and the development of NSF.^5,6 It soon became clear that NSF is a delayed adverse contrast reaction that may cause severe disability and even death. Advanced renal disease and high-risk linear GBCA are the main factors in the pathogenesis of NSF. Additionally, the dose of the agent may play a role. NSF can occur from hours to years after exposure to GBCA. Not all patients with severe kidney disease exposed to high-risk agents developed NSF. Thus, additional factors were proposed to play a role in the pathogenesis of NSF. Among those factors were erythropoietin, metabolic acidosis, anion gap, iron, increased phosphate, zinc loss, proinflammatory conditions/inflammation and angiotensin-converting enzyme (ACE) inhibitors.⁷ Although there is little proof with these assumptions, special care must be taken as shown by this reported patient with multiple inflammatory disorders.

- Gertraud Heinz, MD, MBA; Aart van der Molen, MD; and Giles Roditi, MD; on behalf of the ESUR Contrast Media Safety Committee

Author affiliations: Gertraud Heinz is former President ESUR and Head of the Department of Radiology, Diagnostics and Intervention University Hospital St. Pölten Karl Landsteiner University of Health Sciences.

Correspondence: Gertraud Heinz (gertraud.heinz@stpoelten .lknoe.at)

Disclosures: The authors report no conflict of interest with regard to this article.

References
1. Chuang K, Kaneshiro C, Betancourt J. Nephrogenic systemic fibrosis in a patient with multiple inflammatory disorders. Fed Pract. 2018;35(6):40-43.
2. Thomsen HS; European Society of Urogenital Radiology (ESUR). ESUR guideline: gadolinium based contrast media and nephrogenic systemic fibrosis. Eur Radiol. 2007;17(10):2692-2696.
3. Thomsen HS, Morcos SK, Almén T, et al; ESUR Contrast Medium Safety Committee. Nephrogenic systemic fibrosis and gadolinium-based contrast media: updated ESUR Contrast Media Safety Committee guidelines. Eur Radiol. 2013;23(2):307-318
4. Yang L, Krefting I, Gorovets A, et al. Nephrogenic systemic fibrosis and class labeling of gadolinium-based agents by the Food and Drug Administration. Radiology. 2012;265(1):248-253.
5. Grobner T. Gadolinium—a specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic systemic fibrosis? Nephrol Dial Transplant. 2006;21(4):1104-1108.
6. Marckmann P, Skov L, Rossen K, et al. Nephrogenic systemic fibrosis: suspected causative role of gadodiamide used for contrast-enhanced magnetic resonance imaging. J Am Soc Nephrol. 2006;17(9):2359-2362.
7. Thomsen HS, Bennett CL. Six years after. Acta Radiol. 2012;53(8):827-829.

To the Editor:

With great interest, I read the case report by Chuang, Kaneshiro, and Betancourt.¹ Patients with nephrogenic systemic fibrosis (NSF) are of special interest because the disease is still unclear as mentioned by the authors. Although new cases may occur,² this case raises some concerns that I would like to address.

First, it would be of great interest to know the date when the patient received the high-risk gadolinium-based contrast agent (GBCA) gadoversetamide. Unfortunately, the authors did not mention the date of the injection of the GBCA that probably caused NSF. Due to the obvious association between the applications of special GBCAs in 2006, the US Food and Drug Administration (FDA) warned physicians not to inject these contrast agents in patients with compromised kidney function.³ Moreover, in 2007 the American College of Radiology (ACR) published guidelines for the safe use of GBCAs in patients with renal failure.⁴ Also, the European Medicines Agency (EMA) demanded that companies provide warning in product inserts about the acquisition of NSF in patients with severe kidney injury.⁵

Second, the clinical illustration of the case is inadequate. In the manuscript, we read that the patient acquired NSF-characteristic lesions like peau d’orange skin lesions and contractures of his extremities, but unfortunately, Chuang, Kaneshiro, and Betancourt did not provide figures that show them. On the other hand, Figure 1 shows an uncharacteristic dermal induration around inflammatory and ulcerated skin lesion (pyoderma gangrenosum).¹ Such clinical signs are well known and occur perilesional of different conditions independently of NSF.^6-8

Third, the histological features described as presence of fibrotic tissue in the deep dermis in Figure 2, and dermal fibrosis with thick collagen deposition in Figure 3¹ do not confirm the existence of NSF.

Taken together, the case presented by Chuang, Kaneshiro, and Betancourt contains some unclear aspects; therefore, it is questionable whether the published case describes a patient with NSF or not. In the current presentation, the diagnosis NSF seems to be an overestimation.

NSF still is a poorly understood disorder. Therefore, exactly documented new cases could be of clinical value when providing interesting information. Even single cases could shed some light in the darkness of the pathological mechanisms of this entity. On the other hand, we should not mix the existing cohort of published NSF cases with other scleroderma-like diseases, because this will lead to a confusion. Moreover, such a practice could inhibit the discovery of the pathophysiology of NSF.

- Ingrid Böhm, MD

Author affiliations: Ingrid Böhm is a Physician in the Department of Diagnostics, Interventional and Pediatric Radiology at the University Hospital of Bern, Inselspital, University of Bern in Bern, Switzerland.

Correspondence: Ingrid Böhm ([email protected])

Disclosures: The author reports no conflict of interest with regard to this article.

References
1. Chuang K, Kaneshiro C, Betancourt J. Nephrogenic systemic fibrosis in a patient with multiple inflammatory disorders. Fed Pract . 2018;35(6):40-43.
2. Larson KN, Gagnon AL, Darling MD, Patterson JW, Cropley TG. Nephrogenic systemic fibrosis manifesting a decade after exposure to gadolinium. JAMA Dermatol. 2015;151(10):1117-1120.
3. US Food and Drug Administration. A Public Health Advisory. Gadolinium-containing contrast agents for magnetic resonance imaging (MRI). http://wayback.archive-it.org/7993/20170112033022/http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformation forPatientsandProviders/ucm053112.htm. Published June 8, 2006. Accessed March 15, 2019.
4. Kanal E, Barkovich AJ, Bell C, et al; ACR Blue Ribbon Panel on MR Safety. ACR guidance document for safe MR practices: 2007. AJR Am J Roentgenol. 2007;188(6):1447-1474.
5. European Medicines Agency. Public statement: Vasovist and nephrogenic systemic fibrosis (NSF). https://www.ema.europa.eu/en/news/public-statement-vasovist-nephrogenic-systemic-fibrosis-nsf. Published February 7, 2007. Accessed March 15, 2019.
6. Luke JC. The etiology and modern treatment of varicose ulcer. Can Med Assoc J. 1940;43(3):217-221.
7. Paulsen E, Bygum A. Keratin gel as an adjuvant in the treatment of recalcitrant pyoderma gangrenosum ulcers: a case report. Acta Derm Venereol. 2019;99(2):234-235.
8. Boehm I, Bauer R. Low-dose methotrexate controls a severe form of polyarteritis nodosa. Arch Dermatol. 2000; 136(2):167-169.

Response:

We thank Drs. Heinz, van der Molen, and Roditi for their valuable response. The following is the opinion of the authors and is not representative of the views or policies of our institution. The patient in this case received a gadolinium-based contrast agent (GBCA) in 2015 and was diagnosed with nephrogenic systemic fibrosis (NSF) 8 weeks later. We agree with the correspondents that linear GBCAs should not be used in patients with eGFR < 30 mL/min/1.73 m². To date, a few cases of patients who received GBCA and developed NSF since 2009 have unfortunately continued to be reported in the literature.^1-3 Our intention in publishing this case was to provide ongoing education to the medical community regarding this serious condition to ensure prevention of future cases.

We thank Dr. Böhm for her important inquiry. The patient received a histopathologic diagnosis of NSF. The report from the patient’s left dorsal forearm skin punch biopsy was read by our pathologist as “fibrosis and inflammation consistent with nephrogenic systemic fibrosis,” a diagnosis agreed upon by our colleagues in the dermatology and rheumatology departments based on the rapidity of his symptom onset and progression. While we acknowledge that this patient had other inflammatory disorders of the skin that may have coexisted with the diagnosis, after weighing the preponderance of clinical evidence in support of the biopsy results, we believe that this represents a case of NSF, which is associated with high morbidity and mortality. Thankfully, the patient in this case engaged extensively in physical and occupational therapy and is still alive nearly 4 years later. We would like to thank all the letter writers for their correspondence.

Author Affiliations: Kelley Chuang and Casey Kaneshiro are Hospitalists and Jaime Betancourt is a Pulmonologist, all in the Department of Medicine at the VA Greater Los Angeles Healthcare System in California.

Correspondence: Kelley Chuang ([email protected])

Disclosures: The authors report no conflict of interest with regard to this article.

References
1. Aggarwal A, Froehlich AA, Essah P, Brinster N, High WA, Downs RW. Complications of nephrogenic systemic fibrosis following repeated exposure to gadolinium in a man with hypothyroidism: a case report. J Med Case Rep. 2011;5:566.
2. Fuah KW, Lim CT. Erythema nodosum masking nephrogenic systemic fibrosis as initial skin manifestation. BMC Nephrol. 2017;18(1):249.
3. Koratala A, Bhatti V. Nephrogenic systemic fibrosis. Clin Case Rep. 2017;5(7):1184-1185.

To the Editor:

We read with interest the case report of nephrogenic systemic fibrosis (NSF) by Chuang, Kaneshiro, and Betancourt in the June 2018 issue of Federal Practitioner.¹ It was reported that a 61-year-old Hispanic male patient with a history of IV heroin abuse with end-stage renal disease (ESRD) secondary to membranous glomerulonephritis on hemodialysis and chronic hepatitis C infection received 15 mL gadoversetamide, a linear gadolinium-based contrast agent (GBCA) during magnetic resonance imaging (MRI) of the brain. Hemodialysis was performed 18 hours after the contrast administration.

Eight weeks after his initial presentation, the patient developed pyoderma gangrenosum on his right forearm, which was treated with high-dose steroids. He then developed thickening and induration of his bilateral forearm skin with peau d’orange appearance. NSF was confirmed by a skin biopsy. The patient developed contractures of his upper and lower extremities and was finally wheelchair bound.

This case is very concerning since no NSF cases in patients receiving GBCA have been published since 2009. Unfortunately, the authors give no information on the occurrence of this particular case. Thus, it is unclear whether this case was observed before or after the switch to macrocyclic agents in patients with reduced renal function. The reported patient with ESRD was on hemodialysis and received 15 mL gadoversetamide during MRI of the brain. In 2007 the ESUR (European Society of Urogenital Radiology) published guidelines indicating linear GBCA (gadodiamide, gadoversetamide, gadopentetate dimeglumine) as high-risk agents that may not be used in patients with eGFR < 30 mL/min/1.73 m².^2,3

Consequently in 2007, the European Medicines Agency contraindicated these linear GBCA in patients with chronic kidney disease grades 4 and 5. Also in 2007 the US Food and Drug Administration (FDA) requested a revision of the prescribing information for all 5 GBCA approved in the US.⁴ In response to accumulating more informative data, in 2010 the FDA again used this class labeling approach to more explicitly describe differences in NSF risks among the agents.⁴ FDA regulation and contraindication of the use of low-stability GBCA in patients with advanced renal impairment and robust local policies on the safe use of these agents have resulted in marked reduction in the prevalence of NSF in the US. This case report needs to clarify why a high-risk linear agent was administered to a patient with ESRD.

In 2006 Grobner and Marckmann and colleagues reported their observations of a previously unrecognized link between exposure to gadodiamide and the development of NSF.^5,6 It soon became clear that NSF is a delayed adverse contrast reaction that may cause severe disability and even death. Advanced renal disease and high-risk linear GBCA are the main factors in the pathogenesis of NSF. Additionally, the dose of the agent may play a role. NSF can occur from hours to years after exposure to GBCA. Not all patients with severe kidney disease exposed to high-risk agents developed NSF. Thus, additional factors were proposed to play a role in the pathogenesis of NSF. Among those factors were erythropoietin, metabolic acidosis, anion gap, iron, increased phosphate, zinc loss, proinflammatory conditions/inflammation and angiotensin-converting enzyme (ACE) inhibitors.⁷ Although there is little proof with these assumptions, special care must be taken as shown by this reported patient with multiple inflammatory disorders.

- Gertraud Heinz, MD, MBA; Aart van der Molen, MD; and Giles Roditi, MD; on behalf of the ESUR Contrast Media Safety Committee

Author affiliations: Gertraud Heinz is former President ESUR and Head of the Department of Radiology, Diagnostics and Intervention University Hospital St. Pölten Karl Landsteiner University of Health Sciences.

Correspondence: Gertraud Heinz (gertraud.heinz@stpoelten .lknoe.at)

Disclosures: The authors report no conflict of interest with regard to this article.

References
1. Chuang K, Kaneshiro C, Betancourt J. Nephrogenic systemic fibrosis in a patient with multiple inflammatory disorders. Fed Pract. 2018;35(6):40-43.
2. Thomsen HS; European Society of Urogenital Radiology (ESUR). ESUR guideline: gadolinium based contrast media and nephrogenic systemic fibrosis. Eur Radiol. 2007;17(10):2692-2696.
3. Thomsen HS, Morcos SK, Almén T, et al; ESUR Contrast Medium Safety Committee. Nephrogenic systemic fibrosis and gadolinium-based contrast media: updated ESUR Contrast Media Safety Committee guidelines. Eur Radiol. 2013;23(2):307-318
4. Yang L, Krefting I, Gorovets A, et al. Nephrogenic systemic fibrosis and class labeling of gadolinium-based agents by the Food and Drug Administration. Radiology. 2012;265(1):248-253.
5. Grobner T. Gadolinium—a specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic systemic fibrosis? Nephrol Dial Transplant. 2006;21(4):1104-1108.
6. Marckmann P, Skov L, Rossen K, et al. Nephrogenic systemic fibrosis: suspected causative role of gadodiamide used for contrast-enhanced magnetic resonance imaging. J Am Soc Nephrol. 2006;17(9):2359-2362.
7. Thomsen HS, Bennett CL. Six years after. Acta Radiol. 2012;53(8):827-829.

To the Editor:

With great interest, I read the case report by Chuang, Kaneshiro, and Betancourt.¹ Patients with nephrogenic systemic fibrosis (NSF) are of special interest because the disease is still unclear as mentioned by the authors. Although new cases may occur,² this case raises some concerns that I would like to address.

First, it would be of great interest to know the date when the patient received the high-risk gadolinium-based contrast agent (GBCA) gadoversetamide. Unfortunately, the authors did not mention the date of the injection of the GBCA that probably caused NSF. Due to the obvious association between the applications of special GBCAs in 2006, the US Food and Drug Administration (FDA) warned physicians not to inject these contrast agents in patients with compromised kidney function.³ Moreover, in 2007 the American College of Radiology (ACR) published guidelines for the safe use of GBCAs in patients with renal failure.⁴ Also, the European Medicines Agency (EMA) demanded that companies provide warning in product inserts about the acquisition of NSF in patients with severe kidney injury.⁵

Second, the clinical illustration of the case is inadequate. In the manuscript, we read that the patient acquired NSF-characteristic lesions like peau d’orange skin lesions and contractures of his extremities, but unfortunately, Chuang, Kaneshiro, and Betancourt did not provide figures that show them. On the other hand, Figure 1 shows an uncharacteristic dermal induration around inflammatory and ulcerated skin lesion (pyoderma gangrenosum).¹ Such clinical signs are well known and occur perilesional of different conditions independently of NSF.^6-8

Third, the histological features described as presence of fibrotic tissue in the deep dermis in Figure 2, and dermal fibrosis with thick collagen deposition in Figure 3¹ do not confirm the existence of NSF.

Taken together, the case presented by Chuang, Kaneshiro, and Betancourt contains some unclear aspects; therefore, it is questionable whether the published case describes a patient with NSF or not. In the current presentation, the diagnosis NSF seems to be an overestimation.

NSF still is a poorly understood disorder. Therefore, exactly documented new cases could be of clinical value when providing interesting information. Even single cases could shed some light in the darkness of the pathological mechanisms of this entity. On the other hand, we should not mix the existing cohort of published NSF cases with other scleroderma-like diseases, because this will lead to a confusion. Moreover, such a practice could inhibit the discovery of the pathophysiology of NSF.

- Ingrid Böhm, MD

Author affiliations: Ingrid Böhm is a Physician in the Department of Diagnostics, Interventional and Pediatric Radiology at the University Hospital of Bern, Inselspital, University of Bern in Bern, Switzerland.

Correspondence: Ingrid Böhm ([email protected])

Disclosures: The author reports no conflict of interest with regard to this article.

References
1. Chuang K, Kaneshiro C, Betancourt J. Nephrogenic systemic fibrosis in a patient with multiple inflammatory disorders. Fed Pract . 2018;35(6):40-43.
2. Larson KN, Gagnon AL, Darling MD, Patterson JW, Cropley TG. Nephrogenic systemic fibrosis manifesting a decade after exposure to gadolinium. JAMA Dermatol. 2015;151(10):1117-1120.
3. US Food and Drug Administration. A Public Health Advisory. Gadolinium-containing contrast agents for magnetic resonance imaging (MRI). http://wayback.archive-it.org/7993/20170112033022/http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformation forPatientsandProviders/ucm053112.htm. Published June 8, 2006. Accessed March 15, 2019.
4. Kanal E, Barkovich AJ, Bell C, et al; ACR Blue Ribbon Panel on MR Safety. ACR guidance document for safe MR practices: 2007. AJR Am J Roentgenol. 2007;188(6):1447-1474.
5. European Medicines Agency. Public statement: Vasovist and nephrogenic systemic fibrosis (NSF). https://www.ema.europa.eu/en/news/public-statement-vasovist-nephrogenic-systemic-fibrosis-nsf. Published February 7, 2007. Accessed March 15, 2019.
6. Luke JC. The etiology and modern treatment of varicose ulcer. Can Med Assoc J. 1940;43(3):217-221.
7. Paulsen E, Bygum A. Keratin gel as an adjuvant in the treatment of recalcitrant pyoderma gangrenosum ulcers: a case report. Acta Derm Venereol. 2019;99(2):234-235.
8. Boehm I, Bauer R. Low-dose methotrexate controls a severe form of polyarteritis nodosa. Arch Dermatol. 2000; 136(2):167-169.

Response:

We thank Drs. Heinz, van der Molen, and Roditi for their valuable response. The following is the opinion of the authors and is not representative of the views or policies of our institution. The patient in this case received a gadolinium-based contrast agent (GBCA) in 2015 and was diagnosed with nephrogenic systemic fibrosis (NSF) 8 weeks later. We agree with the correspondents that linear GBCAs should not be used in patients with eGFR < 30 mL/min/1.73 m². To date, a few cases of patients who received GBCA and developed NSF since 2009 have unfortunately continued to be reported in the literature.^1-3 Our intention in publishing this case was to provide ongoing education to the medical community regarding this serious condition to ensure prevention of future cases.

We thank Dr. Böhm for her important inquiry. The patient received a histopathologic diagnosis of NSF. The report from the patient’s left dorsal forearm skin punch biopsy was read by our pathologist as “fibrosis and inflammation consistent with nephrogenic systemic fibrosis,” a diagnosis agreed upon by our colleagues in the dermatology and rheumatology departments based on the rapidity of his symptom onset and progression. While we acknowledge that this patient had other inflammatory disorders of the skin that may have coexisted with the diagnosis, after weighing the preponderance of clinical evidence in support of the biopsy results, we believe that this represents a case of NSF, which is associated with high morbidity and mortality. Thankfully, the patient in this case engaged extensively in physical and occupational therapy and is still alive nearly 4 years later. We would like to thank all the letter writers for their correspondence.

Author Affiliations: Kelley Chuang and Casey Kaneshiro are Hospitalists and Jaime Betancourt is a Pulmonologist, all in the Department of Medicine at the VA Greater Los Angeles Healthcare System in California.

Correspondence: Kelley Chuang ([email protected])

Disclosures: The authors report no conflict of interest with regard to this article.

References
1. Aggarwal A, Froehlich AA, Essah P, Brinster N, High WA, Downs RW. Complications of nephrogenic systemic fibrosis following repeated exposure to gadolinium in a man with hypothyroidism: a case report. J Med Case Rep. 2011;5:566.
2. Fuah KW, Lim CT. Erythema nodosum masking nephrogenic systemic fibrosis as initial skin manifestation. BMC Nephrol. 2017;18(1):249.
3. Koratala A, Bhatti V. Nephrogenic systemic fibrosis. Clin Case Rep. 2017;5(7):1184-1185.

National K9 Veterans Day celebrates the loyalty, bravery, and sacrifice of canine warriors. On March 13, 1942, canines officially became members of the Armed Services, with the Army’s founding of its New War Dog Program, more popularly known as the K9 Corps. The dogs underwent basic training and then entered more specialized preparation just as human soldiers did.² There had been unofficial dogs of war who served courageously and selflessly in almost all of our armed conflicts.³ Indeed, the title of this column is taken from a wonderful article of the same name narrating the heroism of dogs in the 2 world wars.⁴

The dedication of canines to those who serve is not confined to combat or even active duty. Thousands of military and veteran men and women have benefited immensely from their relationship with service and emotional support dogs.

Before I continue, let me state 2 important limitations of this column. First, I am a dog person. Of course, veterans have formed healing and caring relationships with many types of companions. Equine therapy is increasingly recognized as a powerful means of helping veterans reduce distress and find purpose.⁵ Nevertheless, for this column, I will focus exclusively on dogs. Second, there are many worthy organizations, projects, and programs that pair veterans with therapeutic dogs inside and outside the VA. I am in no way an expert and will invariably neglect many of these positive initiatives in this brief review.

The long, proud history of canines in the military and the many moving stories of men and women in and out of uniform for whom dogs have been life changing, if not life-saving, have created 2 ethical dilemmas for the VA that I examine here. Both dilemmas pivot on the terms of official recognition of service dogs, the benefits, and who can qualify for them in the VA.

Under VA regulation and VHA policy, a service companion only can be a dog that is individually trained to do work or perform tasks to assist a person with a disability; dogs whose sole function is to provide emotional support, well-being, comfort, or companionship are not considered service pets.⁶

A valid question to ask is why couldn’t the most vulnerable of these veterans, for instance those with severe mental health conditions, have service dogs that could accompany them into at least most areas of the medical center? Part of the reason is cost: Some training organizations estimate it may cost as much as $27,000 to train service dogs.⁸ Though there are many wonderful volunteer and not-for-profit organizations that train mostly shelter dogs and their veteran handlers—a double rescue—the lengthy process and expense means that many veterans wait years for a companion.

Congressional representatives, ethicists, veterans advocates, and canine therapy groups claim that this was unjust discrimination against those suffering with the equally, if not more disabling, mental health conditions.⁹ For many years, the VA has done a very good deed: For those who qualify for a service dog, VA pays for veterinary care and the equipment to handle the dog, but not boarding, grooming, food, and other miscellaneous expenses.¹⁰ But until 2016, those veterans approved for service dogs in the main had sensory or physical disabilities.

A partial breakthrough emerged when the Center for Compassionate Care Innovation launched the Mental Health Mobility Service Dogs Program that expanded veterinary health benefits to veterans with a “substantial mobility limitation.” For example, veterans whose hypervigilance and hyperarousal are so severe that they cannot attend medical appointments.¹¹

VA experts argue that at this time there is insufficient evidence to fund service dogs as even adjunctive PTSD therapy for the hundreds of veterans who might potentially qualify. It becomes an ethical question of prudent stewardship of public funds and trust. There is certainly plenty of compelling anecdotal testimony that companion canines are a high-benefit, relatively low-risk form of complementary and integrated therapy for the spectrum of trauma disorders that afflict many of the men and women who served in our conflicts. Demonstrating those positive effects scientifically may be more difficult than it seems, although early evidence is promising, and the VA is intensively researching the question.¹² For some veterans and their legislators, the VA has not gone far enough, fast enough in mainstreaming therapy dogs, they are calling for VA to expand veterans’ benefits to include mental health service dogs and to define what benefits would be covered.

National K9 Veterans Day is an important step toward giving dogs of war the homage they have earned, as are increasing efforts to ensure care for military canines throughout their life cycle. But as the seventeenth century poet John Milton wrote when he reflected on his own worth despite his blindness, “Those also serve who only stand and wait.”¹³ The institutions charged to care for those the battle has most burdened are still trying to discover how to properly and proportionately revere that kind of furry valor.

National K9 Veterans Day celebrates the loyalty, bravery, and sacrifice of canine warriors. On March 13, 1942, canines officially became members of the Armed Services, with the Army’s founding of its New War Dog Program, more popularly known as the K9 Corps. The dogs underwent basic training and then entered more specialized preparation just as human soldiers did.² There had been unofficial dogs of war who served courageously and selflessly in almost all of our armed conflicts.³ Indeed, the title of this column is taken from a wonderful article of the same name narrating the heroism of dogs in the 2 world wars.⁴

The dedication of canines to those who serve is not confined to combat or even active duty. Thousands of military and veteran men and women have benefited immensely from their relationship with service and emotional support dogs.

Before I continue, let me state 2 important limitations of this column. First, I am a dog person. Of course, veterans have formed healing and caring relationships with many types of companions. Equine therapy is increasingly recognized as a powerful means of helping veterans reduce distress and find purpose.⁵ Nevertheless, for this column, I will focus exclusively on dogs. Second, there are many worthy organizations, projects, and programs that pair veterans with therapeutic dogs inside and outside the VA. I am in no way an expert and will invariably neglect many of these positive initiatives in this brief review.

The long, proud history of canines in the military and the many moving stories of men and women in and out of uniform for whom dogs have been life changing, if not life-saving, have created 2 ethical dilemmas for the VA that I examine here. Both dilemmas pivot on the terms of official recognition of service dogs, the benefits, and who can qualify for them in the VA.

Under VA regulation and VHA policy, a service companion only can be a dog that is individually trained to do work or perform tasks to assist a person with a disability; dogs whose sole function is to provide emotional support, well-being, comfort, or companionship are not considered service pets.⁶

A valid question to ask is why couldn’t the most vulnerable of these veterans, for instance those with severe mental health conditions, have service dogs that could accompany them into at least most areas of the medical center? Part of the reason is cost: Some training organizations estimate it may cost as much as $27,000 to train service dogs.⁸ Though there are many wonderful volunteer and not-for-profit organizations that train mostly shelter dogs and their veteran handlers—a double rescue—the lengthy process and expense means that many veterans wait years for a companion.

Congressional representatives, ethicists, veterans advocates, and canine therapy groups claim that this was unjust discrimination against those suffering with the equally, if not more disabling, mental health conditions.⁹ For many years, the VA has done a very good deed: For those who qualify for a service dog, VA pays for veterinary care and the equipment to handle the dog, but not boarding, grooming, food, and other miscellaneous expenses.¹⁰ But until 2016, those veterans approved for service dogs in the main had sensory or physical disabilities.

A partial breakthrough emerged when the Center for Compassionate Care Innovation launched the Mental Health Mobility Service Dogs Program that expanded veterinary health benefits to veterans with a “substantial mobility limitation.” For example, veterans whose hypervigilance and hyperarousal are so severe that they cannot attend medical appointments.¹¹

VA experts argue that at this time there is insufficient evidence to fund service dogs as even adjunctive PTSD therapy for the hundreds of veterans who might potentially qualify. It becomes an ethical question of prudent stewardship of public funds and trust. There is certainly plenty of compelling anecdotal testimony that companion canines are a high-benefit, relatively low-risk form of complementary and integrated therapy for the spectrum of trauma disorders that afflict many of the men and women who served in our conflicts. Demonstrating those positive effects scientifically may be more difficult than it seems, although early evidence is promising, and the VA is intensively researching the question.¹² For some veterans and their legislators, the VA has not gone far enough, fast enough in mainstreaming therapy dogs, they are calling for VA to expand veterans’ benefits to include mental health service dogs and to define what benefits would be covered.

National K9 Veterans Day is an important step toward giving dogs of war the homage they have earned, as are increasing efforts to ensure care for military canines throughout their life cycle. But as the seventeenth century poet John Milton wrote when he reflected on his own worth despite his blindness, “Those also serve who only stand and wait.”¹³ The institutions charged to care for those the battle has most burdened are still trying to discover how to properly and proportionately revere that kind of furry valor.

National K9 Veterans Day celebrates the loyalty, bravery, and sacrifice of canine warriors. On March 13, 1942, canines officially became members of the Armed Services, with the Army’s founding of its New War Dog Program, more popularly known as the K9 Corps. The dogs underwent basic training and then entered more specialized preparation just as human soldiers did.² There had been unofficial dogs of war who served courageously and selflessly in almost all of our armed conflicts.³ Indeed, the title of this column is taken from a wonderful article of the same name narrating the heroism of dogs in the 2 world wars.⁴

The dedication of canines to those who serve is not confined to combat or even active duty. Thousands of military and veteran men and women have benefited immensely from their relationship with service and emotional support dogs.

Before I continue, let me state 2 important limitations of this column. First, I am a dog person. Of course, veterans have formed healing and caring relationships with many types of companions. Equine therapy is increasingly recognized as a powerful means of helping veterans reduce distress and find purpose.⁵ Nevertheless, for this column, I will focus exclusively on dogs. Second, there are many worthy organizations, projects, and programs that pair veterans with therapeutic dogs inside and outside the VA. I am in no way an expert and will invariably neglect many of these positive initiatives in this brief review.

The long, proud history of canines in the military and the many moving stories of men and women in and out of uniform for whom dogs have been life changing, if not life-saving, have created 2 ethical dilemmas for the VA that I examine here. Both dilemmas pivot on the terms of official recognition of service dogs, the benefits, and who can qualify for them in the VA.

Under VA regulation and VHA policy, a service companion only can be a dog that is individually trained to do work or perform tasks to assist a person with a disability; dogs whose sole function is to provide emotional support, well-being, comfort, or companionship are not considered service pets.⁶

A valid question to ask is why couldn’t the most vulnerable of these veterans, for instance those with severe mental health conditions, have service dogs that could accompany them into at least most areas of the medical center? Part of the reason is cost: Some training organizations estimate it may cost as much as $27,000 to train service dogs.⁸ Though there are many wonderful volunteer and not-for-profit organizations that train mostly shelter dogs and their veteran handlers—a double rescue—the lengthy process and expense means that many veterans wait years for a companion.

Congressional representatives, ethicists, veterans advocates, and canine therapy groups claim that this was unjust discrimination against those suffering with the equally, if not more disabling, mental health conditions.⁹ For many years, the VA has done a very good deed: For those who qualify for a service dog, VA pays for veterinary care and the equipment to handle the dog, but not boarding, grooming, food, and other miscellaneous expenses.¹⁰ But until 2016, those veterans approved for service dogs in the main had sensory or physical disabilities.

A partial breakthrough emerged when the Center for Compassionate Care Innovation launched the Mental Health Mobility Service Dogs Program that expanded veterinary health benefits to veterans with a “substantial mobility limitation.” For example, veterans whose hypervigilance and hyperarousal are so severe that they cannot attend medical appointments.¹¹

VA experts argue that at this time there is insufficient evidence to fund service dogs as even adjunctive PTSD therapy for the hundreds of veterans who might potentially qualify. It becomes an ethical question of prudent stewardship of public funds and trust. There is certainly plenty of compelling anecdotal testimony that companion canines are a high-benefit, relatively low-risk form of complementary and integrated therapy for the spectrum of trauma disorders that afflict many of the men and women who served in our conflicts. Demonstrating those positive effects scientifically may be more difficult than it seems, although early evidence is promising, and the VA is intensively researching the question.¹² For some veterans and their legislators, the VA has not gone far enough, fast enough in mainstreaming therapy dogs, they are calling for VA to expand veterans’ benefits to include mental health service dogs and to define what benefits would be covered.

National K9 Veterans Day is an important step toward giving dogs of war the homage they have earned, as are increasing efforts to ensure care for military canines throughout their life cycle. But as the seventeenth century poet John Milton wrote when he reflected on his own worth despite his blindness, “Those also serve who only stand and wait.”¹³ The institutions charged to care for those the battle has most burdened are still trying to discover how to properly and proportionately revere that kind of furry valor.

In recent years, pediatricians have learned more about the diversity of gender identities and gender expressions that exist, but many think they have gaps in their knowledge that need to be filled in order to provide better care to these patients.

On April 3, Pediatric News hosted a Twitter question-and-answer session for the purpose of trying to help pediatricians close some of these gaps, including ones related to the medical and mental health issues particular to LGBT patients. During this session Pediatric News’ LGBT Youth Consult columnists, Gerald T. Montano, DO, MS, and Gayathri Chelvakumar, MD, MPH, responded to four questions about working with children and teens who are lesbian, gay, bisexual, transgender, or questioning (LGBTQ). Dr. Montano is an assistant professor of pediatrics at the University of Pittsburgh and an adolescent medicine physician at Children’s Hospital of Pittsburgh of UPMC. Dr. Chelvakumar, MD, MPH, is an attending physician in the division of adolescent medicine at Nationwide Children’s Hospital and an assistant professor of clinical pediatrics at the Ohio State University, both in Columbus.

The following is an edited version of the Q&A session.
 

Question 1: How do people become aware they are lesbian, gay, bisexual, transgender?

Dr. Montano: For many adolescents, the teenage years are the time that these identities are forming and that questions around sexuality and gender identity may arise. Check out #genderunicorn! It illustrates the spectrum of normal gender and sexual identities that are part of the human experience. Many LGBT people recall how they felt when they were younger but couldn’t find the right words until they were older (usually during adolescence).

Dr. Chelvakumar: Every person’s experience is unique. I have had patients tell me they knew who they were attracted to in kindergarten, and other patients who are still figuring it out in college. It is important to note that every experience is valid.
 

Question 2: How can we address some of the specific health concerns of LGBT youth?

Dr. Chelvakumar: We need to educate ourselves. The American Academy of Pediatrics has a great resource for this, “Ensuring Comprehensive Care and Support for Transgender and Gender Diverse Children and Adolescents (Pediatrics. 2019 Oct. doi: 10.1542/peds.2018-2162).

Dr. Chelvakumar: Some LGBTQ youth are at increased risk of depression, anxiety, and suicidality related to stigma and internal/external transphobia/homophobia, NOT their identities.

Dr. Montano: A lot of LGBT youth report that health care providers fixate on sexual activity, even though that was not the reason why they came to the clinic.

Dr. Chelvakumar: A lot of these youth feel that providers won’t understand their needs or may discriminate against them because of their LGBTQ identity. This is why it is important to make sure our health care spaces are welcoming to everyone.

Dr. Montano: The role of the psychiatrist is not to determine the person’s gender identity or sexual orientation; rather, they should focus on making others feel comfortable with themselves.
 

Question 3: How can we make our clinics a safe space for LGBT youth?

Dr. Chelvakumar: Ensure that ALL clinic staff receive training on culturally affirming care of LGBTQ people. The National LGBT Health Education Center (@LGBTHealthEdCtr) offers some of these resources.

Dr. Montano: Train everyone in the clinic to be sensitive and aware of the needs of LGBT patients; it only takes one person to make a clinical experience horrible for an LGBT person.

Dr. Chelvakumar: To me, culturally affirming care means being aware of the spectrum of identities and experiences of all of our patients/families and being respectful of these identities. I also like the term cultural humility – we must continually learn about these diverse experiences.

Dr. Montano: Remember that if they get upset, these children and teens are not mad at you, they are mad at the situation.

Dr. Chelvakumar: An easy way to show that a clinic is a safe space is to clearly display a nondiscrimination policy, such as “We serve and respect all patients regardless of gender identity, race, sexual orientation, religion, socioeconomic status ... ”

Dr. Montano: Not every LGBT youth will disclose their sexual orientation or gender identity to the provider, even if the clinic appears welcoming. I suggest you begin a conversation with a patient by telling the patient your own pronouns, opening the door to additional conversations.

Dr. Chelvakumar: Many organizations are moving to universally asking questions about gender identity and pronouns. In the pediatric population, this can be difficult given privacy/confidentiality concerns. I usually ask these questions when obtaining my sensitive sexual history.
 

Question 4: What is gender dysphoria, and how is it treated?

Dr. Montano: Gender dysphoria is the distress related to gender identity that does not match sex/gender assigned at birth. Treat the distress, not the identity. There are many ways to treat gender dysphoria. You can provide social support, use pubertal blockers to prevent the development of secondary sex characteristics during adolescence, and/or use hormones or surgery to develop characteristics of the affirmed gender. And there is no “right” treatment for gender dysphoria. Each treatment is tailored to the needs of the youth.

Dr. Chelvakumar: It is important to recognize that each person’s journey/transition is different. Our job as providers is to help them on the path that will help them live their lives as their authentic selves. This may or may not involve taking medication and/or undergoing surgery.

Dr. Montano: Providers should respect the wishes of those who want to affirm their gender identity that makes sense to the patient and not try to impose their own idea of what transitioning should “look like.”

Dr. Chelvakumar: There are many guidelines that exist for patients with gender dysphoria. The World Professional Association for Transgender Health, the Endocrine Society, and University of California, San Francisco’s Center of Excellence for Transgender Health are all excellent resources.
 

In recent years, pediatricians have learned more about the diversity of gender identities and gender expressions that exist, but many think they have gaps in their knowledge that need to be filled in order to provide better care to these patients.

On April 3, Pediatric News hosted a Twitter question-and-answer session for the purpose of trying to help pediatricians close some of these gaps, including ones related to the medical and mental health issues particular to LGBT patients. During this session Pediatric News’ LGBT Youth Consult columnists, Gerald T. Montano, DO, MS, and Gayathri Chelvakumar, MD, MPH, responded to four questions about working with children and teens who are lesbian, gay, bisexual, transgender, or questioning (LGBTQ). Dr. Montano is an assistant professor of pediatrics at the University of Pittsburgh and an adolescent medicine physician at Children’s Hospital of Pittsburgh of UPMC. Dr. Chelvakumar, MD, MPH, is an attending physician in the division of adolescent medicine at Nationwide Children’s Hospital and an assistant professor of clinical pediatrics at the Ohio State University, both in Columbus.

The following is an edited version of the Q&A session.
 

Question 1: How do people become aware they are lesbian, gay, bisexual, transgender?

Dr. Montano: For many adolescents, the teenage years are the time that these identities are forming and that questions around sexuality and gender identity may arise. Check out #genderunicorn! It illustrates the spectrum of normal gender and sexual identities that are part of the human experience. Many LGBT people recall how they felt when they were younger but couldn’t find the right words until they were older (usually during adolescence).

Dr. Chelvakumar: Every person’s experience is unique. I have had patients tell me they knew who they were attracted to in kindergarten, and other patients who are still figuring it out in college. It is important to note that every experience is valid.
 

Question 2: How can we address some of the specific health concerns of LGBT youth?

Dr. Chelvakumar: We need to educate ourselves. The American Academy of Pediatrics has a great resource for this, “Ensuring Comprehensive Care and Support for Transgender and Gender Diverse Children and Adolescents (Pediatrics. 2019 Oct. doi: 10.1542/peds.2018-2162).

Dr. Chelvakumar: Some LGBTQ youth are at increased risk of depression, anxiety, and suicidality related to stigma and internal/external transphobia/homophobia, NOT their identities.

Dr. Montano: A lot of LGBT youth report that health care providers fixate on sexual activity, even though that was not the reason why they came to the clinic.

Dr. Chelvakumar: A lot of these youth feel that providers won’t understand their needs or may discriminate against them because of their LGBTQ identity. This is why it is important to make sure our health care spaces are welcoming to everyone.

Dr. Montano: The role of the psychiatrist is not to determine the person’s gender identity or sexual orientation; rather, they should focus on making others feel comfortable with themselves.
 

Question 3: How can we make our clinics a safe space for LGBT youth?

Dr. Chelvakumar: Ensure that ALL clinic staff receive training on culturally affirming care of LGBTQ people. The National LGBT Health Education Center (@LGBTHealthEdCtr) offers some of these resources.

Dr. Montano: Train everyone in the clinic to be sensitive and aware of the needs of LGBT patients; it only takes one person to make a clinical experience horrible for an LGBT person.

Dr. Chelvakumar: To me, culturally affirming care means being aware of the spectrum of identities and experiences of all of our patients/families and being respectful of these identities. I also like the term cultural humility – we must continually learn about these diverse experiences.

Dr. Montano: Remember that if they get upset, these children and teens are not mad at you, they are mad at the situation.

Dr. Chelvakumar: An easy way to show that a clinic is a safe space is to clearly display a nondiscrimination policy, such as “We serve and respect all patients regardless of gender identity, race, sexual orientation, religion, socioeconomic status ... ”

Dr. Montano: Not every LGBT youth will disclose their sexual orientation or gender identity to the provider, even if the clinic appears welcoming. I suggest you begin a conversation with a patient by telling the patient your own pronouns, opening the door to additional conversations.

Dr. Chelvakumar: Many organizations are moving to universally asking questions about gender identity and pronouns. In the pediatric population, this can be difficult given privacy/confidentiality concerns. I usually ask these questions when obtaining my sensitive sexual history.
 

Question 4: What is gender dysphoria, and how is it treated?

Dr. Montano: Gender dysphoria is the distress related to gender identity that does not match sex/gender assigned at birth. Treat the distress, not the identity. There are many ways to treat gender dysphoria. You can provide social support, use pubertal blockers to prevent the development of secondary sex characteristics during adolescence, and/or use hormones or surgery to develop characteristics of the affirmed gender. And there is no “right” treatment for gender dysphoria. Each treatment is tailored to the needs of the youth.

Dr. Chelvakumar: It is important to recognize that each person’s journey/transition is different. Our job as providers is to help them on the path that will help them live their lives as their authentic selves. This may or may not involve taking medication and/or undergoing surgery.

Dr. Montano: Providers should respect the wishes of those who want to affirm their gender identity that makes sense to the patient and not try to impose their own idea of what transitioning should “look like.”

Dr. Chelvakumar: There are many guidelines that exist for patients with gender dysphoria. The World Professional Association for Transgender Health, the Endocrine Society, and University of California, San Francisco’s Center of Excellence for Transgender Health are all excellent resources.
 

In recent years, pediatricians have learned more about the diversity of gender identities and gender expressions that exist, but many think they have gaps in their knowledge that need to be filled in order to provide better care to these patients.

On April 3, Pediatric News hosted a Twitter question-and-answer session for the purpose of trying to help pediatricians close some of these gaps, including ones related to the medical and mental health issues particular to LGBT patients. During this session Pediatric News’ LGBT Youth Consult columnists, Gerald T. Montano, DO, MS, and Gayathri Chelvakumar, MD, MPH, responded to four questions about working with children and teens who are lesbian, gay, bisexual, transgender, or questioning (LGBTQ). Dr. Montano is an assistant professor of pediatrics at the University of Pittsburgh and an adolescent medicine physician at Children’s Hospital of Pittsburgh of UPMC. Dr. Chelvakumar, MD, MPH, is an attending physician in the division of adolescent medicine at Nationwide Children’s Hospital and an assistant professor of clinical pediatrics at the Ohio State University, both in Columbus.

The following is an edited version of the Q&A session.
 

Question 1: How do people become aware they are lesbian, gay, bisexual, transgender?

Dr. Montano: For many adolescents, the teenage years are the time that these identities are forming and that questions around sexuality and gender identity may arise. Check out #genderunicorn! It illustrates the spectrum of normal gender and sexual identities that are part of the human experience. Many LGBT people recall how they felt when they were younger but couldn’t find the right words until they were older (usually during adolescence).

Dr. Chelvakumar: Every person’s experience is unique. I have had patients tell me they knew who they were attracted to in kindergarten, and other patients who are still figuring it out in college. It is important to note that every experience is valid.
 

Question 2: How can we address some of the specific health concerns of LGBT youth?

Dr. Chelvakumar: We need to educate ourselves. The American Academy of Pediatrics has a great resource for this, “Ensuring Comprehensive Care and Support for Transgender and Gender Diverse Children and Adolescents (Pediatrics. 2019 Oct. doi: 10.1542/peds.2018-2162).

Dr. Chelvakumar: Some LGBTQ youth are at increased risk of depression, anxiety, and suicidality related to stigma and internal/external transphobia/homophobia, NOT their identities.

Dr. Montano: A lot of LGBT youth report that health care providers fixate on sexual activity, even though that was not the reason why they came to the clinic.

Dr. Chelvakumar: A lot of these youth feel that providers won’t understand their needs or may discriminate against them because of their LGBTQ identity. This is why it is important to make sure our health care spaces are welcoming to everyone.

Dr. Montano: The role of the psychiatrist is not to determine the person’s gender identity or sexual orientation; rather, they should focus on making others feel comfortable with themselves.
 

Question 3: How can we make our clinics a safe space for LGBT youth?

Dr. Chelvakumar: Ensure that ALL clinic staff receive training on culturally affirming care of LGBTQ people. The National LGBT Health Education Center (@LGBTHealthEdCtr) offers some of these resources.

Dr. Montano: Train everyone in the clinic to be sensitive and aware of the needs of LGBT patients; it only takes one person to make a clinical experience horrible for an LGBT person.

Dr. Chelvakumar: To me, culturally affirming care means being aware of the spectrum of identities and experiences of all of our patients/families and being respectful of these identities. I also like the term cultural humility – we must continually learn about these diverse experiences.

Dr. Montano: Remember that if they get upset, these children and teens are not mad at you, they are mad at the situation.

Dr. Chelvakumar: An easy way to show that a clinic is a safe space is to clearly display a nondiscrimination policy, such as “We serve and respect all patients regardless of gender identity, race, sexual orientation, religion, socioeconomic status ... ”

Dr. Montano: Not every LGBT youth will disclose their sexual orientation or gender identity to the provider, even if the clinic appears welcoming. I suggest you begin a conversation with a patient by telling the patient your own pronouns, opening the door to additional conversations.

Dr. Chelvakumar: Many organizations are moving to universally asking questions about gender identity and pronouns. In the pediatric population, this can be difficult given privacy/confidentiality concerns. I usually ask these questions when obtaining my sensitive sexual history.
 

Question 4: What is gender dysphoria, and how is it treated?

Dr. Montano: Gender dysphoria is the distress related to gender identity that does not match sex/gender assigned at birth. Treat the distress, not the identity. There are many ways to treat gender dysphoria. You can provide social support, use pubertal blockers to prevent the development of secondary sex characteristics during adolescence, and/or use hormones or surgery to develop characteristics of the affirmed gender. And there is no “right” treatment for gender dysphoria. Each treatment is tailored to the needs of the youth.

Dr. Chelvakumar: It is important to recognize that each person’s journey/transition is different. Our job as providers is to help them on the path that will help them live their lives as their authentic selves. This may or may not involve taking medication and/or undergoing surgery.

Dr. Montano: Providers should respect the wishes of those who want to affirm their gender identity that makes sense to the patient and not try to impose their own idea of what transitioning should “look like.”

Dr. Chelvakumar: There are many guidelines that exist for patients with gender dysphoria. The World Professional Association for Transgender Health, the Endocrine Society, and University of California, San Francisco’s Center of Excellence for Transgender Health are all excellent resources.
 

What’s the role of anecdotal medical histories in the era of evidence-based medicine?

Mitchel L. Zoler/MDedge News

Two days of testimony and discussion by a Food and Drug Administration advisory committee that gave new scrutiny to emerging complications and signals of complications in patients who received breast implants showed that powerful, emotion-filled vignettes from affected patients could engender sympathy and recommendations for action by an expert panel. But the anecdotal histories fell short of producing a clear committee consensus on dramatic, immediate changes in FDA policy, such as joining a renewed ban on certain types of breast implants linked with a rare lymphoma, a step recently taken by 38 other countries, including 33 European countries acting in concert through the European Union.

The disconnect between gripping testimony and limited panel recommendations was most stark for a complication that’s been named Breast Implant Illness (BII) by patients on the Internet. Many breast implant recipients have reported life-changing symptoms that appeared after implant placement, most often fatigue, joint and muscle pain, brain fog, neurologic symptoms, immune dysfunction, skin manifestations, and autoimmune disease or symptoms. By my count, 22 people spoke about their harrowing experiences with BII symptoms out of the 77 who stepped to the panel’s public-comment mic during 4 hours of public testimony over 2-days of hearings, often saying that they had experienced dramatic improvements after their implants came out. The meeting of the General and Plastic Surgery Devices Panel of the Medical Devices Advisory Committee also heard presentations from two experts who ran some of the first reported studies on BII, or a BII-like syndrome called Autoimmune Syndrome Induced by Adjuvants (ASIA) described by Jan W.C. Tervaert, MD, professor of medicine and director of rheumatology at the University of Alberta in Edmonton. Dr. Tervaert and his associates published their findings about ASIA in the rheumatology literature last year (Clin Rheumatol. 2018 Feb;37[2]:483-93), and during his talk before the FDA panel, he said that silicone breast implants and the surgical mesh often used with them could be ASIA triggers.

Panel members seemed to mostly believe that the evidence they heard about BII did no more than hint at a possible association between breast implants and BII symptoms that required additional study. Many agreed on the need to include mention of the most common BII-linked patient complaints in informed consent material, but some were reluctant about even taking that step.

Mitchel L. Zoler/MDedge News

“I do not mention BII to patients. It’s not a disease; it’s a constellation of symptoms,” said panel member and plastic surgeon Pierre M. Chevray, MD, from Houston Methodist Hospital. The evidence for BII “is extremely anecdotal,” he said in an interview at the end of the 2-day session. Descriptions of BII “have been mainly published on social media. One reason why I don’t tell patients [about BII as part of informed consent] is because right now the evidence of a link is weak. We don’t yet even have a definition of this as an illness. A first step is to define it,” said Dr. Chevray, who has a very active implant practice. Other plastic surgeons were more accepting of BII as a real complication, although they agreed it needs much more study. During the testimony period, St. Louis plastic surgeon Patricia A. McGuire, MD, highlighted the challenge of teasing apart whether real symptoms are truly related to implants or are simply common ailments that accumulate during middle-age in many women. Dr. McGuire and some of her associates published an assessment of the challenges and possible solutions to studying BII that appeared shortly before the hearing (Plast Reconstr Surg. 2019 March;143[3S]:74S-81S),

Consensus recommendations from the panel to the FDA to address BII included having a single registry that would include all U.S. patients who receive breast implants (recently launched as the National Breast Implant Registry), inclusion of a control group, and collection of data at baseline and after regular follow-up intervals that includes a variety of measures relevant to autoimmune and rheumatologic disorders. Several panel members cited inadequate postmarketing safety surveillance by manufacturers in the years since breast implants returned to the U.S. market, and earlier in March, the FDA issued warning letters to two of the four companies that market U.S. breast implants over their inadequate long-term safety follow-up.

The panel’s decisions about the other major implant-associated health risk it considered, breast implant associated anaplastic large cell lymphoma (BIA-ALCL), faced a different sort of challenge. First described as linked to breast implants in 2011, today there is little doubt that BIA-ALCL is a consequence of breast implants, what several patients derisively called a “man-made cancer.” The key issue the committee grappled with was whether the calculated incidence of BIA-ALCL was at a frequency that warranted a ban on at least selected breast implant types. Mark W. Clemens, MD, a plastic surgeon at MD Anderson Cancer Center in Houston, told the panel that he calculated the Allergan Biocell group of implants, which have textured surfaces that allows for easier and more stable placement in patients, linked with an incidence of BIA-ALCL that was sevenfold to eightfold higher than that with smooth implants. That’s against a background of an overall incidence of about one case for every 20,000 U.S. implant recipients, Dr. Clemens said.

Many testifying patients, including several of the eight who described a personal history of BIA-ALCL, called for a ban on the sale of at least some breast implants because of their role in causing lymphoma. That sentiment was shared by Dr. Chevray, who endorsed a ban on “salt-loss” implants (the method that makes Biocell implants) during his closing comments to his fellow panel members. But earlier during panel discussions, others on the committee pushed back against implant bans, leaving the FDA’s eventual decision on this issue unclear. Evidence presented during the hearings suggests that implants cause ALCL by triggering a local “inflammatory milieu” and that different types of implants can have varying levels of potency for producing this milieu.

Mitchel L. Zoler/MDedge News

Perhaps the closest congruence between what patients called for and what the committee recommended was on informed consent. “No doubt, patients feel that informed consent failed them,” concluded panel member Karen E. Burke, MD, a New York dermatologist who was one of two panel discussants for the topic.

In addition to many suggestions on how to improve informed consent and public awareness lobbed at FDA staffers during the session by panel members, the final public comment of the 2 days came from Laurie A. Casas, MD, a Chicago plastic surgeon affiliated with the University of Chicago and a member of the board of directors of the American Society of Aesthetic Plastic Surgery (also know as the Aesthetic Society). During her testimony, Dr. Casas said “Over the past 2 days, we heard that patients need a structured educational checklist for informed consent. The Aesthetic Society hears you,” and promised that the website of the Society’s publication, the Aesthetic Surgery Journal, will soon feature a safety checklist for people receiving breast implants that will get updated as new information becomes available. She also highlighted the need for a comprehensive registry and long-term follow-up of implant recipients by the plastic surgeons who treated them.

In addition to better informed consent, patients who came to the hearing clearly also hoped to raise awareness in the general American public about the potential dangers from breast implants and the need to follow patients who receive implants. The 2 days of hearing accomplished that in part just by taking place. The New York Times and The Washington Post ran at least a couple of articles apiece on implant safety just before or during the hearings, while a more regional paper, the Philadelphia Inquirer, ran one article, as presumably did many other newspapers, broadcast outlets, and websites across America. Much of the coverage focused on compelling and moving personal stories from patients.

Women who have been having adverse effects from breast implants “have felt dismissed,” noted panel member Natalie C. Portis, PhD, a clinical psychologist from Oakland, Calif., and the patient representative on the advisory committee. “We need to listen to women that something real is happening.”

Dr. Tervaert, Dr. Chevray, Dr. McGuire, Dr. Clemens, Dr. Burke, Dr. Casas, and Dr. Portis had no relevant commercial disclosures.

[email protected]
 

What’s the role of anecdotal medical histories in the era of evidence-based medicine?

Mitchel L. Zoler/MDedge News

Two days of testimony and discussion by a Food and Drug Administration advisory committee that gave new scrutiny to emerging complications and signals of complications in patients who received breast implants showed that powerful, emotion-filled vignettes from affected patients could engender sympathy and recommendations for action by an expert panel. But the anecdotal histories fell short of producing a clear committee consensus on dramatic, immediate changes in FDA policy, such as joining a renewed ban on certain types of breast implants linked with a rare lymphoma, a step recently taken by 38 other countries, including 33 European countries acting in concert through the European Union.

The disconnect between gripping testimony and limited panel recommendations was most stark for a complication that’s been named Breast Implant Illness (BII) by patients on the Internet. Many breast implant recipients have reported life-changing symptoms that appeared after implant placement, most often fatigue, joint and muscle pain, brain fog, neurologic symptoms, immune dysfunction, skin manifestations, and autoimmune disease or symptoms. By my count, 22 people spoke about their harrowing experiences with BII symptoms out of the 77 who stepped to the panel’s public-comment mic during 4 hours of public testimony over 2-days of hearings, often saying that they had experienced dramatic improvements after their implants came out. The meeting of the General and Plastic Surgery Devices Panel of the Medical Devices Advisory Committee also heard presentations from two experts who ran some of the first reported studies on BII, or a BII-like syndrome called Autoimmune Syndrome Induced by Adjuvants (ASIA) described by Jan W.C. Tervaert, MD, professor of medicine and director of rheumatology at the University of Alberta in Edmonton. Dr. Tervaert and his associates published their findings about ASIA in the rheumatology literature last year (Clin Rheumatol. 2018 Feb;37[2]:483-93), and during his talk before the FDA panel, he said that silicone breast implants and the surgical mesh often used with them could be ASIA triggers.

Panel members seemed to mostly believe that the evidence they heard about BII did no more than hint at a possible association between breast implants and BII symptoms that required additional study. Many agreed on the need to include mention of the most common BII-linked patient complaints in informed consent material, but some were reluctant about even taking that step.

Mitchel L. Zoler/MDedge News

“I do not mention BII to patients. It’s not a disease; it’s a constellation of symptoms,” said panel member and plastic surgeon Pierre M. Chevray, MD, from Houston Methodist Hospital. The evidence for BII “is extremely anecdotal,” he said in an interview at the end of the 2-day session. Descriptions of BII “have been mainly published on social media. One reason why I don’t tell patients [about BII as part of informed consent] is because right now the evidence of a link is weak. We don’t yet even have a definition of this as an illness. A first step is to define it,” said Dr. Chevray, who has a very active implant practice. Other plastic surgeons were more accepting of BII as a real complication, although they agreed it needs much more study. During the testimony period, St. Louis plastic surgeon Patricia A. McGuire, MD, highlighted the challenge of teasing apart whether real symptoms are truly related to implants or are simply common ailments that accumulate during middle-age in many women. Dr. McGuire and some of her associates published an assessment of the challenges and possible solutions to studying BII that appeared shortly before the hearing (Plast Reconstr Surg. 2019 March;143[3S]:74S-81S),

Consensus recommendations from the panel to the FDA to address BII included having a single registry that would include all U.S. patients who receive breast implants (recently launched as the National Breast Implant Registry), inclusion of a control group, and collection of data at baseline and after regular follow-up intervals that includes a variety of measures relevant to autoimmune and rheumatologic disorders. Several panel members cited inadequate postmarketing safety surveillance by manufacturers in the years since breast implants returned to the U.S. market, and earlier in March, the FDA issued warning letters to two of the four companies that market U.S. breast implants over their inadequate long-term safety follow-up.

The panel’s decisions about the other major implant-associated health risk it considered, breast implant associated anaplastic large cell lymphoma (BIA-ALCL), faced a different sort of challenge. First described as linked to breast implants in 2011, today there is little doubt that BIA-ALCL is a consequence of breast implants, what several patients derisively called a “man-made cancer.” The key issue the committee grappled with was whether the calculated incidence of BIA-ALCL was at a frequency that warranted a ban on at least selected breast implant types. Mark W. Clemens, MD, a plastic surgeon at MD Anderson Cancer Center in Houston, told the panel that he calculated the Allergan Biocell group of implants, which have textured surfaces that allows for easier and more stable placement in patients, linked with an incidence of BIA-ALCL that was sevenfold to eightfold higher than that with smooth implants. That’s against a background of an overall incidence of about one case for every 20,000 U.S. implant recipients, Dr. Clemens said.

Many testifying patients, including several of the eight who described a personal history of BIA-ALCL, called for a ban on the sale of at least some breast implants because of their role in causing lymphoma. That sentiment was shared by Dr. Chevray, who endorsed a ban on “salt-loss” implants (the method that makes Biocell implants) during his closing comments to his fellow panel members. But earlier during panel discussions, others on the committee pushed back against implant bans, leaving the FDA’s eventual decision on this issue unclear. Evidence presented during the hearings suggests that implants cause ALCL by triggering a local “inflammatory milieu” and that different types of implants can have varying levels of potency for producing this milieu.

Mitchel L. Zoler/MDedge News

Perhaps the closest congruence between what patients called for and what the committee recommended was on informed consent. “No doubt, patients feel that informed consent failed them,” concluded panel member Karen E. Burke, MD, a New York dermatologist who was one of two panel discussants for the topic.

In addition to many suggestions on how to improve informed consent and public awareness lobbed at FDA staffers during the session by panel members, the final public comment of the 2 days came from Laurie A. Casas, MD, a Chicago plastic surgeon affiliated with the University of Chicago and a member of the board of directors of the American Society of Aesthetic Plastic Surgery (also know as the Aesthetic Society). During her testimony, Dr. Casas said “Over the past 2 days, we heard that patients need a structured educational checklist for informed consent. The Aesthetic Society hears you,” and promised that the website of the Society’s publication, the Aesthetic Surgery Journal, will soon feature a safety checklist for people receiving breast implants that will get updated as new information becomes available. She also highlighted the need for a comprehensive registry and long-term follow-up of implant recipients by the plastic surgeons who treated them.

In addition to better informed consent, patients who came to the hearing clearly also hoped to raise awareness in the general American public about the potential dangers from breast implants and the need to follow patients who receive implants. The 2 days of hearing accomplished that in part just by taking place. The New York Times and The Washington Post ran at least a couple of articles apiece on implant safety just before or during the hearings, while a more regional paper, the Philadelphia Inquirer, ran one article, as presumably did many other newspapers, broadcast outlets, and websites across America. Much of the coverage focused on compelling and moving personal stories from patients.

Women who have been having adverse effects from breast implants “have felt dismissed,” noted panel member Natalie C. Portis, PhD, a clinical psychologist from Oakland, Calif., and the patient representative on the advisory committee. “We need to listen to women that something real is happening.”

Dr. Tervaert, Dr. Chevray, Dr. McGuire, Dr. Clemens, Dr. Burke, Dr. Casas, and Dr. Portis had no relevant commercial disclosures.

[email protected]
 

What’s the role of anecdotal medical histories in the era of evidence-based medicine?

Mitchel L. Zoler/MDedge News

Two days of testimony and discussion by a Food and Drug Administration advisory committee that gave new scrutiny to emerging complications and signals of complications in patients who received breast implants showed that powerful, emotion-filled vignettes from affected patients could engender sympathy and recommendations for action by an expert panel. But the anecdotal histories fell short of producing a clear committee consensus on dramatic, immediate changes in FDA policy, such as joining a renewed ban on certain types of breast implants linked with a rare lymphoma, a step recently taken by 38 other countries, including 33 European countries acting in concert through the European Union.

The disconnect between gripping testimony and limited panel recommendations was most stark for a complication that’s been named Breast Implant Illness (BII) by patients on the Internet. Many breast implant recipients have reported life-changing symptoms that appeared after implant placement, most often fatigue, joint and muscle pain, brain fog, neurologic symptoms, immune dysfunction, skin manifestations, and autoimmune disease or symptoms. By my count, 22 people spoke about their harrowing experiences with BII symptoms out of the 77 who stepped to the panel’s public-comment mic during 4 hours of public testimony over 2-days of hearings, often saying that they had experienced dramatic improvements after their implants came out. The meeting of the General and Plastic Surgery Devices Panel of the Medical Devices Advisory Committee also heard presentations from two experts who ran some of the first reported studies on BII, or a BII-like syndrome called Autoimmune Syndrome Induced by Adjuvants (ASIA) described by Jan W.C. Tervaert, MD, professor of medicine and director of rheumatology at the University of Alberta in Edmonton. Dr. Tervaert and his associates published their findings about ASIA in the rheumatology literature last year (Clin Rheumatol. 2018 Feb;37[2]:483-93), and during his talk before the FDA panel, he said that silicone breast implants and the surgical mesh often used with them could be ASIA triggers.

Panel members seemed to mostly believe that the evidence they heard about BII did no more than hint at a possible association between breast implants and BII symptoms that required additional study. Many agreed on the need to include mention of the most common BII-linked patient complaints in informed consent material, but some were reluctant about even taking that step.

Mitchel L. Zoler/MDedge News

“I do not mention BII to patients. It’s not a disease; it’s a constellation of symptoms,” said panel member and plastic surgeon Pierre M. Chevray, MD, from Houston Methodist Hospital. The evidence for BII “is extremely anecdotal,” he said in an interview at the end of the 2-day session. Descriptions of BII “have been mainly published on social media. One reason why I don’t tell patients [about BII as part of informed consent] is because right now the evidence of a link is weak. We don’t yet even have a definition of this as an illness. A first step is to define it,” said Dr. Chevray, who has a very active implant practice. Other plastic surgeons were more accepting of BII as a real complication, although they agreed it needs much more study. During the testimony period, St. Louis plastic surgeon Patricia A. McGuire, MD, highlighted the challenge of teasing apart whether real symptoms are truly related to implants or are simply common ailments that accumulate during middle-age in many women. Dr. McGuire and some of her associates published an assessment of the challenges and possible solutions to studying BII that appeared shortly before the hearing (Plast Reconstr Surg. 2019 March;143[3S]:74S-81S),

Consensus recommendations from the panel to the FDA to address BII included having a single registry that would include all U.S. patients who receive breast implants (recently launched as the National Breast Implant Registry), inclusion of a control group, and collection of data at baseline and after regular follow-up intervals that includes a variety of measures relevant to autoimmune and rheumatologic disorders. Several panel members cited inadequate postmarketing safety surveillance by manufacturers in the years since breast implants returned to the U.S. market, and earlier in March, the FDA issued warning letters to two of the four companies that market U.S. breast implants over their inadequate long-term safety follow-up.

The panel’s decisions about the other major implant-associated health risk it considered, breast implant associated anaplastic large cell lymphoma (BIA-ALCL), faced a different sort of challenge. First described as linked to breast implants in 2011, today there is little doubt that BIA-ALCL is a consequence of breast implants, what several patients derisively called a “man-made cancer.” The key issue the committee grappled with was whether the calculated incidence of BIA-ALCL was at a frequency that warranted a ban on at least selected breast implant types. Mark W. Clemens, MD, a plastic surgeon at MD Anderson Cancer Center in Houston, told the panel that he calculated the Allergan Biocell group of implants, which have textured surfaces that allows for easier and more stable placement in patients, linked with an incidence of BIA-ALCL that was sevenfold to eightfold higher than that with smooth implants. That’s against a background of an overall incidence of about one case for every 20,000 U.S. implant recipients, Dr. Clemens said.

Many testifying patients, including several of the eight who described a personal history of BIA-ALCL, called for a ban on the sale of at least some breast implants because of their role in causing lymphoma. That sentiment was shared by Dr. Chevray, who endorsed a ban on “salt-loss” implants (the method that makes Biocell implants) during his closing comments to his fellow panel members. But earlier during panel discussions, others on the committee pushed back against implant bans, leaving the FDA’s eventual decision on this issue unclear. Evidence presented during the hearings suggests that implants cause ALCL by triggering a local “inflammatory milieu” and that different types of implants can have varying levels of potency for producing this milieu.

Mitchel L. Zoler/MDedge News

Perhaps the closest congruence between what patients called for and what the committee recommended was on informed consent. “No doubt, patients feel that informed consent failed them,” concluded panel member Karen E. Burke, MD, a New York dermatologist who was one of two panel discussants for the topic.

In addition to many suggestions on how to improve informed consent and public awareness lobbed at FDA staffers during the session by panel members, the final public comment of the 2 days came from Laurie A. Casas, MD, a Chicago plastic surgeon affiliated with the University of Chicago and a member of the board of directors of the American Society of Aesthetic Plastic Surgery (also know as the Aesthetic Society). During her testimony, Dr. Casas said “Over the past 2 days, we heard that patients need a structured educational checklist for informed consent. The Aesthetic Society hears you,” and promised that the website of the Society’s publication, the Aesthetic Surgery Journal, will soon feature a safety checklist for people receiving breast implants that will get updated as new information becomes available. She also highlighted the need for a comprehensive registry and long-term follow-up of implant recipients by the plastic surgeons who treated them.

In addition to better informed consent, patients who came to the hearing clearly also hoped to raise awareness in the general American public about the potential dangers from breast implants and the need to follow patients who receive implants. The 2 days of hearing accomplished that in part just by taking place. The New York Times and The Washington Post ran at least a couple of articles apiece on implant safety just before or during the hearings, while a more regional paper, the Philadelphia Inquirer, ran one article, as presumably did many other newspapers, broadcast outlets, and websites across America. Much of the coverage focused on compelling and moving personal stories from patients.

Women who have been having adverse effects from breast implants “have felt dismissed,” noted panel member Natalie C. Portis, PhD, a clinical psychologist from Oakland, Calif., and the patient representative on the advisory committee. “We need to listen to women that something real is happening.”

Dr. Tervaert, Dr. Chevray, Dr. McGuire, Dr. Clemens, Dr. Burke, Dr. Casas, and Dr. Portis had no relevant commercial disclosures.

[email protected]
 

Acetylsalicylic acid has been around for nearly 200 years. It traces its history back to a French chemist (Charles Frederic Gerhardt) and 2 German chemists (Felix Hoffmann and Arthur Eichengrün) who worked at Bayer, the company that launched the pain reliever under the name “aspirin” in 1899. It is now one of the most commonly used medications in the world.

No wonder our patients are confused!

With aspirin's anti-inflammatory properties in mind, researchers conducted randomized trials for secondary prevention of heart attacks in the 1970s; low-dose aspirin was proven effective in reducing risk for a second myocardial infarction. These trials led to speculation that aspirin might be effective for primary prevention as well. Indeed, in the 1980s the large Physicians' Health Study found aspirin reduced the incidence of first heart attack in healthy physicians by 44%.¹ Unfortunately, there was no reduction in mortality from heart disease and it was only effective for those older than 50.

The downside of aspirin was a slight increase in the incidence of hemorrhagic stroke and bleeding requiring transfusion. Nonetheless, many healthy adults started taking daily aspirin hoping to prevent a heart attack.

In this issue of JFP, Smith and colleagues summarize the 2016 recommendations of the US Preventive Services Task Force (USPSTF) regarding aspirin for primary prevention, as well as the 4 large aspirin prevention trials published in 2018 subsequent to the USPSTF recommendations. The USPSTF recommended aspirin for adults ages 50 to 59 with a 10-year cardiovascular risk of at least 10% (B recommendation). For those ages 60-69, the USPSTF recommendation for aspirin as primary prevention has a “C” rating, meaning that patient preference is important to consider in balancing benefit and harms. For those 70 and older, the USPSTF gave aspirin an “I” (insufficient evidence) rating because of increased risk for bleeding. It is important to note that the positive B recommendation for those ages 50-59 is based not only on cardiovascular risk reduction but also on a slight risk reduction for colon cancer for those taking aspirin for at least 10 years.

The 4 new, large randomized trials published in 2018, however, cast doubt on the USPSTF recommendations because the results of these trials were negative for the most part. The bottom line is that daily aspirin for prevention is definitely not for everyone and perhaps not for anyone except those who have established vascular disease or are at high risk for vascular disease and low risk for bleeding.

No wonder patients are confused!
Smith recommends that, before prescribing aspirin to healthy adults for prevention, we assess each individual’s personal cardiovascular and bleeding risk using an online decision tool called Aspirin-Guide (www.aspiringuide.com). I agree.

Acetylsalicylic acid has been around for nearly 200 years. It traces its history back to a French chemist (Charles Frederic Gerhardt) and 2 German chemists (Felix Hoffmann and Arthur Eichengrün) who worked at Bayer, the company that launched the pain reliever under the name “aspirin” in 1899. It is now one of the most commonly used medications in the world.

No wonder our patients are confused!

With aspirin's anti-inflammatory properties in mind, researchers conducted randomized trials for secondary prevention of heart attacks in the 1970s; low-dose aspirin was proven effective in reducing risk for a second myocardial infarction. These trials led to speculation that aspirin might be effective for primary prevention as well. Indeed, in the 1980s the large Physicians' Health Study found aspirin reduced the incidence of first heart attack in healthy physicians by 44%.¹ Unfortunately, there was no reduction in mortality from heart disease and it was only effective for those older than 50.

The downside of aspirin was a slight increase in the incidence of hemorrhagic stroke and bleeding requiring transfusion. Nonetheless, many healthy adults started taking daily aspirin hoping to prevent a heart attack.

In this issue of JFP, Smith and colleagues summarize the 2016 recommendations of the US Preventive Services Task Force (USPSTF) regarding aspirin for primary prevention, as well as the 4 large aspirin prevention trials published in 2018 subsequent to the USPSTF recommendations. The USPSTF recommended aspirin for adults ages 50 to 59 with a 10-year cardiovascular risk of at least 10% (B recommendation). For those ages 60-69, the USPSTF recommendation for aspirin as primary prevention has a “C” rating, meaning that patient preference is important to consider in balancing benefit and harms. For those 70 and older, the USPSTF gave aspirin an “I” (insufficient evidence) rating because of increased risk for bleeding. It is important to note that the positive B recommendation for those ages 50-59 is based not only on cardiovascular risk reduction but also on a slight risk reduction for colon cancer for those taking aspirin for at least 10 years.

The 4 new, large randomized trials published in 2018, however, cast doubt on the USPSTF recommendations because the results of these trials were negative for the most part. The bottom line is that daily aspirin for prevention is definitely not for everyone and perhaps not for anyone except those who have established vascular disease or are at high risk for vascular disease and low risk for bleeding.

No wonder patients are confused!
Smith recommends that, before prescribing aspirin to healthy adults for prevention, we assess each individual’s personal cardiovascular and bleeding risk using an online decision tool called Aspirin-Guide (www.aspiringuide.com). I agree.

Acetylsalicylic acid has been around for nearly 200 years. It traces its history back to a French chemist (Charles Frederic Gerhardt) and 2 German chemists (Felix Hoffmann and Arthur Eichengrün) who worked at Bayer, the company that launched the pain reliever under the name “aspirin” in 1899. It is now one of the most commonly used medications in the world.

No wonder our patients are confused!

With aspirin's anti-inflammatory properties in mind, researchers conducted randomized trials for secondary prevention of heart attacks in the 1970s; low-dose aspirin was proven effective in reducing risk for a second myocardial infarction. These trials led to speculation that aspirin might be effective for primary prevention as well. Indeed, in the 1980s the large Physicians' Health Study found aspirin reduced the incidence of first heart attack in healthy physicians by 44%.¹ Unfortunately, there was no reduction in mortality from heart disease and it was only effective for those older than 50.

The downside of aspirin was a slight increase in the incidence of hemorrhagic stroke and bleeding requiring transfusion. Nonetheless, many healthy adults started taking daily aspirin hoping to prevent a heart attack.

In this issue of JFP, Smith and colleagues summarize the 2016 recommendations of the US Preventive Services Task Force (USPSTF) regarding aspirin for primary prevention, as well as the 4 large aspirin prevention trials published in 2018 subsequent to the USPSTF recommendations. The USPSTF recommended aspirin for adults ages 50 to 59 with a 10-year cardiovascular risk of at least 10% (B recommendation). For those ages 60-69, the USPSTF recommendation for aspirin as primary prevention has a “C” rating, meaning that patient preference is important to consider in balancing benefit and harms. For those 70 and older, the USPSTF gave aspirin an “I” (insufficient evidence) rating because of increased risk for bleeding. It is important to note that the positive B recommendation for those ages 50-59 is based not only on cardiovascular risk reduction but also on a slight risk reduction for colon cancer for those taking aspirin for at least 10 years.

The 4 new, large randomized trials published in 2018, however, cast doubt on the USPSTF recommendations because the results of these trials were negative for the most part. The bottom line is that daily aspirin for prevention is definitely not for everyone and perhaps not for anyone except those who have established vascular disease or are at high risk for vascular disease and low risk for bleeding.

No wonder patients are confused!
Smith recommends that, before prescribing aspirin to healthy adults for prevention, we assess each individual’s personal cardiovascular and bleeding risk using an online decision tool called Aspirin-Guide (www.aspiringuide.com). I agree.

To the Editor:

I read with interest the informative Cutis case report by Krooks and Weatherall¹ in which the authors not only described the case of a 66-year-old man whose diagnosis of bone marrow biopsy–confirmed acute myeloid leukemia (AML) presented concurrently with skin biopsy–confirmed leukemia cutis but also discussed the poor prognosis of individuals with acute myelogenous leukemia cutis. Their patient died within 5 weeks of establishing the diagnosis. In addition, lateral and frontal photographs of the patient’s face demonstrated diffuse infiltrative plaques of leukemia cutis; he had swollen eyelids and lips with distortion of the nose secondary to dermal infiltration of leukemic myeloid cells.¹ Although not emphasized by the authors, the patient appeared to have a leonine facies and at least partial loss of the lateral eyebrows.

Malignancy-associated leonine facies resulting from infiltration of the skin by neoplastic cells has been reported in a patient with metastatic breast carcinoma.^2,3 However, it predominantly occurs in patients with hematologic dyscrasias such as leukemia cutis, lymphoma (ie, cutaneous B cell, cutaneous T cell, Hodgkin), plasmacytoma, and systemic mastocytosis.^3,4 The report by Krooks and Weatherall¹ adds AML-associated leukemia cutis to the previously observed types of leukemia cutis–related leonine facies in patients with acute lymphocytic leukemia, acute myelomonocytic leukemia, and chronic lymphocytic leukemia.^3,4

Partial or complete loss of eyebrows in the setting of leonine facies has a limited differential diagnosis.^3,5 In addition to cancer, the associated disorders include adnexal mucin deposition (alopecia mucinosis), granulomatous conditions (sarcoidosis), infectious diseases (leprosy), inherited syndromes (Setleis syndrome), photoallergic dermatoses (actinic reticuloid), and viral conditions (viral-associated trichodysplasia).^3-9 Neoplasms associated with leonine facies and eyebrow loss include lymphomas (mycosis fungoides and unspecified cutaneous T-cell lymphoma), systemic mastocytosis and leukemia cutis secondary to acute lymphocytic leukemia, acute myelomonocytic leukemia, and now AML.^1,3-5

The eyebrow loss associated with leonine facies often is not reversible once the causative cell of the associated condition (eg, granulomas of mycobacteria-infected histiocytes in leprosy, neoplastic lymphocytes in cutaneous T-cell lymphoma) has infiltrated the area of the eyebrows and abolished the preexisting hair follicles; however, follow-up descriptions of patients after treatment of other conditions that cause eyebrow loss usually are not reported. Indeed, there was partial reappearance of the eyebrows in a woman with systemic mastocytosis–associated loss of the eyebrows after malignancy-related treatment was reinitiated and the infiltrative facial plaques that had created her leonine facies had decreased in size.⁵ It is reasonable to speculate that the eyebrows may have reappeared in the patient reported by Krooks and Weatherall¹ and his leonine facies–associated facial plaques may have resolved if he had underwent and responded to treatment with antineoplastic chemotherapy.

To the Editor:

I read with interest the informative Cutis case report by Krooks and Weatherall¹ in which the authors not only described the case of a 66-year-old man whose diagnosis of bone marrow biopsy–confirmed acute myeloid leukemia (AML) presented concurrently with skin biopsy–confirmed leukemia cutis but also discussed the poor prognosis of individuals with acute myelogenous leukemia cutis. Their patient died within 5 weeks of establishing the diagnosis. In addition, lateral and frontal photographs of the patient’s face demonstrated diffuse infiltrative plaques of leukemia cutis; he had swollen eyelids and lips with distortion of the nose secondary to dermal infiltration of leukemic myeloid cells.¹ Although not emphasized by the authors, the patient appeared to have a leonine facies and at least partial loss of the lateral eyebrows.

Malignancy-associated leonine facies resulting from infiltration of the skin by neoplastic cells has been reported in a patient with metastatic breast carcinoma.^2,3 However, it predominantly occurs in patients with hematologic dyscrasias such as leukemia cutis, lymphoma (ie, cutaneous B cell, cutaneous T cell, Hodgkin), plasmacytoma, and systemic mastocytosis.^3,4 The report by Krooks and Weatherall¹ adds AML-associated leukemia cutis to the previously observed types of leukemia cutis–related leonine facies in patients with acute lymphocytic leukemia, acute myelomonocytic leukemia, and chronic lymphocytic leukemia.^3,4

Partial or complete loss of eyebrows in the setting of leonine facies has a limited differential diagnosis.^3,5 In addition to cancer, the associated disorders include adnexal mucin deposition (alopecia mucinosis), granulomatous conditions (sarcoidosis), infectious diseases (leprosy), inherited syndromes (Setleis syndrome), photoallergic dermatoses (actinic reticuloid), and viral conditions (viral-associated trichodysplasia).^3-9 Neoplasms associated with leonine facies and eyebrow loss include lymphomas (mycosis fungoides and unspecified cutaneous T-cell lymphoma), systemic mastocytosis and leukemia cutis secondary to acute lymphocytic leukemia, acute myelomonocytic leukemia, and now AML.^1,3-5

The eyebrow loss associated with leonine facies often is not reversible once the causative cell of the associated condition (eg, granulomas of mycobacteria-infected histiocytes in leprosy, neoplastic lymphocytes in cutaneous T-cell lymphoma) has infiltrated the area of the eyebrows and abolished the preexisting hair follicles; however, follow-up descriptions of patients after treatment of other conditions that cause eyebrow loss usually are not reported. Indeed, there was partial reappearance of the eyebrows in a woman with systemic mastocytosis–associated loss of the eyebrows after malignancy-related treatment was reinitiated and the infiltrative facial plaques that had created her leonine facies had decreased in size.⁵ It is reasonable to speculate that the eyebrows may have reappeared in the patient reported by Krooks and Weatherall¹ and his leonine facies–associated facial plaques may have resolved if he had underwent and responded to treatment with antineoplastic chemotherapy.

To the Editor:

I read with interest the informative Cutis case report by Krooks and Weatherall¹ in which the authors not only described the case of a 66-year-old man whose diagnosis of bone marrow biopsy–confirmed acute myeloid leukemia (AML) presented concurrently with skin biopsy–confirmed leukemia cutis but also discussed the poor prognosis of individuals with acute myelogenous leukemia cutis. Their patient died within 5 weeks of establishing the diagnosis. In addition, lateral and frontal photographs of the patient’s face demonstrated diffuse infiltrative plaques of leukemia cutis; he had swollen eyelids and lips with distortion of the nose secondary to dermal infiltration of leukemic myeloid cells.¹ Although not emphasized by the authors, the patient appeared to have a leonine facies and at least partial loss of the lateral eyebrows.

Malignancy-associated leonine facies resulting from infiltration of the skin by neoplastic cells has been reported in a patient with metastatic breast carcinoma.^2,3 However, it predominantly occurs in patients with hematologic dyscrasias such as leukemia cutis, lymphoma (ie, cutaneous B cell, cutaneous T cell, Hodgkin), plasmacytoma, and systemic mastocytosis.^3,4 The report by Krooks and Weatherall¹ adds AML-associated leukemia cutis to the previously observed types of leukemia cutis–related leonine facies in patients with acute lymphocytic leukemia, acute myelomonocytic leukemia, and chronic lymphocytic leukemia.^3,4

Partial or complete loss of eyebrows in the setting of leonine facies has a limited differential diagnosis.^3,5 In addition to cancer, the associated disorders include adnexal mucin deposition (alopecia mucinosis), granulomatous conditions (sarcoidosis), infectious diseases (leprosy), inherited syndromes (Setleis syndrome), photoallergic dermatoses (actinic reticuloid), and viral conditions (viral-associated trichodysplasia).^3-9 Neoplasms associated with leonine facies and eyebrow loss include lymphomas (mycosis fungoides and unspecified cutaneous T-cell lymphoma), systemic mastocytosis and leukemia cutis secondary to acute lymphocytic leukemia, acute myelomonocytic leukemia, and now AML.^1,3-5

The eyebrow loss associated with leonine facies often is not reversible once the causative cell of the associated condition (eg, granulomas of mycobacteria-infected histiocytes in leprosy, neoplastic lymphocytes in cutaneous T-cell lymphoma) has infiltrated the area of the eyebrows and abolished the preexisting hair follicles; however, follow-up descriptions of patients after treatment of other conditions that cause eyebrow loss usually are not reported. Indeed, there was partial reappearance of the eyebrows in a woman with systemic mastocytosis–associated loss of the eyebrows after malignancy-related treatment was reinitiated and the infiltrative facial plaques that had created her leonine facies had decreased in size.⁵ It is reasonable to speculate that the eyebrows may have reappeared in the patient reported by Krooks and Weatherall¹ and his leonine facies–associated facial plaques may have resolved if he had underwent and responded to treatment with antineoplastic chemotherapy.