Article

Accessible and effective mental health services are a vital component of the Veterans Health Administration (VHA) mission to provide exceptional care that improves veterans’ health and well-being. Veterans are seeking mental health care at the VHA at significantly higher rates than in previous years. From 2009 through 2024, the number of veterans who received direct mental health care from the VHA increased 78%.¹ The proportion of veterans enrolled in the VHA who also received direct mental health care expanded from 23% of total enrollees in 2009 to 33% in 2024. The increase in VHA mental health care delivery is also reflected in the number of outpatient mental health care and treatment visits at the VHA, which increased from 12.7 million to 21.5 million over the same period.

The Sergeant First Class (SFC) Heath Robinson Honoring Our Promise to Address Comprehensive Toxics (PACT) Act of 2022 expanded eligibility for VHA services, including mental health care and counseling, to new cohorts of toxic-exposed veterans. From 2022 to 2024, > 680,000 veterans enrolled in VHA care, and 45% of those were PACT Act-eligible cohorts.² Research highlighted the high prevalence of physical and psychiatric comorbidities in toxic-exposed veterans.³ As such, the VHA may face greater demand for direct mental health care with these newly eligible cohorts of veterans.

Veterans often have mental health conditions (eg, depression, posttraumatic stress disorder [PTSD]), substance use disorders (SUDs), unique military experiences (eg, deployments), and injuries and illnesses (eg, traumatic brain injury [TBI]) that increase the complexity of their clinical presentation. The varied nature of these mental health conditions, as well as veterans’ unique military-related experiences, necessitates specialized centers focused on distinct high-priority areas of mental health in the VHA.

A series of public laws charged the US Department of Veterans Affairs (VA) with developing specialized mental health Centers of Excellence (CoEs) focused on high-priority areas of veteran mental health. The first of these laws, Public Law 98- 528, established the National Center for PTSD (NCPTSD), which opened in 1989.⁴ In 1996, Congress established specialized mental health CoEs known as Mental Illness Research, Education, and Clinical Centers (MIRECCs) across the VHA.⁵ To address the unique needs of post-9/11 veterans, 3 additional specialized centers were established in 2005.⁶ Finally, under the authority of the Secretary of the VA, specialized mental health CoEs were established to focus on SUD and integrated health care.

There are 17 geographically diverse mental health CoEs and MIRECCs across the VA (Table). CoEs are embedded in VA medical centers (VAMCs) with strong medical school academic affiliations. Organizational oversight of the CoEs is provided by the VA Office of Mental Health and Office of Suicide Prevention, respectively. As part of the oversight process, CoEs submit annual reports detailing their advancements in research, education and training, and clinical activities, as well as participate in a peer-reviewed renewal process.

These specialized centers are united in a shared tripartite mission to generate new knowledge about the causes and treatments of mental health conditions, to educate and train VHA clinicians and personnel, and to develop and implement innovative clinical programs within the VHA. This combined focus on research, education, and improved clinical care reduces the time from discovery to implementation and improves the health and well-being of veterans.

Examples of this acceleration translation from scientific discovery to clinical practice are evident throughout mental health CoEs. The NCPTSD is a leader in research on PTSD and traumatic stress. Its work led to the development of national training programs for VHA clinicians, facilitating the broad dissemination of efficacious PTSD treatments across the enterprise.⁷ Researchers at the Veterans Integrated Service Network (VISN) 21 Sierra Pacific MIRECC identified depression as a significant risk factor for dementia and subsequently launched the first multisite trial of repetitive transcranial magnetic stimulation (rTMS) in the VHA in 2012 (CSP #556: the effectiveness of rTMS in depressed VA patients).⁸ This project laid the groundwork for the national clinical rTMS program launched in 2017, which is now clinically available at 60 VAMCs. In the largest pragmatic randomized clinical trial of its kind, the VISN 4 Philadelphia and Pittsburgh MIRECC found that pharmacogenomic testing significantly reduced the number of prescription medications with predicted drug-gene interactions and improved clinical outcomes among veterans with depression.⁹

Mental health CoEs are also leaders in suicide prevention, a top clinical priority for the VHA. The VISN 2 New York MIRECC developed Project Life Force, a safety planning skills group for veterans with suicidal ideation, now implemented across 10 VAMCs, including telehealth hubs, outpatient settings, and veteran peer programs.¹⁰ The VISN 2 CoE for Suicide Prevention and VISN 19 Rocky Mountain MIRECC coordinate key suicide prevention services for VA, including the analysis of suicide surveillance data; evaluation of national VA suicide prevention initiatives; the support of veterans, families, and clinicians; and enhanced access to evidence-based treatments for at-risk veterans.

Mental health CoEs are a key operational partner in VHA treatment of SUDs. The CoEs in Substance Addiction Treatment and Education (CESATEs) are national resources dedicated to improving the quality, clinical outcomes, and cost-effectiveness of VHA SUD treatment. CESATEs developed and implemented a national rollout of an effective treatment for stimulant use disorders, training staff at > 120 VA programs. The VISN 1 Mid-Atlantic MIRECC’s focus on SUD and comorbid/co-occurring mental health conditions has highlighted the significant prevalence of these conditions and the impact they have on treatment response.¹¹

Serious mental illness (SMI) (eg, schizophrenia, schizoaffective disorder) impacts up to 5% of veterans.¹² VISN 22 Desert Pacific MIRECC has developed interventions to improve the lives of veterans with SMI. Its research established supported employment as an effective intervention to improve outcomes in veterans with psychotic disorders and supported its implementation in the VHA.¹³ Peer specialists are a cornerstone in the VHA commitment to recovery-oriented services for veterans with SMI. VISN 5 Capitol MIRECC has long championed research, clinical training, and educational activities that contributed to the effective deployment of peer specialists across the VHA enterprise.

Veterans have unique military-related experiences (eg, deployment, traumatic stress, transition to civilian status) and injuries and illnesses (eg, TBI, posttraumatic headaches) that significantly impact their mental health and quality of life.

The period between active duty and transition to civilian status is a critical time in a veteran’s life. The VISN 17 CoE Veteran Sponsorship Initiative connects veterans with VA care within 30 days postdischarge, with the option of additional support in the community. The VISN 22 CoE for Stress and Mental Health (CESAMH) develops, evaluates, and disseminates diagnostics and treatments for veterans affected by traumatic events and brain injuries, with a unique focus on supporting their whole health needs. The VISN 6 Mid-Atlantic MIRECC leads the ongoing VISN-6 Post-Deployment Mental Health (PDMH) study, the largest biorepository of post-9/11 veterans. PDMH has greatly expanded the understanding of the unique needs of post-9/11 veterans, with > 100 peer-reviewed publications to date. Veterans with mild TBI frequently experience chronic posttraumatic headaches that can be disabling and nonresponsive to treatment. The VISN 20 Northwest MIRECC demonstrated that prazosin, a repurposed, low-cost, widely available, nonaddictive medication, can safely and effectively reduce the frequency of these headaches and improve functional impairment in veterans and active-duty service members.¹⁴

Increased and enhanced access to effective mental health treatment is a priority for VA. In 2007, the VA launched the National Primary Care Mental Health Integration program, which integrated mental health services into primary care settings. The Center for Integrated Healthcare (CIH) has supported the VA in these efforts. In 2024, CIH trained > 5000 health care staff on high-fidelity integration of behavioral health and medical care. VA has also focused on increasing access to mental health services via expanded telehealth offerings. The VISN 16 MIRECC, with its unique focus on increasing access to care for rural veterans via distance-based and digital health technology, supported the VA Offices of Mental Health and Connected Care to virtualize mental health care and promote adoption and sustained use of VA Video Connect across the enterprise.

Specialized MH CoEs are uniquely equipped to support the VHA in providing training and education to VA clinicians, veterans, care partners and family members, and the community on high-priority mental health topics. Education is a core component of the MH CoEs tripartite mission. As such, MH CoEs offer national trainings, conferences, consultation services, clinical demonstration projects, development of clinical dashboards and toolkits, and public awareness campaigns. Researchers, educators, and clinicians at the CoEs frequently serve as subject matter experts on topics aligned with their respective missions. Several national rollout programs that disseminated evidence-based treatments for mental health conditions to the field (eg, cognitive behavioral therapy for depression, cognitive behavioral therapy for insomnia, and prolonged exposure) were developed at specialized CoEs.

The VHA provides advanced training, residencies, and fellowships to > 120,000 trainees annually. Many of these trainees choose to remain at the VA. Seven of 10 VHA psychologists and 6 of 10 VHA physicians trained within the VHA prior to their employment.¹⁵ The MH CoEs and MIRECCs play an important role in preparing these trainees for VHA mental health careers. These centers are funded to provide advanced postdoctoral training to physicians as well as allied health professionals in clinical and counseling psychology, social work, pharmacy, and nursing. Training is not limited to postdoctoral fellows: graduate students, residents, and interns from affiliated accredited training programs may rotate through mental health CoEs each academic year.

Conclusions

For > 30 years, mental health CoEs have brought thousands of veterans advanced treatments for their mental health needs and helped reduce death by suicide. The centers have a bright future ahead, harnessing advances in artificial intelligence and genomics to permit the matching of the individual veterans to the treatment most likely to benefit them. Precision medicine, as espoused by the Hannon Act, will not only encourage the efficient use of health care resources but also rapidly reduce pain in veterans with mental health and SUDs.

Accessible and effective mental health services are a vital component of the Veterans Health Administration (VHA) mission to provide exceptional care that improves veterans’ health and well-being. Veterans are seeking mental health care at the VHA at significantly higher rates than in previous years. From 2009 through 2024, the number of veterans who received direct mental health care from the VHA increased 78%.¹ The proportion of veterans enrolled in the VHA who also received direct mental health care expanded from 23% of total enrollees in 2009 to 33% in 2024. The increase in VHA mental health care delivery is also reflected in the number of outpatient mental health care and treatment visits at the VHA, which increased from 12.7 million to 21.5 million over the same period.

The Sergeant First Class (SFC) Heath Robinson Honoring Our Promise to Address Comprehensive Toxics (PACT) Act of 2022 expanded eligibility for VHA services, including mental health care and counseling, to new cohorts of toxic-exposed veterans. From 2022 to 2024, > 680,000 veterans enrolled in VHA care, and 45% of those were PACT Act-eligible cohorts.² Research highlighted the high prevalence of physical and psychiatric comorbidities in toxic-exposed veterans.³ As such, the VHA may face greater demand for direct mental health care with these newly eligible cohorts of veterans.

Veterans often have mental health conditions (eg, depression, posttraumatic stress disorder [PTSD]), substance use disorders (SUDs), unique military experiences (eg, deployments), and injuries and illnesses (eg, traumatic brain injury [TBI]) that increase the complexity of their clinical presentation. The varied nature of these mental health conditions, as well as veterans’ unique military-related experiences, necessitates specialized centers focused on distinct high-priority areas of mental health in the VHA.

A series of public laws charged the US Department of Veterans Affairs (VA) with developing specialized mental health Centers of Excellence (CoEs) focused on high-priority areas of veteran mental health. The first of these laws, Public Law 98- 528, established the National Center for PTSD (NCPTSD), which opened in 1989.⁴ In 1996, Congress established specialized mental health CoEs known as Mental Illness Research, Education, and Clinical Centers (MIRECCs) across the VHA.⁵ To address the unique needs of post-9/11 veterans, 3 additional specialized centers were established in 2005.⁶ Finally, under the authority of the Secretary of the VA, specialized mental health CoEs were established to focus on SUD and integrated health care.

There are 17 geographically diverse mental health CoEs and MIRECCs across the VA (Table). CoEs are embedded in VA medical centers (VAMCs) with strong medical school academic affiliations. Organizational oversight of the CoEs is provided by the VA Office of Mental Health and Office of Suicide Prevention, respectively. As part of the oversight process, CoEs submit annual reports detailing their advancements in research, education and training, and clinical activities, as well as participate in a peer-reviewed renewal process.

These specialized centers are united in a shared tripartite mission to generate new knowledge about the causes and treatments of mental health conditions, to educate and train VHA clinicians and personnel, and to develop and implement innovative clinical programs within the VHA. This combined focus on research, education, and improved clinical care reduces the time from discovery to implementation and improves the health and well-being of veterans.

Examples of this acceleration translation from scientific discovery to clinical practice are evident throughout mental health CoEs. The NCPTSD is a leader in research on PTSD and traumatic stress. Its work led to the development of national training programs for VHA clinicians, facilitating the broad dissemination of efficacious PTSD treatments across the enterprise.⁷ Researchers at the Veterans Integrated Service Network (VISN) 21 Sierra Pacific MIRECC identified depression as a significant risk factor for dementia and subsequently launched the first multisite trial of repetitive transcranial magnetic stimulation (rTMS) in the VHA in 2012 (CSP #556: the effectiveness of rTMS in depressed VA patients).⁸ This project laid the groundwork for the national clinical rTMS program launched in 2017, which is now clinically available at 60 VAMCs. In the largest pragmatic randomized clinical trial of its kind, the VISN 4 Philadelphia and Pittsburgh MIRECC found that pharmacogenomic testing significantly reduced the number of prescription medications with predicted drug-gene interactions and improved clinical outcomes among veterans with depression.⁹

Mental health CoEs are also leaders in suicide prevention, a top clinical priority for the VHA. The VISN 2 New York MIRECC developed Project Life Force, a safety planning skills group for veterans with suicidal ideation, now implemented across 10 VAMCs, including telehealth hubs, outpatient settings, and veteran peer programs.¹⁰ The VISN 2 CoE for Suicide Prevention and VISN 19 Rocky Mountain MIRECC coordinate key suicide prevention services for VA, including the analysis of suicide surveillance data; evaluation of national VA suicide prevention initiatives; the support of veterans, families, and clinicians; and enhanced access to evidence-based treatments for at-risk veterans.

Mental health CoEs are a key operational partner in VHA treatment of SUDs. The CoEs in Substance Addiction Treatment and Education (CESATEs) are national resources dedicated to improving the quality, clinical outcomes, and cost-effectiveness of VHA SUD treatment. CESATEs developed and implemented a national rollout of an effective treatment for stimulant use disorders, training staff at > 120 VA programs. The VISN 1 Mid-Atlantic MIRECC’s focus on SUD and comorbid/co-occurring mental health conditions has highlighted the significant prevalence of these conditions and the impact they have on treatment response.¹¹

Serious mental illness (SMI) (eg, schizophrenia, schizoaffective disorder) impacts up to 5% of veterans.¹² VISN 22 Desert Pacific MIRECC has developed interventions to improve the lives of veterans with SMI. Its research established supported employment as an effective intervention to improve outcomes in veterans with psychotic disorders and supported its implementation in the VHA.¹³ Peer specialists are a cornerstone in the VHA commitment to recovery-oriented services for veterans with SMI. VISN 5 Capitol MIRECC has long championed research, clinical training, and educational activities that contributed to the effective deployment of peer specialists across the VHA enterprise.

Veterans have unique military-related experiences (eg, deployment, traumatic stress, transition to civilian status) and injuries and illnesses (eg, TBI, posttraumatic headaches) that significantly impact their mental health and quality of life.

The period between active duty and transition to civilian status is a critical time in a veteran’s life. The VISN 17 CoE Veteran Sponsorship Initiative connects veterans with VA care within 30 days postdischarge, with the option of additional support in the community. The VISN 22 CoE for Stress and Mental Health (CESAMH) develops, evaluates, and disseminates diagnostics and treatments for veterans affected by traumatic events and brain injuries, with a unique focus on supporting their whole health needs. The VISN 6 Mid-Atlantic MIRECC leads the ongoing VISN-6 Post-Deployment Mental Health (PDMH) study, the largest biorepository of post-9/11 veterans. PDMH has greatly expanded the understanding of the unique needs of post-9/11 veterans, with > 100 peer-reviewed publications to date. Veterans with mild TBI frequently experience chronic posttraumatic headaches that can be disabling and nonresponsive to treatment. The VISN 20 Northwest MIRECC demonstrated that prazosin, a repurposed, low-cost, widely available, nonaddictive medication, can safely and effectively reduce the frequency of these headaches and improve functional impairment in veterans and active-duty service members.¹⁴

Increased and enhanced access to effective mental health treatment is a priority for VA. In 2007, the VA launched the National Primary Care Mental Health Integration program, which integrated mental health services into primary care settings. The Center for Integrated Healthcare (CIH) has supported the VA in these efforts. In 2024, CIH trained > 5000 health care staff on high-fidelity integration of behavioral health and medical care. VA has also focused on increasing access to mental health services via expanded telehealth offerings. The VISN 16 MIRECC, with its unique focus on increasing access to care for rural veterans via distance-based and digital health technology, supported the VA Offices of Mental Health and Connected Care to virtualize mental health care and promote adoption and sustained use of VA Video Connect across the enterprise.

Specialized MH CoEs are uniquely equipped to support the VHA in providing training and education to VA clinicians, veterans, care partners and family members, and the community on high-priority mental health topics. Education is a core component of the MH CoEs tripartite mission. As such, MH CoEs offer national trainings, conferences, consultation services, clinical demonstration projects, development of clinical dashboards and toolkits, and public awareness campaigns. Researchers, educators, and clinicians at the CoEs frequently serve as subject matter experts on topics aligned with their respective missions. Several national rollout programs that disseminated evidence-based treatments for mental health conditions to the field (eg, cognitive behavioral therapy for depression, cognitive behavioral therapy for insomnia, and prolonged exposure) were developed at specialized CoEs.

The VHA provides advanced training, residencies, and fellowships to > 120,000 trainees annually. Many of these trainees choose to remain at the VA. Seven of 10 VHA psychologists and 6 of 10 VHA physicians trained within the VHA prior to their employment.¹⁵ The MH CoEs and MIRECCs play an important role in preparing these trainees for VHA mental health careers. These centers are funded to provide advanced postdoctoral training to physicians as well as allied health professionals in clinical and counseling psychology, social work, pharmacy, and nursing. Training is not limited to postdoctoral fellows: graduate students, residents, and interns from affiliated accredited training programs may rotate through mental health CoEs each academic year.

Conclusions

For > 30 years, mental health CoEs have brought thousands of veterans advanced treatments for their mental health needs and helped reduce death by suicide. The centers have a bright future ahead, harnessing advances in artificial intelligence and genomics to permit the matching of the individual veterans to the treatment most likely to benefit them. Precision medicine, as espoused by the Hannon Act, will not only encourage the efficient use of health care resources but also rapidly reduce pain in veterans with mental health and SUDs.

Accessible and effective mental health services are a vital component of the Veterans Health Administration (VHA) mission to provide exceptional care that improves veterans’ health and well-being. Veterans are seeking mental health care at the VHA at significantly higher rates than in previous years. From 2009 through 2024, the number of veterans who received direct mental health care from the VHA increased 78%.¹ The proportion of veterans enrolled in the VHA who also received direct mental health care expanded from 23% of total enrollees in 2009 to 33% in 2024. The increase in VHA mental health care delivery is also reflected in the number of outpatient mental health care and treatment visits at the VHA, which increased from 12.7 million to 21.5 million over the same period.

The Sergeant First Class (SFC) Heath Robinson Honoring Our Promise to Address Comprehensive Toxics (PACT) Act of 2022 expanded eligibility for VHA services, including mental health care and counseling, to new cohorts of toxic-exposed veterans. From 2022 to 2024, > 680,000 veterans enrolled in VHA care, and 45% of those were PACT Act-eligible cohorts.² Research highlighted the high prevalence of physical and psychiatric comorbidities in toxic-exposed veterans.³ As such, the VHA may face greater demand for direct mental health care with these newly eligible cohorts of veterans.

Veterans often have mental health conditions (eg, depression, posttraumatic stress disorder [PTSD]), substance use disorders (SUDs), unique military experiences (eg, deployments), and injuries and illnesses (eg, traumatic brain injury [TBI]) that increase the complexity of their clinical presentation. The varied nature of these mental health conditions, as well as veterans’ unique military-related experiences, necessitates specialized centers focused on distinct high-priority areas of mental health in the VHA.

A series of public laws charged the US Department of Veterans Affairs (VA) with developing specialized mental health Centers of Excellence (CoEs) focused on high-priority areas of veteran mental health. The first of these laws, Public Law 98- 528, established the National Center for PTSD (NCPTSD), which opened in 1989.⁴ In 1996, Congress established specialized mental health CoEs known as Mental Illness Research, Education, and Clinical Centers (MIRECCs) across the VHA.⁵ To address the unique needs of post-9/11 veterans, 3 additional specialized centers were established in 2005.⁶ Finally, under the authority of the Secretary of the VA, specialized mental health CoEs were established to focus on SUD and integrated health care.

There are 17 geographically diverse mental health CoEs and MIRECCs across the VA (Table). CoEs are embedded in VA medical centers (VAMCs) with strong medical school academic affiliations. Organizational oversight of the CoEs is provided by the VA Office of Mental Health and Office of Suicide Prevention, respectively. As part of the oversight process, CoEs submit annual reports detailing their advancements in research, education and training, and clinical activities, as well as participate in a peer-reviewed renewal process.

These specialized centers are united in a shared tripartite mission to generate new knowledge about the causes and treatments of mental health conditions, to educate and train VHA clinicians and personnel, and to develop and implement innovative clinical programs within the VHA. This combined focus on research, education, and improved clinical care reduces the time from discovery to implementation and improves the health and well-being of veterans.

Examples of this acceleration translation from scientific discovery to clinical practice are evident throughout mental health CoEs. The NCPTSD is a leader in research on PTSD and traumatic stress. Its work led to the development of national training programs for VHA clinicians, facilitating the broad dissemination of efficacious PTSD treatments across the enterprise.⁷ Researchers at the Veterans Integrated Service Network (VISN) 21 Sierra Pacific MIRECC identified depression as a significant risk factor for dementia and subsequently launched the first multisite trial of repetitive transcranial magnetic stimulation (rTMS) in the VHA in 2012 (CSP #556: the effectiveness of rTMS in depressed VA patients).⁸ This project laid the groundwork for the national clinical rTMS program launched in 2017, which is now clinically available at 60 VAMCs. In the largest pragmatic randomized clinical trial of its kind, the VISN 4 Philadelphia and Pittsburgh MIRECC found that pharmacogenomic testing significantly reduced the number of prescription medications with predicted drug-gene interactions and improved clinical outcomes among veterans with depression.⁹

Mental health CoEs are also leaders in suicide prevention, a top clinical priority for the VHA. The VISN 2 New York MIRECC developed Project Life Force, a safety planning skills group for veterans with suicidal ideation, now implemented across 10 VAMCs, including telehealth hubs, outpatient settings, and veteran peer programs.¹⁰ The VISN 2 CoE for Suicide Prevention and VISN 19 Rocky Mountain MIRECC coordinate key suicide prevention services for VA, including the analysis of suicide surveillance data; evaluation of national VA suicide prevention initiatives; the support of veterans, families, and clinicians; and enhanced access to evidence-based treatments for at-risk veterans.

Mental health CoEs are a key operational partner in VHA treatment of SUDs. The CoEs in Substance Addiction Treatment and Education (CESATEs) are national resources dedicated to improving the quality, clinical outcomes, and cost-effectiveness of VHA SUD treatment. CESATEs developed and implemented a national rollout of an effective treatment for stimulant use disorders, training staff at > 120 VA programs. The VISN 1 Mid-Atlantic MIRECC’s focus on SUD and comorbid/co-occurring mental health conditions has highlighted the significant prevalence of these conditions and the impact they have on treatment response.¹¹

Serious mental illness (SMI) (eg, schizophrenia, schizoaffective disorder) impacts up to 5% of veterans.¹² VISN 22 Desert Pacific MIRECC has developed interventions to improve the lives of veterans with SMI. Its research established supported employment as an effective intervention to improve outcomes in veterans with psychotic disorders and supported its implementation in the VHA.¹³ Peer specialists are a cornerstone in the VHA commitment to recovery-oriented services for veterans with SMI. VISN 5 Capitol MIRECC has long championed research, clinical training, and educational activities that contributed to the effective deployment of peer specialists across the VHA enterprise.

Veterans have unique military-related experiences (eg, deployment, traumatic stress, transition to civilian status) and injuries and illnesses (eg, TBI, posttraumatic headaches) that significantly impact their mental health and quality of life.

The period between active duty and transition to civilian status is a critical time in a veteran’s life. The VISN 17 CoE Veteran Sponsorship Initiative connects veterans with VA care within 30 days postdischarge, with the option of additional support in the community. The VISN 22 CoE for Stress and Mental Health (CESAMH) develops, evaluates, and disseminates diagnostics and treatments for veterans affected by traumatic events and brain injuries, with a unique focus on supporting their whole health needs. The VISN 6 Mid-Atlantic MIRECC leads the ongoing VISN-6 Post-Deployment Mental Health (PDMH) study, the largest biorepository of post-9/11 veterans. PDMH has greatly expanded the understanding of the unique needs of post-9/11 veterans, with > 100 peer-reviewed publications to date. Veterans with mild TBI frequently experience chronic posttraumatic headaches that can be disabling and nonresponsive to treatment. The VISN 20 Northwest MIRECC demonstrated that prazosin, a repurposed, low-cost, widely available, nonaddictive medication, can safely and effectively reduce the frequency of these headaches and improve functional impairment in veterans and active-duty service members.¹⁴

Increased and enhanced access to effective mental health treatment is a priority for VA. In 2007, the VA launched the National Primary Care Mental Health Integration program, which integrated mental health services into primary care settings. The Center for Integrated Healthcare (CIH) has supported the VA in these efforts. In 2024, CIH trained > 5000 health care staff on high-fidelity integration of behavioral health and medical care. VA has also focused on increasing access to mental health services via expanded telehealth offerings. The VISN 16 MIRECC, with its unique focus on increasing access to care for rural veterans via distance-based and digital health technology, supported the VA Offices of Mental Health and Connected Care to virtualize mental health care and promote adoption and sustained use of VA Video Connect across the enterprise.

Specialized MH CoEs are uniquely equipped to support the VHA in providing training and education to VA clinicians, veterans, care partners and family members, and the community on high-priority mental health topics. Education is a core component of the MH CoEs tripartite mission. As such, MH CoEs offer national trainings, conferences, consultation services, clinical demonstration projects, development of clinical dashboards and toolkits, and public awareness campaigns. Researchers, educators, and clinicians at the CoEs frequently serve as subject matter experts on topics aligned with their respective missions. Several national rollout programs that disseminated evidence-based treatments for mental health conditions to the field (eg, cognitive behavioral therapy for depression, cognitive behavioral therapy for insomnia, and prolonged exposure) were developed at specialized CoEs.

The VHA provides advanced training, residencies, and fellowships to > 120,000 trainees annually. Many of these trainees choose to remain at the VA. Seven of 10 VHA psychologists and 6 of 10 VHA physicians trained within the VHA prior to their employment.¹⁵ The MH CoEs and MIRECCs play an important role in preparing these trainees for VHA mental health careers. These centers are funded to provide advanced postdoctoral training to physicians as well as allied health professionals in clinical and counseling psychology, social work, pharmacy, and nursing. Training is not limited to postdoctoral fellows: graduate students, residents, and interns from affiliated accredited training programs may rotate through mental health CoEs each academic year.

Conclusions

For > 30 years, mental health CoEs have brought thousands of veterans advanced treatments for their mental health needs and helped reduce death by suicide. The centers have a bright future ahead, harnessing advances in artificial intelligence and genomics to permit the matching of the individual veterans to the treatment most likely to benefit them. Precision medicine, as espoused by the Hannon Act, will not only encourage the efficient use of health care resources but also rapidly reduce pain in veterans with mental health and SUDs.

Cognitive behavioral therapy (CBT) is supported as an effective treatment for depression by clinical practice guidelines from the US Department of Veterans Affairs (VA) and US Department of Defense.^1-3 Despite research supporting the use of evidence-based CBT for anxiety, mood, and emotional disorders, patient access to these interventions is limited.⁴ One barrier to CBT for anxiety, mood, and emotional disorders is the traditional use of single-disorder protocols (SDPs) to separately treat each disorder (eg, major depression, generalized anxiety disorder, panic disorder).

Use of SDPs places a high burden on clinicians, requiring them to learn and competently implement multiple different manualized interventions for each anxiety, mood, or emotional disorder encountered in practice.⁴ It is common for individuals who present with an anxiety, mood, or emotional disorder to experience co-occurring disorders.⁵ Traditional SDP-based CBT may require multiple SDPs to address co-occurring disorders, extending time in treatment and increasing training burden. There is evidence that even when an SDP is used, co-occurring difficulties may decrease in intensity.⁶ Thus, evidence-based CBT for 1 presenting concern may positively affect co-occurring difficulties that are not the primary treatment target.⁶

Unified Protocol (UP) is a transdiagnostic CBT intervention for anxiety and mood disorders. UP targets emotional experiences (eg, negative affect and emotional distress) that are present in multiple anxiety, depression, and emotional disorders. UP is organized into 8 modules and uses interventions present in other CBT SDPs, such as teaching objective assessment methods to clients, motivational enhancement and goal setting, emotion psychoeducation, mindful awareness, cognitive reframing, and exposure principles as mechanisms of change (Table 1).⁴ UP is an ideal intervention for addressing a number of anxiety, mood, and emotional disorders as well as addressing cooccurring disorders within the same course of treatment.

UP has been compared to SDPs; studies illustrate that UP is equivalent to SDPs at the end of treatment and at 6 months posttreatment.^4,7 Additionally, patients who received UP experienced symptom reduction for multiple co-occurring disorders.⁷ Furthermore, patients were less likely to drop out of UP when compared with SDPs.⁴

Studies have reported positive impacts on affective disorders with UP. A 2019 meta-analysis found significant reductions in depression and anxiety-related disorders.⁸ Additionally, UP has been shown to be effective when delivered in person and via telehealth.^9,10 UP has also been successfully used in veterans.¹¹ While traditional models of UP (1-2 sessions weekly) have a lower dropout rate than SDPs, UP and CBT dropout rates still leave room for improvement.^12-14 Specifically, rates of attrition from SDP CBT and transdiagnostic CBT protocols range from 9% to 35%, and dropout reduces the likelihood of attaining a full therapeutic dose of any course of CBT. Notably, accelerated delivery of CBT (ie, ≥ 3 sessions/wk) has been shown to reduce risk of dropout.^14,15

Veterans are at increased risk for suicide, and anxiety and mood disorders are associated with increased risk of suicide attempt and death.^16,17 Very few veterans who could benefit from high-quality CBT interventions, whether SDP or UP, are able to access them. Only 6.3% of veterans received ≥1 session of an evidence-based CBT SDP for posttraumatic stress disorder (PTSD) at 6 clinics evaluated in 2010.¹⁸

We identified 2 strategies to increase access to and completion of an evidence-based CBT course. First, the use of transdiagnostic UP instead of SDPs reduced burden on therapists and allowed them to address presenting and co-occurring disorders within the same course of care. Second, the use of an accelerated model of service delivery reduced dropout risk. Training clinicians to deliver UP is efficient and cost-effective, considering clinicians use core strategies that can be tailored and flexibly applied to a range of emotional difficulties. Thus, implementing UP may decrease barriers to receiving an optimal dose of an evidence-based CBT delivered with fidelity in a time- and cost-efficient manner.⁴ Two studies have found no evidence of differences in outcomes between UP and SDPs, suggesting that training and supervising clinicians in a single transdiagnostic UP intervention may prepare them to treat heterogeneous and co-occurring anxiety, mood, and emotional disorders with less burden than learning multiple SDPs.^7,19

Delivering UP in an accelerated or massed format (≥4 sessions/wk) instead of the traditional spaced model (1 session/wk) has empirical support but has not been widely implemented. This approach, sometimes referred to as a UP-intensive outpatient program (UP-IOP) or UP-intensive outpatient track (UP-IOT), has been shown to be feasible, acceptable, and effective, with increased completion rates compared with traditional UP delivery (1-2 sessions/wk).^20-22

Ragsdale et al describe a 2-week IOP with multiple treatment tracks, including a general track.²⁰ The general track includes massed UP and additional standard services, including case management, wellness services, family services, and a single session effective behaviors group. Additional augmentation services are available when clinically indicated (eg, repetitive transcranial magnetic stimulation, transcranial direct current stimulation, psychoeducation, motivational interviewing, relapse prevention). In other words, this was an UP-IOP.²⁰

Thompson-Brenner et al described a successful implementation of massed UP applied in intensive treatment settings, such as residential and day-hospital programs, for eating disorders. Patients reported improvements in 3 UP targets: experiential avoidance, mindfulness, and anxiety.²¹ Watkins et al evaluated a 2-week IOP using CBT for comorbid substance use and mental health disorders, including prolonged exposure, UP, and relapse prevention for substance use disorders. Participants were post-9/11 veterans and activeduty personnel. Results indicated that UP reduced PTSD and depressive symptoms following treatment. Furthermore, the retention rate (91%) was higher than retention in outpatient treatment (39%-65%), supporting the IOP model as a strategy to reduce dropout.²²

Massed psychotherapy has been extended to IOP programs for PTSD treatment within the Veterans Health Administration (VHA). Yamokoski et al found that patients who completed an IOP that included massed CBT for PTSD had high retention, high satisfaction, and significant reduction in self-reported co-occurring depression symptoms. The authors also found that this model of care could be implemented and sustained within a VHA facility using minimal staffing resources.²³

The UP-IOP models described by Ragsdale et al and Watkins et al included massed UP as the primary evidence-based practice (EBP) with adjunctive groups (eg, wellness and educational groups and access to complementary interventions such as mindfulness and yoga); they found that adding these groups increased retention and patient- reported satisfaction (ie, UP-IOP).^20,22 The addition of wellness education alongside a primary EBP aligns with the VHA focus on whole health well-being and wellness. This includes understanding factors that motivate a patient toward health and well-being, providing health education, and offering access to complementary interventions such as mindfulness.²⁴

Dryden et al described the whole health transformation within VHA as a proactive approach to addressing both employee and patient wellness. Their research found that the whole health model promoted wellbeing in patients and staff and these improvements were sustained during the COVID-19 pandemic. Dryden et al also noted that virtual technologies facilitated continued whole health implementation.²⁵

The literature illustrates that (1) massed UP can be delivered with complementary education and wellness offerings that may increase retention and satisfaction by enriching treatment (eg, delivering UP-IOP); (2) whole health, including wellness education and complementary interventions (eg, mindfulness, motivational enhancement), promotes well-being in patients and clinicians; and (3) whole health education and complementary interventions can be delivered virtually.

IVET

Health Care Need

Veterans Affairs Pacific Islands Health Care System (VAPIHCS) provides medical services to veterans in the Hawaiian Islands, American Samoa, Guam, and Saipan spanning nearly 4000 miles across the Pacific Ocean. Prior to implementation of this program, veterans who received care at VAPIHCS had little to no access to UP in outpatient settings and no access to UP in residential settings. Access to UP depended on the presence of a therapist trained in UP within a given clinic and was geographically limited to the location of the UP-trained therapist. The limited outpatient access to UP was restricted to the traditional UP delivery model (eg, about 1 session/wk); thus, there was no access to accelerated UP for veterans served at VAPIHCS. In the fiscal year prior to implementation of the massed UP program, > 1000 VAPIHCS veterans had been diagnosed with obsessive-compulsive related disorder or anxiety. A massed-UP program with weekly rolling admissions would support access to UP for more veterans over 12 months, and the virtual treatment modality would reduce barriers for diverse and underserved veterans, making care more equitable and inclusive.

Successful implementation and sustainment of an EBP prompted the establishment of this UP program. In 2022, VAPIHCS launched the Intensive Virtual Evidence- Based Psychotherapy Team (iVET) for treatment of PTSD. This clinic and associated EBP project demonstrated that massed (≥3 individual sessions/wk) of prolonged exposure (PE) therapy, delivered virtually to a geographically diverse veteran population with PTSD, resulted in significant reductions in PTSD, depression, and anxiety symptoms and substance use risk factors, with very high retention rates. The iVET for PTSD program was feasible, acceptable, and effective, with veterans reporting significant improvement in quality of life and high satisfaction with their mental health services.¹⁵ Given the known benefits of transdiagnostic UP treatment (vs SDPs), the need for accelerated UP, and success with accelerated PE, our goal was to spread the EBP of massed (≥3 sessions/ wk) virtual psychotherapy to other presenting problems (eg, anxiety disorders with or without co-occurring unipolar depression) using transdiagnostic UP.

Program Description

The program implemented within outpatient mental health services at VAPIHCS was iVET for the treatment of anxiety with or without co-occurring depression. The program model consists of an accelerated course of UP and whole health education provided via VA Video Connect (VVC), the VA video telehealth platform. iVET is a 2- to 4-week program and consists of 3 parts: (1) massed individual UP for transdiagnostic treatment of anxiety and co-occurring depression, (2) group whole health and wellness classes, and (3) individual health coaching to address personal wellness goals. Programming is offered over 10-hour days to increase access across multiple time zones, especially to allow participation from Guam and Saipan.

When a patient is referred to iVET, the first contact is a video (or telephone) appointment with a registered nurse (RN) for a screening session. The screening session is designed to provide education about the program (including interventions, time commitment, and resources required for participation). Following education, the RN completes a safety screening, including screening for suicidal ideation and risk, as well as intimate partner violence risk. If urgent safety concerns are present, a licensed social worker or psychologist joins the screening to complete further risk assessment and address any safety concerns.

Following screening, patients are scheduled for a VVC telehealth intake with a licensed therapist (social worker or psychologist) to complete a diagnostic interview. Patients are sent a secure link to complete a measurement-based care (MBC) battery of self-report measures, including assessments of demographics, anxiety symptoms, depression symptoms, substance use, psychological flexibility, quality of life, and satisfaction with mental health care. The results of the diagnostic interview and self-report measures are discussed with the patient during the intake session to plan next steps and support shared decision-making. This initial VVC intake not only allows for fit assessment but also serves to troubleshoot technical difficulties with the virtual platforms.

Notably, there are minimal exclusion criteria for participation in iVET. These include active unmanaged psychosis or manic symptoms, recent suicidal crises (attempt within 8 weeks), active nonsuicidal self-injury (within 8 weeks), and moderate to severe cognitive impairment. Following intake, patients are scheduled to begin their course of care with iVET. Upon completion of intake, patients receive program materials for individual and group classes and are told they will receive email links for all VVC telehealth appointments. Patients are admitted to the iVET on a rolling basis, thereby increasing access compared with closed group and/or cohort models of care.

Patients receiving iVET attend 2 to 4 telehealth appointments daily and complete exercises between sessions. The primary iVET for Anxiety program EBP intervention is a massed or accelerated individual course of UP, which includes 8 primary components: assessment, goals and motivation, understanding emotions, mindful emotion awareness, cognitive flexibility, countering emotional behaviors, understanding and confronting physical sensations, and emotional exposures. UP is delivered in 4 to 8 individual sessions weekly (60-90 minutes each), allowing completion of the full UP protocol with fidelity in 2 to 4 weeks. In addition to primary EBP intervention, patients participate in 4 group sessions weekly (50 minutes each) of a whole health and wellness education class and have access to 1 individual health coaching session weekly (30- 60 minutes) to set wellness goals and receive coaching. During iVET, patients are invited to complete MBC batteries of self-report measures assessing anxiety symptoms, depression symptoms, substance use, psychological flexibility, quality of life, and satisfaction with mental health care at sessions 1, 5, 9, 13, and the final UP session. Following discharge from the iVET, patients are offered 1-, 3-, and 6-month individual postdischarge check-up sessions with a therapist, during which they are invited to complete MBC measures and review relapse prevention and maintenance of treatment gains. Likewise, patients are offered 1-, 3-, and 6-month individual postdischarge check-up sessions with an RN focused on maintaining wellness gains.

The iVET for Anxiety staff has 3 therapists (psychologists or social workers) and 1 RN. Additionally, the iVET for Anxiety is supported by a program manager and a program support assistant who support 2 programs total (the iVET for Anxiety plus another mental health program). The primary cost of the program is staff salary. Additional resources included computer equipment for staff and supplies (eg, printed materials for patients and office supplies). Due to the virtual environment of care, iVET staff telework and do not require physical space within VAPIHCS.

Outcomes

Veterans receiving iVET for Anxiety are invited to complete MBC multiple times, including pretreatment, during UP treatment (sessions 1, 5, 9, 13, and the final session), and posttreatment (1, 3, and 6 months). MBC measures include self-reported demographics; a 2-item measure of satisfaction with mental health services; the Acceptance and Action Questionnaire II,²⁶ the Brief Addiction Monitor-Intensive Outpatient Program, ²⁷ the Generalized Anxiety Disorder-7,²⁸ the Patient Health Questionnaire (PHQ-9),²⁹ and the Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form.³⁰

Forty-two veterans completed the iVET for Anxiety program, with a retention rate of 87.5% completing . 16 sessions of massed UP (Table 2). Veterans reported reduced anxiety (P < .001), depression (P < .001), and substance use risk (P < .001). Veterans experienced improved acceptance of emotional experiences (P < .001) and quality of life (P < .001), based on paired sample t tests comparing session 1 vs final session scores on the self-reported measures. Veterans also reported high satisfaction with mental health care in iVET for Anxiety.

Veterans experienced reduced thoughts of death or suicidal ideation (SI) based on responses to item 9 of PHQ-9. When SI was categorically analyzed (presence vs absence) using PHQ-9 item 9, there was an association observed between absence of SI and completion of a course of massed UP that does not appear to be due to chance, (X² [1, N = 42) = 3.94; P = .047). In addition, veterans who completed the program showed a significant decrease in SI severity measured continuously (range, 0-3) on PHQ-9 item 9 (P < .05) (Table 3).

Future Directions

The aim of this program is to see sustained patient outcomes as iVET continues to serve more veterans. Another line of inquiry is longer- term follow-up, given that long-term follow- up was not addressed in this project. We also hope that the accelerated model of care can be applied to treatment of other presenting concerns (eg, relationship difficulties, insomnia). Expansion of accelerated mental health treatment into other federal and nonfederal health care settings is another area worthy of future inquiry. Exploration of staff satisfaction and burnout related to providing accelerated UP is another important future direction. Relatedly, assessment of the staff burden to learn 1 transdiagnostic EBP vs learning multiple SDPs is another future direction. Likewise, exploration of institutional benefits of investment in transdiagnostic training, supervision, and consultation for UP vs multiple SDPs may be important. These areas could also result in insightful, beneficial evidence of the effectiveness of massed UP to add to the existing literature.

Conclusions

UP for transdiagnostic treatment of anxiety, depressive, and emotional disorders has demonstrated reduced suffering and improved functioning and is supported by multiple clinical practice guidelines.^1-4 Federal practitioners are positioned to improve access to this intervention, thereby reducing pain and improving lives. Indeed, it is crucial to envision a future state in which access to UP for a range of anxiety and depressive disorders is improved and broad, retention rates are dramatically improved, and clinicians providing UP do not experience the high burden and burnout associated with needing to learn and implement a variety of SDPs. Development of these programs, or similar tracks within existing programs, that provide massed or accelerated UP for transdiagnostic treatment of a range of anxiety and depressive disorders with virtual delivery options, is imperative to advance improved care for patients and clinicians.

Federal health care settings treating patients with anxiety and depression, such as those within the US Department of Defense, Indian Health Services, Bureau of Prisons, and VHA, are positioned to implement programs like iVET. Moreover, at the institutional level, investment in training and supervision in the transdiagnostic UP as opposed to multiple SDPs warrants consideration. We believe this model of care has great merit and foresee a future where all patients seeking treatment for anxiety and depression have the option to complete an accelerated or massed course of transdiagnostic care with UP if they so desire. Our experiences with iVET illustrate the feasibility, acceptability, and sustainability of such programs without requiring substantial staffing and financial resources.

Cognitive behavioral therapy (CBT) is supported as an effective treatment for depression by clinical practice guidelines from the US Department of Veterans Affairs (VA) and US Department of Defense.^1-3 Despite research supporting the use of evidence-based CBT for anxiety, mood, and emotional disorders, patient access to these interventions is limited.⁴ One barrier to CBT for anxiety, mood, and emotional disorders is the traditional use of single-disorder protocols (SDPs) to separately treat each disorder (eg, major depression, generalized anxiety disorder, panic disorder).

Use of SDPs places a high burden on clinicians, requiring them to learn and competently implement multiple different manualized interventions for each anxiety, mood, or emotional disorder encountered in practice.⁴ It is common for individuals who present with an anxiety, mood, or emotional disorder to experience co-occurring disorders.⁵ Traditional SDP-based CBT may require multiple SDPs to address co-occurring disorders, extending time in treatment and increasing training burden. There is evidence that even when an SDP is used, co-occurring difficulties may decrease in intensity.⁶ Thus, evidence-based CBT for 1 presenting concern may positively affect co-occurring difficulties that are not the primary treatment target.⁶

Unified Protocol (UP) is a transdiagnostic CBT intervention for anxiety and mood disorders. UP targets emotional experiences (eg, negative affect and emotional distress) that are present in multiple anxiety, depression, and emotional disorders. UP is organized into 8 modules and uses interventions present in other CBT SDPs, such as teaching objective assessment methods to clients, motivational enhancement and goal setting, emotion psychoeducation, mindful awareness, cognitive reframing, and exposure principles as mechanisms of change (Table 1).⁴ UP is an ideal intervention for addressing a number of anxiety, mood, and emotional disorders as well as addressing cooccurring disorders within the same course of treatment.

UP has been compared to SDPs; studies illustrate that UP is equivalent to SDPs at the end of treatment and at 6 months posttreatment.^4,7 Additionally, patients who received UP experienced symptom reduction for multiple co-occurring disorders.⁷ Furthermore, patients were less likely to drop out of UP when compared with SDPs.⁴

Studies have reported positive impacts on affective disorders with UP. A 2019 meta-analysis found significant reductions in depression and anxiety-related disorders.⁸ Additionally, UP has been shown to be effective when delivered in person and via telehealth.^9,10 UP has also been successfully used in veterans.¹¹ While traditional models of UP (1-2 sessions weekly) have a lower dropout rate than SDPs, UP and CBT dropout rates still leave room for improvement.^12-14 Specifically, rates of attrition from SDP CBT and transdiagnostic CBT protocols range from 9% to 35%, and dropout reduces the likelihood of attaining a full therapeutic dose of any course of CBT. Notably, accelerated delivery of CBT (ie, ≥ 3 sessions/wk) has been shown to reduce risk of dropout.^14,15

Veterans are at increased risk for suicide, and anxiety and mood disorders are associated with increased risk of suicide attempt and death.^16,17 Very few veterans who could benefit from high-quality CBT interventions, whether SDP or UP, are able to access them. Only 6.3% of veterans received ≥1 session of an evidence-based CBT SDP for posttraumatic stress disorder (PTSD) at 6 clinics evaluated in 2010.¹⁸

We identified 2 strategies to increase access to and completion of an evidence-based CBT course. First, the use of transdiagnostic UP instead of SDPs reduced burden on therapists and allowed them to address presenting and co-occurring disorders within the same course of care. Second, the use of an accelerated model of service delivery reduced dropout risk. Training clinicians to deliver UP is efficient and cost-effective, considering clinicians use core strategies that can be tailored and flexibly applied to a range of emotional difficulties. Thus, implementing UP may decrease barriers to receiving an optimal dose of an evidence-based CBT delivered with fidelity in a time- and cost-efficient manner.⁴ Two studies have found no evidence of differences in outcomes between UP and SDPs, suggesting that training and supervising clinicians in a single transdiagnostic UP intervention may prepare them to treat heterogeneous and co-occurring anxiety, mood, and emotional disorders with less burden than learning multiple SDPs.^7,19

Delivering UP in an accelerated or massed format (≥4 sessions/wk) instead of the traditional spaced model (1 session/wk) has empirical support but has not been widely implemented. This approach, sometimes referred to as a UP-intensive outpatient program (UP-IOP) or UP-intensive outpatient track (UP-IOT), has been shown to be feasible, acceptable, and effective, with increased completion rates compared with traditional UP delivery (1-2 sessions/wk).^20-22

Ragsdale et al describe a 2-week IOP with multiple treatment tracks, including a general track.²⁰ The general track includes massed UP and additional standard services, including case management, wellness services, family services, and a single session effective behaviors group. Additional augmentation services are available when clinically indicated (eg, repetitive transcranial magnetic stimulation, transcranial direct current stimulation, psychoeducation, motivational interviewing, relapse prevention). In other words, this was an UP-IOP.²⁰

Thompson-Brenner et al described a successful implementation of massed UP applied in intensive treatment settings, such as residential and day-hospital programs, for eating disorders. Patients reported improvements in 3 UP targets: experiential avoidance, mindfulness, and anxiety.²¹ Watkins et al evaluated a 2-week IOP using CBT for comorbid substance use and mental health disorders, including prolonged exposure, UP, and relapse prevention for substance use disorders. Participants were post-9/11 veterans and activeduty personnel. Results indicated that UP reduced PTSD and depressive symptoms following treatment. Furthermore, the retention rate (91%) was higher than retention in outpatient treatment (39%-65%), supporting the IOP model as a strategy to reduce dropout.²²

Massed psychotherapy has been extended to IOP programs for PTSD treatment within the Veterans Health Administration (VHA). Yamokoski et al found that patients who completed an IOP that included massed CBT for PTSD had high retention, high satisfaction, and significant reduction in self-reported co-occurring depression symptoms. The authors also found that this model of care could be implemented and sustained within a VHA facility using minimal staffing resources.²³

The UP-IOP models described by Ragsdale et al and Watkins et al included massed UP as the primary evidence-based practice (EBP) with adjunctive groups (eg, wellness and educational groups and access to complementary interventions such as mindfulness and yoga); they found that adding these groups increased retention and patient- reported satisfaction (ie, UP-IOP).^20,22 The addition of wellness education alongside a primary EBP aligns with the VHA focus on whole health well-being and wellness. This includes understanding factors that motivate a patient toward health and well-being, providing health education, and offering access to complementary interventions such as mindfulness.²⁴

Dryden et al described the whole health transformation within VHA as a proactive approach to addressing both employee and patient wellness. Their research found that the whole health model promoted wellbeing in patients and staff and these improvements were sustained during the COVID-19 pandemic. Dryden et al also noted that virtual technologies facilitated continued whole health implementation.²⁵

The literature illustrates that (1) massed UP can be delivered with complementary education and wellness offerings that may increase retention and satisfaction by enriching treatment (eg, delivering UP-IOP); (2) whole health, including wellness education and complementary interventions (eg, mindfulness, motivational enhancement), promotes well-being in patients and clinicians; and (3) whole health education and complementary interventions can be delivered virtually.

IVET

Health Care Need

Veterans Affairs Pacific Islands Health Care System (VAPIHCS) provides medical services to veterans in the Hawaiian Islands, American Samoa, Guam, and Saipan spanning nearly 4000 miles across the Pacific Ocean. Prior to implementation of this program, veterans who received care at VAPIHCS had little to no access to UP in outpatient settings and no access to UP in residential settings. Access to UP depended on the presence of a therapist trained in UP within a given clinic and was geographically limited to the location of the UP-trained therapist. The limited outpatient access to UP was restricted to the traditional UP delivery model (eg, about 1 session/wk); thus, there was no access to accelerated UP for veterans served at VAPIHCS. In the fiscal year prior to implementation of the massed UP program, > 1000 VAPIHCS veterans had been diagnosed with obsessive-compulsive related disorder or anxiety. A massed-UP program with weekly rolling admissions would support access to UP for more veterans over 12 months, and the virtual treatment modality would reduce barriers for diverse and underserved veterans, making care more equitable and inclusive.

Successful implementation and sustainment of an EBP prompted the establishment of this UP program. In 2022, VAPIHCS launched the Intensive Virtual Evidence- Based Psychotherapy Team (iVET) for treatment of PTSD. This clinic and associated EBP project demonstrated that massed (≥3 individual sessions/wk) of prolonged exposure (PE) therapy, delivered virtually to a geographically diverse veteran population with PTSD, resulted in significant reductions in PTSD, depression, and anxiety symptoms and substance use risk factors, with very high retention rates. The iVET for PTSD program was feasible, acceptable, and effective, with veterans reporting significant improvement in quality of life and high satisfaction with their mental health services.¹⁵ Given the known benefits of transdiagnostic UP treatment (vs SDPs), the need for accelerated UP, and success with accelerated PE, our goal was to spread the EBP of massed (≥3 sessions/ wk) virtual psychotherapy to other presenting problems (eg, anxiety disorders with or without co-occurring unipolar depression) using transdiagnostic UP.

Program Description

The program implemented within outpatient mental health services at VAPIHCS was iVET for the treatment of anxiety with or without co-occurring depression. The program model consists of an accelerated course of UP and whole health education provided via VA Video Connect (VVC), the VA video telehealth platform. iVET is a 2- to 4-week program and consists of 3 parts: (1) massed individual UP for transdiagnostic treatment of anxiety and co-occurring depression, (2) group whole health and wellness classes, and (3) individual health coaching to address personal wellness goals. Programming is offered over 10-hour days to increase access across multiple time zones, especially to allow participation from Guam and Saipan.

When a patient is referred to iVET, the first contact is a video (or telephone) appointment with a registered nurse (RN) for a screening session. The screening session is designed to provide education about the program (including interventions, time commitment, and resources required for participation). Following education, the RN completes a safety screening, including screening for suicidal ideation and risk, as well as intimate partner violence risk. If urgent safety concerns are present, a licensed social worker or psychologist joins the screening to complete further risk assessment and address any safety concerns.

Following screening, patients are scheduled for a VVC telehealth intake with a licensed therapist (social worker or psychologist) to complete a diagnostic interview. Patients are sent a secure link to complete a measurement-based care (MBC) battery of self-report measures, including assessments of demographics, anxiety symptoms, depression symptoms, substance use, psychological flexibility, quality of life, and satisfaction with mental health care. The results of the diagnostic interview and self-report measures are discussed with the patient during the intake session to plan next steps and support shared decision-making. This initial VVC intake not only allows for fit assessment but also serves to troubleshoot technical difficulties with the virtual platforms.

Notably, there are minimal exclusion criteria for participation in iVET. These include active unmanaged psychosis or manic symptoms, recent suicidal crises (attempt within 8 weeks), active nonsuicidal self-injury (within 8 weeks), and moderate to severe cognitive impairment. Following intake, patients are scheduled to begin their course of care with iVET. Upon completion of intake, patients receive program materials for individual and group classes and are told they will receive email links for all VVC telehealth appointments. Patients are admitted to the iVET on a rolling basis, thereby increasing access compared with closed group and/or cohort models of care.

Patients receiving iVET attend 2 to 4 telehealth appointments daily and complete exercises between sessions. The primary iVET for Anxiety program EBP intervention is a massed or accelerated individual course of UP, which includes 8 primary components: assessment, goals and motivation, understanding emotions, mindful emotion awareness, cognitive flexibility, countering emotional behaviors, understanding and confronting physical sensations, and emotional exposures. UP is delivered in 4 to 8 individual sessions weekly (60-90 minutes each), allowing completion of the full UP protocol with fidelity in 2 to 4 weeks. In addition to primary EBP intervention, patients participate in 4 group sessions weekly (50 minutes each) of a whole health and wellness education class and have access to 1 individual health coaching session weekly (30- 60 minutes) to set wellness goals and receive coaching. During iVET, patients are invited to complete MBC batteries of self-report measures assessing anxiety symptoms, depression symptoms, substance use, psychological flexibility, quality of life, and satisfaction with mental health care at sessions 1, 5, 9, 13, and the final UP session. Following discharge from the iVET, patients are offered 1-, 3-, and 6-month individual postdischarge check-up sessions with a therapist, during which they are invited to complete MBC measures and review relapse prevention and maintenance of treatment gains. Likewise, patients are offered 1-, 3-, and 6-month individual postdischarge check-up sessions with an RN focused on maintaining wellness gains.

The iVET for Anxiety staff has 3 therapists (psychologists or social workers) and 1 RN. Additionally, the iVET for Anxiety is supported by a program manager and a program support assistant who support 2 programs total (the iVET for Anxiety plus another mental health program). The primary cost of the program is staff salary. Additional resources included computer equipment for staff and supplies (eg, printed materials for patients and office supplies). Due to the virtual environment of care, iVET staff telework and do not require physical space within VAPIHCS.

Outcomes

Veterans receiving iVET for Anxiety are invited to complete MBC multiple times, including pretreatment, during UP treatment (sessions 1, 5, 9, 13, and the final session), and posttreatment (1, 3, and 6 months). MBC measures include self-reported demographics; a 2-item measure of satisfaction with mental health services; the Acceptance and Action Questionnaire II,²⁶ the Brief Addiction Monitor-Intensive Outpatient Program, ²⁷ the Generalized Anxiety Disorder-7,²⁸ the Patient Health Questionnaire (PHQ-9),²⁹ and the Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form.³⁰

Forty-two veterans completed the iVET for Anxiety program, with a retention rate of 87.5% completing . 16 sessions of massed UP (Table 2). Veterans reported reduced anxiety (P < .001), depression (P < .001), and substance use risk (P < .001). Veterans experienced improved acceptance of emotional experiences (P < .001) and quality of life (P < .001), based on paired sample t tests comparing session 1 vs final session scores on the self-reported measures. Veterans also reported high satisfaction with mental health care in iVET for Anxiety.

Veterans experienced reduced thoughts of death or suicidal ideation (SI) based on responses to item 9 of PHQ-9. When SI was categorically analyzed (presence vs absence) using PHQ-9 item 9, there was an association observed between absence of SI and completion of a course of massed UP that does not appear to be due to chance, (X² [1, N = 42) = 3.94; P = .047). In addition, veterans who completed the program showed a significant decrease in SI severity measured continuously (range, 0-3) on PHQ-9 item 9 (P < .05) (Table 3).

Future Directions

The aim of this program is to see sustained patient outcomes as iVET continues to serve more veterans. Another line of inquiry is longer- term follow-up, given that long-term follow- up was not addressed in this project. We also hope that the accelerated model of care can be applied to treatment of other presenting concerns (eg, relationship difficulties, insomnia). Expansion of accelerated mental health treatment into other federal and nonfederal health care settings is another area worthy of future inquiry. Exploration of staff satisfaction and burnout related to providing accelerated UP is another important future direction. Relatedly, assessment of the staff burden to learn 1 transdiagnostic EBP vs learning multiple SDPs is another future direction. Likewise, exploration of institutional benefits of investment in transdiagnostic training, supervision, and consultation for UP vs multiple SDPs may be important. These areas could also result in insightful, beneficial evidence of the effectiveness of massed UP to add to the existing literature.

Conclusions

UP for transdiagnostic treatment of anxiety, depressive, and emotional disorders has demonstrated reduced suffering and improved functioning and is supported by multiple clinical practice guidelines.^1-4 Federal practitioners are positioned to improve access to this intervention, thereby reducing pain and improving lives. Indeed, it is crucial to envision a future state in which access to UP for a range of anxiety and depressive disorders is improved and broad, retention rates are dramatically improved, and clinicians providing UP do not experience the high burden and burnout associated with needing to learn and implement a variety of SDPs. Development of these programs, or similar tracks within existing programs, that provide massed or accelerated UP for transdiagnostic treatment of a range of anxiety and depressive disorders with virtual delivery options, is imperative to advance improved care for patients and clinicians.

Federal health care settings treating patients with anxiety and depression, such as those within the US Department of Defense, Indian Health Services, Bureau of Prisons, and VHA, are positioned to implement programs like iVET. Moreover, at the institutional level, investment in training and supervision in the transdiagnostic UP as opposed to multiple SDPs warrants consideration. We believe this model of care has great merit and foresee a future where all patients seeking treatment for anxiety and depression have the option to complete an accelerated or massed course of transdiagnostic care with UP if they so desire. Our experiences with iVET illustrate the feasibility, acceptability, and sustainability of such programs without requiring substantial staffing and financial resources.

Cognitive behavioral therapy (CBT) is supported as an effective treatment for depression by clinical practice guidelines from the US Department of Veterans Affairs (VA) and US Department of Defense.^1-3 Despite research supporting the use of evidence-based CBT for anxiety, mood, and emotional disorders, patient access to these interventions is limited.⁴ One barrier to CBT for anxiety, mood, and emotional disorders is the traditional use of single-disorder protocols (SDPs) to separately treat each disorder (eg, major depression, generalized anxiety disorder, panic disorder).

Use of SDPs places a high burden on clinicians, requiring them to learn and competently implement multiple different manualized interventions for each anxiety, mood, or emotional disorder encountered in practice.⁴ It is common for individuals who present with an anxiety, mood, or emotional disorder to experience co-occurring disorders.⁵ Traditional SDP-based CBT may require multiple SDPs to address co-occurring disorders, extending time in treatment and increasing training burden. There is evidence that even when an SDP is used, co-occurring difficulties may decrease in intensity.⁶ Thus, evidence-based CBT for 1 presenting concern may positively affect co-occurring difficulties that are not the primary treatment target.⁶

Unified Protocol (UP) is a transdiagnostic CBT intervention for anxiety and mood disorders. UP targets emotional experiences (eg, negative affect and emotional distress) that are present in multiple anxiety, depression, and emotional disorders. UP is organized into 8 modules and uses interventions present in other CBT SDPs, such as teaching objective assessment methods to clients, motivational enhancement and goal setting, emotion psychoeducation, mindful awareness, cognitive reframing, and exposure principles as mechanisms of change (Table 1).⁴ UP is an ideal intervention for addressing a number of anxiety, mood, and emotional disorders as well as addressing cooccurring disorders within the same course of treatment.

UP has been compared to SDPs; studies illustrate that UP is equivalent to SDPs at the end of treatment and at 6 months posttreatment.^4,7 Additionally, patients who received UP experienced symptom reduction for multiple co-occurring disorders.⁷ Furthermore, patients were less likely to drop out of UP when compared with SDPs.⁴

Studies have reported positive impacts on affective disorders with UP. A 2019 meta-analysis found significant reductions in depression and anxiety-related disorders.⁸ Additionally, UP has been shown to be effective when delivered in person and via telehealth.^9,10 UP has also been successfully used in veterans.¹¹ While traditional models of UP (1-2 sessions weekly) have a lower dropout rate than SDPs, UP and CBT dropout rates still leave room for improvement.^12-14 Specifically, rates of attrition from SDP CBT and transdiagnostic CBT protocols range from 9% to 35%, and dropout reduces the likelihood of attaining a full therapeutic dose of any course of CBT. Notably, accelerated delivery of CBT (ie, ≥ 3 sessions/wk) has been shown to reduce risk of dropout.^14,15

Veterans are at increased risk for suicide, and anxiety and mood disorders are associated with increased risk of suicide attempt and death.^16,17 Very few veterans who could benefit from high-quality CBT interventions, whether SDP or UP, are able to access them. Only 6.3% of veterans received ≥1 session of an evidence-based CBT SDP for posttraumatic stress disorder (PTSD) at 6 clinics evaluated in 2010.¹⁸

We identified 2 strategies to increase access to and completion of an evidence-based CBT course. First, the use of transdiagnostic UP instead of SDPs reduced burden on therapists and allowed them to address presenting and co-occurring disorders within the same course of care. Second, the use of an accelerated model of service delivery reduced dropout risk. Training clinicians to deliver UP is efficient and cost-effective, considering clinicians use core strategies that can be tailored and flexibly applied to a range of emotional difficulties. Thus, implementing UP may decrease barriers to receiving an optimal dose of an evidence-based CBT delivered with fidelity in a time- and cost-efficient manner.⁴ Two studies have found no evidence of differences in outcomes between UP and SDPs, suggesting that training and supervising clinicians in a single transdiagnostic UP intervention may prepare them to treat heterogeneous and co-occurring anxiety, mood, and emotional disorders with less burden than learning multiple SDPs.^7,19

Delivering UP in an accelerated or massed format (≥4 sessions/wk) instead of the traditional spaced model (1 session/wk) has empirical support but has not been widely implemented. This approach, sometimes referred to as a UP-intensive outpatient program (UP-IOP) or UP-intensive outpatient track (UP-IOT), has been shown to be feasible, acceptable, and effective, with increased completion rates compared with traditional UP delivery (1-2 sessions/wk).^20-22

Ragsdale et al describe a 2-week IOP with multiple treatment tracks, including a general track.²⁰ The general track includes massed UP and additional standard services, including case management, wellness services, family services, and a single session effective behaviors group. Additional augmentation services are available when clinically indicated (eg, repetitive transcranial magnetic stimulation, transcranial direct current stimulation, psychoeducation, motivational interviewing, relapse prevention). In other words, this was an UP-IOP.²⁰

Thompson-Brenner et al described a successful implementation of massed UP applied in intensive treatment settings, such as residential and day-hospital programs, for eating disorders. Patients reported improvements in 3 UP targets: experiential avoidance, mindfulness, and anxiety.²¹ Watkins et al evaluated a 2-week IOP using CBT for comorbid substance use and mental health disorders, including prolonged exposure, UP, and relapse prevention for substance use disorders. Participants were post-9/11 veterans and activeduty personnel. Results indicated that UP reduced PTSD and depressive symptoms following treatment. Furthermore, the retention rate (91%) was higher than retention in outpatient treatment (39%-65%), supporting the IOP model as a strategy to reduce dropout.²²

Massed psychotherapy has been extended to IOP programs for PTSD treatment within the Veterans Health Administration (VHA). Yamokoski et al found that patients who completed an IOP that included massed CBT for PTSD had high retention, high satisfaction, and significant reduction in self-reported co-occurring depression symptoms. The authors also found that this model of care could be implemented and sustained within a VHA facility using minimal staffing resources.²³

The UP-IOP models described by Ragsdale et al and Watkins et al included massed UP as the primary evidence-based practice (EBP) with adjunctive groups (eg, wellness and educational groups and access to complementary interventions such as mindfulness and yoga); they found that adding these groups increased retention and patient- reported satisfaction (ie, UP-IOP).^20,22 The addition of wellness education alongside a primary EBP aligns with the VHA focus on whole health well-being and wellness. This includes understanding factors that motivate a patient toward health and well-being, providing health education, and offering access to complementary interventions such as mindfulness.²⁴

Dryden et al described the whole health transformation within VHA as a proactive approach to addressing both employee and patient wellness. Their research found that the whole health model promoted wellbeing in patients and staff and these improvements were sustained during the COVID-19 pandemic. Dryden et al also noted that virtual technologies facilitated continued whole health implementation.²⁵

The literature illustrates that (1) massed UP can be delivered with complementary education and wellness offerings that may increase retention and satisfaction by enriching treatment (eg, delivering UP-IOP); (2) whole health, including wellness education and complementary interventions (eg, mindfulness, motivational enhancement), promotes well-being in patients and clinicians; and (3) whole health education and complementary interventions can be delivered virtually.

IVET

Health Care Need

Veterans Affairs Pacific Islands Health Care System (VAPIHCS) provides medical services to veterans in the Hawaiian Islands, American Samoa, Guam, and Saipan spanning nearly 4000 miles across the Pacific Ocean. Prior to implementation of this program, veterans who received care at VAPIHCS had little to no access to UP in outpatient settings and no access to UP in residential settings. Access to UP depended on the presence of a therapist trained in UP within a given clinic and was geographically limited to the location of the UP-trained therapist. The limited outpatient access to UP was restricted to the traditional UP delivery model (eg, about 1 session/wk); thus, there was no access to accelerated UP for veterans served at VAPIHCS. In the fiscal year prior to implementation of the massed UP program, > 1000 VAPIHCS veterans had been diagnosed with obsessive-compulsive related disorder or anxiety. A massed-UP program with weekly rolling admissions would support access to UP for more veterans over 12 months, and the virtual treatment modality would reduce barriers for diverse and underserved veterans, making care more equitable and inclusive.

Successful implementation and sustainment of an EBP prompted the establishment of this UP program. In 2022, VAPIHCS launched the Intensive Virtual Evidence- Based Psychotherapy Team (iVET) for treatment of PTSD. This clinic and associated EBP project demonstrated that massed (≥3 individual sessions/wk) of prolonged exposure (PE) therapy, delivered virtually to a geographically diverse veteran population with PTSD, resulted in significant reductions in PTSD, depression, and anxiety symptoms and substance use risk factors, with very high retention rates. The iVET for PTSD program was feasible, acceptable, and effective, with veterans reporting significant improvement in quality of life and high satisfaction with their mental health services.¹⁵ Given the known benefits of transdiagnostic UP treatment (vs SDPs), the need for accelerated UP, and success with accelerated PE, our goal was to spread the EBP of massed (≥3 sessions/ wk) virtual psychotherapy to other presenting problems (eg, anxiety disorders with or without co-occurring unipolar depression) using transdiagnostic UP.

Program Description

The program implemented within outpatient mental health services at VAPIHCS was iVET for the treatment of anxiety with or without co-occurring depression. The program model consists of an accelerated course of UP and whole health education provided via VA Video Connect (VVC), the VA video telehealth platform. iVET is a 2- to 4-week program and consists of 3 parts: (1) massed individual UP for transdiagnostic treatment of anxiety and co-occurring depression, (2) group whole health and wellness classes, and (3) individual health coaching to address personal wellness goals. Programming is offered over 10-hour days to increase access across multiple time zones, especially to allow participation from Guam and Saipan.

When a patient is referred to iVET, the first contact is a video (or telephone) appointment with a registered nurse (RN) for a screening session. The screening session is designed to provide education about the program (including interventions, time commitment, and resources required for participation). Following education, the RN completes a safety screening, including screening for suicidal ideation and risk, as well as intimate partner violence risk. If urgent safety concerns are present, a licensed social worker or psychologist joins the screening to complete further risk assessment and address any safety concerns.

Following screening, patients are scheduled for a VVC telehealth intake with a licensed therapist (social worker or psychologist) to complete a diagnostic interview. Patients are sent a secure link to complete a measurement-based care (MBC) battery of self-report measures, including assessments of demographics, anxiety symptoms, depression symptoms, substance use, psychological flexibility, quality of life, and satisfaction with mental health care. The results of the diagnostic interview and self-report measures are discussed with the patient during the intake session to plan next steps and support shared decision-making. This initial VVC intake not only allows for fit assessment but also serves to troubleshoot technical difficulties with the virtual platforms.

Notably, there are minimal exclusion criteria for participation in iVET. These include active unmanaged psychosis or manic symptoms, recent suicidal crises (attempt within 8 weeks), active nonsuicidal self-injury (within 8 weeks), and moderate to severe cognitive impairment. Following intake, patients are scheduled to begin their course of care with iVET. Upon completion of intake, patients receive program materials for individual and group classes and are told they will receive email links for all VVC telehealth appointments. Patients are admitted to the iVET on a rolling basis, thereby increasing access compared with closed group and/or cohort models of care.

Patients receiving iVET attend 2 to 4 telehealth appointments daily and complete exercises between sessions. The primary iVET for Anxiety program EBP intervention is a massed or accelerated individual course of UP, which includes 8 primary components: assessment, goals and motivation, understanding emotions, mindful emotion awareness, cognitive flexibility, countering emotional behaviors, understanding and confronting physical sensations, and emotional exposures. UP is delivered in 4 to 8 individual sessions weekly (60-90 minutes each), allowing completion of the full UP protocol with fidelity in 2 to 4 weeks. In addition to primary EBP intervention, patients participate in 4 group sessions weekly (50 minutes each) of a whole health and wellness education class and have access to 1 individual health coaching session weekly (30- 60 minutes) to set wellness goals and receive coaching. During iVET, patients are invited to complete MBC batteries of self-report measures assessing anxiety symptoms, depression symptoms, substance use, psychological flexibility, quality of life, and satisfaction with mental health care at sessions 1, 5, 9, 13, and the final UP session. Following discharge from the iVET, patients are offered 1-, 3-, and 6-month individual postdischarge check-up sessions with a therapist, during which they are invited to complete MBC measures and review relapse prevention and maintenance of treatment gains. Likewise, patients are offered 1-, 3-, and 6-month individual postdischarge check-up sessions with an RN focused on maintaining wellness gains.

The iVET for Anxiety staff has 3 therapists (psychologists or social workers) and 1 RN. Additionally, the iVET for Anxiety is supported by a program manager and a program support assistant who support 2 programs total (the iVET for Anxiety plus another mental health program). The primary cost of the program is staff salary. Additional resources included computer equipment for staff and supplies (eg, printed materials for patients and office supplies). Due to the virtual environment of care, iVET staff telework and do not require physical space within VAPIHCS.

Outcomes

Veterans receiving iVET for Anxiety are invited to complete MBC multiple times, including pretreatment, during UP treatment (sessions 1, 5, 9, 13, and the final session), and posttreatment (1, 3, and 6 months). MBC measures include self-reported demographics; a 2-item measure of satisfaction with mental health services; the Acceptance and Action Questionnaire II,²⁶ the Brief Addiction Monitor-Intensive Outpatient Program, ²⁷ the Generalized Anxiety Disorder-7,²⁸ the Patient Health Questionnaire (PHQ-9),²⁹ and the Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form.³⁰

Forty-two veterans completed the iVET for Anxiety program, with a retention rate of 87.5% completing . 16 sessions of massed UP (Table 2). Veterans reported reduced anxiety (P < .001), depression (P < .001), and substance use risk (P < .001). Veterans experienced improved acceptance of emotional experiences (P < .001) and quality of life (P < .001), based on paired sample t tests comparing session 1 vs final session scores on the self-reported measures. Veterans also reported high satisfaction with mental health care in iVET for Anxiety.

Veterans experienced reduced thoughts of death or suicidal ideation (SI) based on responses to item 9 of PHQ-9. When SI was categorically analyzed (presence vs absence) using PHQ-9 item 9, there was an association observed between absence of SI and completion of a course of massed UP that does not appear to be due to chance, (X² [1, N = 42) = 3.94; P = .047). In addition, veterans who completed the program showed a significant decrease in SI severity measured continuously (range, 0-3) on PHQ-9 item 9 (P < .05) (Table 3).

Future Directions

The aim of this program is to see sustained patient outcomes as iVET continues to serve more veterans. Another line of inquiry is longer- term follow-up, given that long-term follow- up was not addressed in this project. We also hope that the accelerated model of care can be applied to treatment of other presenting concerns (eg, relationship difficulties, insomnia). Expansion of accelerated mental health treatment into other federal and nonfederal health care settings is another area worthy of future inquiry. Exploration of staff satisfaction and burnout related to providing accelerated UP is another important future direction. Relatedly, assessment of the staff burden to learn 1 transdiagnostic EBP vs learning multiple SDPs is another future direction. Likewise, exploration of institutional benefits of investment in transdiagnostic training, supervision, and consultation for UP vs multiple SDPs may be important. These areas could also result in insightful, beneficial evidence of the effectiveness of massed UP to add to the existing literature.

Conclusions

UP for transdiagnostic treatment of anxiety, depressive, and emotional disorders has demonstrated reduced suffering and improved functioning and is supported by multiple clinical practice guidelines.^1-4 Federal practitioners are positioned to improve access to this intervention, thereby reducing pain and improving lives. Indeed, it is crucial to envision a future state in which access to UP for a range of anxiety and depressive disorders is improved and broad, retention rates are dramatically improved, and clinicians providing UP do not experience the high burden and burnout associated with needing to learn and implement a variety of SDPs. Development of these programs, or similar tracks within existing programs, that provide massed or accelerated UP for transdiagnostic treatment of a range of anxiety and depressive disorders with virtual delivery options, is imperative to advance improved care for patients and clinicians.

Federal health care settings treating patients with anxiety and depression, such as those within the US Department of Defense, Indian Health Services, Bureau of Prisons, and VHA, are positioned to implement programs like iVET. Moreover, at the institutional level, investment in training and supervision in the transdiagnostic UP as opposed to multiple SDPs warrants consideration. We believe this model of care has great merit and foresee a future where all patients seeking treatment for anxiety and depression have the option to complete an accelerated or massed course of transdiagnostic care with UP if they so desire. Our experiences with iVET illustrate the feasibility, acceptability, and sustainability of such programs without requiring substantial staffing and financial resources.

Lichen planus (LP) is a chronic inflammatory condition affecting the skin (cutaneous LP), mucous membranes (oral, ocular, or vulvar LP), hair (lichen planopilaris [LPP]), and nails that predominantly occurs in middle-aged adults. Although the true etiology remains unknown, the pathogenesis of LP is thought to involve multiple factors. Several human leukocyte antigen (HLA) alleles have been associated with LP and its variants, including HLA-B27, HLA-B51, HLA-DR1 (cutaneous and oral LP), HLA-DRB1*11, and HLA-DQB1*03 (LPP). Additionally, HLA-Bw57 has been reported to be associated with oral LP in a cohort of British patients.¹ In addition to HLA alleles, genetic polymorphisms in cytokines including IL-4, IL-6, IL-18, interferon (IFN) γ, and tumor necrosis factor (TNF) α and its receptor have been found to be associated with LP.² Beyond genetics, chronic viral infection has been implicated in the development of LP. Systemic infection with the hepatitis C virus has been linked to the development of oral LP by promoting the recruitment of hepatitis C virus–specific CD8+ T cells from peripheral blood to the oral lesions, where they exhibit a terminally differentiated effector status.³ Another report found an association between human herpesvirus 7 (HHV-7) and cutaneous LP; in this study, HHV-7 RNA was detected in plasmacytoid dendritic cells but not T cells and diminished after treatment, providing evidence for dendritic cells being involved in the HHV-7–mediated pathogenesis of cutaneous LP.⁴ These findings were further corroborated by another study of oral LP patients that found enhanced infiltration of plasmacytoid and myeloid dendritic cells and upregulation in toll-like receptor and IFN-γ signaling.⁴

In addition to immune cell dysregulation, LP and its variants have been linked to neurogenic inflammation. In oral LP lesions, neurokinin 1 receptor and substance P were highly expressed and demonstrated a positive correlation with the expression of apoptotic marker caspase-3 and proliferation marker Ki-67.⁵ These results suggest that neuropeptides may be involved in cell proliferation and turnover in oral LP. Similarly, in patients with LPP, substance P was more abundant in affected areas, whereas another neuropeptide, calcitonin gene-related peptide, was more highly expressed in unaffected areas,⁶ further supporting the pathogenic role of neurogenic inflammation in LP.

A mucosal variant that often goes undiagnosed is vulvar LP. Although no distinct pathologic mechanism for vulvar LP has been established, prior reports found an association with autoantibodies.^7,8 In patients with erosive vulvar LP, epidermal-binding basement membrane zone antibodies were detected in epidermal skin biopsies and in circulation with reactivity to bullous pemphigoid antigens 180 (9/11 [81.8%] patients) and 230 (2/11 [18.2%] patients).⁷ A similar study in patients with vulvar lichen sclerosus found similar proportions of circulating antibodies reactive to bullous pemphigoid antigens 180 (6/7 [85.7%] patients) and 230 (1/7 [14.3%] patients).⁸ Erosive vulvar LP has been shown to be associated with autoimmune disease (eg, alopecia areata, celiac disease and pernicious anemia),⁹ which suggests that the previously reported autoreactive antibodies^7,8 are secondary to autoimmunity rather than primary drivers of vulvar LP pathogenesis.

Certain medications also have been reported to cause cutaneous lichenoid drug eruptions. Although they can clinically and histologically mimic classic LP, lichenoid drug eruptions are a distinct entity. Common inciting medications include thiazide diuretics, angiotensin-converting enzyme inhibitors, anti-inflammatory drugs, antimalarials, checkpoint inhibitors, antimicrobials, antihypertensives, antidiabetics, and psychiatric drugs. The exact pathologic mechanism of lichenoid drug eruptions currently is unclear but is thought to involve the binding of drug molecules to the cell-surface proteins of the epidermis, creating an antigenic hapten stimulus for CD8+T cells and triggering apoptosis of keratinocytes.¹

The clinical severity of LP can range from mild localized disease to widespread and debilitating involvement. Multiple treatment modalities have been developed for management of LP, including topical and intralesional corticosteroids, phototherapy, Janus kinase inhibitors, phosphodiesterase-4 inhibitors, and anti–TNF-α inhibitors. Herein, we provide a narrative review and summary of the use of the TNF-α inhibitor adalimumab as a potential effective treatment for patients with LP.

Methods

We conducted a PubMed search of articles indexed for MEDLINE from 2005 to 2025 using the terms adalimumab AND lichen planus or adalimumab AND lichen. Articles that reported cases of oral LP, cutaneous LP, LPP, or lichenoid eruptions and adalimumab therapy were included in our review. Articles that used non-adalimumab TNF-α inhibitors were excluded. Using the search terms, 2 independent reviewers (M.G. and N.E.) conducted the literature review then screened the articles based on the inclusion and exclusion criteria. Our literature search yielded 40 articles, of which 20 met the criteria for inclusion in our narrative review.

Results

Our literature search yielded 11 patients with LP who were treated with adalimumab across studies (Table 1).^10-16 Prior LP treatments included topical corticosteroids (11/11 [100%]), disease-modifying antirheumatic drugs (6/11 [54.5%]), retinoids (4/11 [36.4%]), and psoralen plus UVA (1/11 [36.4%]). Adalimumab was administered subcutaneously following 4 treatment regimens: (1) 160 mg in week 1, then 80 mg in week 2, then 40 mg weekly for a median duration of 36 weeks (6/11 [54.5%]); (2) 80 mg in week 1, then 40 mg in week 2, 40 mg every 2 weeks for 20 weeks (1/11 [9.1%]); (3) 80 mg in week 1, then 40 mg every 2 weeks for a median duration of 12 weeks (2/11 [18.2%]); and (4) 40 mg every 2 weeks (2/11 [18.2%]). Adalimumab generally was well tolerated, with only 1 (9.1%) patient experiencing minor stress-related mucocutaneous flares on the tongue and extremities that resolved spontaneously.¹² Remission was achieved in 5 (45.5%) patients, with time to remission ranging from 2 to 4 months after adalimumab therapy, with a median of 2.5 months. In 1 (9.1%) patient with bullous LP, adalimumab therapy led to remission after 10 weeks. In both cases of oral and cutaneous LP (2/11 [18.2%]), remission was achieved after 2 months of treatment. Of the 2 LPP patients reported, 1 had hair regrowth after 9 months, and the other experienced remission after 3 months of adalimumab therapy. In the 1 (9.1%) case of annular LP, adalimumab treatment led to remission after 4 months. Five (45.5%) patients with vulvar LP treated with adalimumab for at least 9 months demonstrated improved Vulvar Quality of Life Index scores without improvement in their mucosal LP lesions. In 4 of the 5 (80.0%) patients who experienced remission after adalimumab treatment, remission lasted at least 6 to 10 months, with a median of 6 months; remission duration was not reported in 1 (20.0%) patient.

Paradoxically, our review of the literature yielded 12 patients in whom adalimumab was associated with lichenoid-type eruptions across 9 studies (Table 2).^17-29 The conditions for which these patients were undergoing treatment with adalimumab included ulcerative colitis,¹⁷ psoriasis,^18,19 Crohn disease,^20,26 rheumatoid arthritis,^21-23,26 oligoarthritis,²⁴ and ankylosing spondylitis.²⁵ Lichenoid drug eruptions occurred on the legs (5/12 [41.7%]), arms (3/12 [25%]), oral mucosa (2/12 [16.7%]), and forehead or scalp (2/12 [16.7%]). Onset of time to these lichenoid eruptions ranged from 2 weeks to 17 months, with a median of 4 months. Adalimumab was discontinued in 9 (75.0%) patients and was continued in 3 (25.0%). One patient who had an onset of their lichenoid eruption after 17 months of treatment with adalimumab continued to receive adalimumab therapy with the addition of topical corticosteroids, which led to resolution of their oral lesions and partial remission of their cutaneous lesions. In 1 (8.3%) patient with localized buccal lichenoid eruptions, discontinuation of adalimumab on its own was sufficient to completely clear the lesions. Seven patients (7/12 [58.3%]) received topical corticosteroids with minimal (2/12 [16.7%]) or moderate (4/12 [33.3%]) improvement, and 1 (8.3%) patient did not have reported outcomes data. Eosinophils were detected within the adalimumab-associated lichenoid eruptions in 3 (25.0%) patients.^17,20,22

In addition to its association with lichenoid drug eruptions, adalimumab also was reported to induce LPP in a patient who was being treated for Behçet disease,²⁹ oral LP in a patient being treated for Crohn disease,²⁷ and cutaneous LP in a patient being treated for Crohn disease (Table 2).²⁸ Time to onset ranged from 4 to 10 months, with a median of 6 months. Adalimumab was discontinued in 2 of 3 (66.7%) patients and was continued in the other patient (33.3%). After cessation of adalimumab therapy, administration of topical steroids led to complete resolution in the case of associated oral LP. In contrast, in adalimumab-induced cutaneous LP, initial topical corticosteroid treatment led to progression of lesions, which mostly resolved after adalimumab cessation. In 1 patient with LPP in whom adalimumab therapy could not be discontinued, topical corticosteroid and methotrexate therapy reduced the perifollicular erythema and stabilized the alopecia without full remission.

Comment

Conventional treatment modalities for LP often include topical corticosteroids as first-line therapy, with systemic corticosteroids, phototherapy, retinoids, or immunosuppressants (eg, cyclosporine or methotrexate) reserved for more severe or widespread disease. Historically, these approaches primarily have aimed to control symptoms rather than achieve long-term resolution; however, novel therapies including biologics and targeted immunomodulators show potential to induce sustained remission and improve quality of life for patients with refractory or mucosal LP.

In all reports where adalimumab was used to treat LP, patients initially received topical corticosteroids. While corticosteroids and other immunosuppressive agents are standard therapies, they often provide only temporary relief and may have an unfavorable side effect profile. Our review highlights the emerging role of adalimumab, a TNF-α inhibitor, in off-label management of LP subtypes, including cutaneous, mucosal, and vulvar LP and LPP. In several small case series and reports, patients treated with adalimumab experienced clinical improvement, including symptom resolution and quality-of-life enhancement, as well as complete remission, indicating a durable response.

The potential benefit of adalimumab in treating LP must be balanced with its paradoxical risk for inducing lichenoid eruptions as well as LP and its variants, as identified in our narrative review that included reports of patients receiving this biologic for other indications.^17-29 Since adalimumab is a fully humanized antibody, the development of neutralizing antibodies may not account for drug-induced LP and lichenoid eruptions. Given that it blocks TNF-α, adalimumab may induce these lesions through a cytokine imbalance. This is supported by data demonstrating enhanced type I IFN-related proteins in plaques of patients with psoriasiform lesions treated with TNF-α inhibitors.²⁶ These drug-induced eruptions often resolved or improved with topical corticosteroids after discontinuation, but their occurrence underscores the complexity of therapeutically targeting TNF-α in the management of LP. Our literature review suggests that adalimumab may offer therapeutic benefit in select cases of LP refractory to conventional therapy, especially when systemic control is required. Nonetheless, the risk for LP and lichenoid reactions necessitates cautious use and further investigation.

Conclusion

While the current evidence is limited to case reports and series, adalimumab shows promise as an effective and tolerable off-label treatment for LP, particularly in patients who are unresponsive to conventional immunosuppressive therapies. Remission or clinically significant improvement was achieved in several cases; however, the potential for adalimumab to induce LP and lichenoid eruptions underscores the need for careful patient selection and monitoring. Further prospective studies and larger cohorts are warranted to better define the safety and efficacy of adalimumab in treating LP lesions.

Lichen planus (LP) is a chronic inflammatory condition affecting the skin (cutaneous LP), mucous membranes (oral, ocular, or vulvar LP), hair (lichen planopilaris [LPP]), and nails that predominantly occurs in middle-aged adults. Although the true etiology remains unknown, the pathogenesis of LP is thought to involve multiple factors. Several human leukocyte antigen (HLA) alleles have been associated with LP and its variants, including HLA-B27, HLA-B51, HLA-DR1 (cutaneous and oral LP), HLA-DRB1*11, and HLA-DQB1*03 (LPP). Additionally, HLA-Bw57 has been reported to be associated with oral LP in a cohort of British patients.¹ In addition to HLA alleles, genetic polymorphisms in cytokines including IL-4, IL-6, IL-18, interferon (IFN) γ, and tumor necrosis factor (TNF) α and its receptor have been found to be associated with LP.² Beyond genetics, chronic viral infection has been implicated in the development of LP. Systemic infection with the hepatitis C virus has been linked to the development of oral LP by promoting the recruitment of hepatitis C virus–specific CD8+ T cells from peripheral blood to the oral lesions, where they exhibit a terminally differentiated effector status.³ Another report found an association between human herpesvirus 7 (HHV-7) and cutaneous LP; in this study, HHV-7 RNA was detected in plasmacytoid dendritic cells but not T cells and diminished after treatment, providing evidence for dendritic cells being involved in the HHV-7–mediated pathogenesis of cutaneous LP.⁴ These findings were further corroborated by another study of oral LP patients that found enhanced infiltration of plasmacytoid and myeloid dendritic cells and upregulation in toll-like receptor and IFN-γ signaling.⁴

In addition to immune cell dysregulation, LP and its variants have been linked to neurogenic inflammation. In oral LP lesions, neurokinin 1 receptor and substance P were highly expressed and demonstrated a positive correlation with the expression of apoptotic marker caspase-3 and proliferation marker Ki-67.⁵ These results suggest that neuropeptides may be involved in cell proliferation and turnover in oral LP. Similarly, in patients with LPP, substance P was more abundant in affected areas, whereas another neuropeptide, calcitonin gene-related peptide, was more highly expressed in unaffected areas,⁶ further supporting the pathogenic role of neurogenic inflammation in LP.

A mucosal variant that often goes undiagnosed is vulvar LP. Although no distinct pathologic mechanism for vulvar LP has been established, prior reports found an association with autoantibodies.^7,8 In patients with erosive vulvar LP, epidermal-binding basement membrane zone antibodies were detected in epidermal skin biopsies and in circulation with reactivity to bullous pemphigoid antigens 180 (9/11 [81.8%] patients) and 230 (2/11 [18.2%] patients).⁷ A similar study in patients with vulvar lichen sclerosus found similar proportions of circulating antibodies reactive to bullous pemphigoid antigens 180 (6/7 [85.7%] patients) and 230 (1/7 [14.3%] patients).⁸ Erosive vulvar LP has been shown to be associated with autoimmune disease (eg, alopecia areata, celiac disease and pernicious anemia),⁹ which suggests that the previously reported autoreactive antibodies^7,8 are secondary to autoimmunity rather than primary drivers of vulvar LP pathogenesis.

Certain medications also have been reported to cause cutaneous lichenoid drug eruptions. Although they can clinically and histologically mimic classic LP, lichenoid drug eruptions are a distinct entity. Common inciting medications include thiazide diuretics, angiotensin-converting enzyme inhibitors, anti-inflammatory drugs, antimalarials, checkpoint inhibitors, antimicrobials, antihypertensives, antidiabetics, and psychiatric drugs. The exact pathologic mechanism of lichenoid drug eruptions currently is unclear but is thought to involve the binding of drug molecules to the cell-surface proteins of the epidermis, creating an antigenic hapten stimulus for CD8+T cells and triggering apoptosis of keratinocytes.¹

The clinical severity of LP can range from mild localized disease to widespread and debilitating involvement. Multiple treatment modalities have been developed for management of LP, including topical and intralesional corticosteroids, phototherapy, Janus kinase inhibitors, phosphodiesterase-4 inhibitors, and anti–TNF-α inhibitors. Herein, we provide a narrative review and summary of the use of the TNF-α inhibitor adalimumab as a potential effective treatment for patients with LP.

Methods

We conducted a PubMed search of articles indexed for MEDLINE from 2005 to 2025 using the terms adalimumab AND lichen planus or adalimumab AND lichen. Articles that reported cases of oral LP, cutaneous LP, LPP, or lichenoid eruptions and adalimumab therapy were included in our review. Articles that used non-adalimumab TNF-α inhibitors were excluded. Using the search terms, 2 independent reviewers (M.G. and N.E.) conducted the literature review then screened the articles based on the inclusion and exclusion criteria. Our literature search yielded 40 articles, of which 20 met the criteria for inclusion in our narrative review.

Results

Our literature search yielded 11 patients with LP who were treated with adalimumab across studies (Table 1).^10-16 Prior LP treatments included topical corticosteroids (11/11 [100%]), disease-modifying antirheumatic drugs (6/11 [54.5%]), retinoids (4/11 [36.4%]), and psoralen plus UVA (1/11 [36.4%]). Adalimumab was administered subcutaneously following 4 treatment regimens: (1) 160 mg in week 1, then 80 mg in week 2, then 40 mg weekly for a median duration of 36 weeks (6/11 [54.5%]); (2) 80 mg in week 1, then 40 mg in week 2, 40 mg every 2 weeks for 20 weeks (1/11 [9.1%]); (3) 80 mg in week 1, then 40 mg every 2 weeks for a median duration of 12 weeks (2/11 [18.2%]); and (4) 40 mg every 2 weeks (2/11 [18.2%]). Adalimumab generally was well tolerated, with only 1 (9.1%) patient experiencing minor stress-related mucocutaneous flares on the tongue and extremities that resolved spontaneously.¹² Remission was achieved in 5 (45.5%) patients, with time to remission ranging from 2 to 4 months after adalimumab therapy, with a median of 2.5 months. In 1 (9.1%) patient with bullous LP, adalimumab therapy led to remission after 10 weeks. In both cases of oral and cutaneous LP (2/11 [18.2%]), remission was achieved after 2 months of treatment. Of the 2 LPP patients reported, 1 had hair regrowth after 9 months, and the other experienced remission after 3 months of adalimumab therapy. In the 1 (9.1%) case of annular LP, adalimumab treatment led to remission after 4 months. Five (45.5%) patients with vulvar LP treated with adalimumab for at least 9 months demonstrated improved Vulvar Quality of Life Index scores without improvement in their mucosal LP lesions. In 4 of the 5 (80.0%) patients who experienced remission after adalimumab treatment, remission lasted at least 6 to 10 months, with a median of 6 months; remission duration was not reported in 1 (20.0%) patient.

Paradoxically, our review of the literature yielded 12 patients in whom adalimumab was associated with lichenoid-type eruptions across 9 studies (Table 2).^17-29 The conditions for which these patients were undergoing treatment with adalimumab included ulcerative colitis,¹⁷ psoriasis,^18,19 Crohn disease,^20,26 rheumatoid arthritis,^21-23,26 oligoarthritis,²⁴ and ankylosing spondylitis.²⁵ Lichenoid drug eruptions occurred on the legs (5/12 [41.7%]), arms (3/12 [25%]), oral mucosa (2/12 [16.7%]), and forehead or scalp (2/12 [16.7%]). Onset of time to these lichenoid eruptions ranged from 2 weeks to 17 months, with a median of 4 months. Adalimumab was discontinued in 9 (75.0%) patients and was continued in 3 (25.0%). One patient who had an onset of their lichenoid eruption after 17 months of treatment with adalimumab continued to receive adalimumab therapy with the addition of topical corticosteroids, which led to resolution of their oral lesions and partial remission of their cutaneous lesions. In 1 (8.3%) patient with localized buccal lichenoid eruptions, discontinuation of adalimumab on its own was sufficient to completely clear the lesions. Seven patients (7/12 [58.3%]) received topical corticosteroids with minimal (2/12 [16.7%]) or moderate (4/12 [33.3%]) improvement, and 1 (8.3%) patient did not have reported outcomes data. Eosinophils were detected within the adalimumab-associated lichenoid eruptions in 3 (25.0%) patients.^17,20,22

In addition to its association with lichenoid drug eruptions, adalimumab also was reported to induce LPP in a patient who was being treated for Behçet disease,²⁹ oral LP in a patient being treated for Crohn disease,²⁷ and cutaneous LP in a patient being treated for Crohn disease (Table 2).²⁸ Time to onset ranged from 4 to 10 months, with a median of 6 months. Adalimumab was discontinued in 2 of 3 (66.7%) patients and was continued in the other patient (33.3%). After cessation of adalimumab therapy, administration of topical steroids led to complete resolution in the case of associated oral LP. In contrast, in adalimumab-induced cutaneous LP, initial topical corticosteroid treatment led to progression of lesions, which mostly resolved after adalimumab cessation. In 1 patient with LPP in whom adalimumab therapy could not be discontinued, topical corticosteroid and methotrexate therapy reduced the perifollicular erythema and stabilized the alopecia without full remission.

Comment

Conventional treatment modalities for LP often include topical corticosteroids as first-line therapy, with systemic corticosteroids, phototherapy, retinoids, or immunosuppressants (eg, cyclosporine or methotrexate) reserved for more severe or widespread disease. Historically, these approaches primarily have aimed to control symptoms rather than achieve long-term resolution; however, novel therapies including biologics and targeted immunomodulators show potential to induce sustained remission and improve quality of life for patients with refractory or mucosal LP.

In all reports where adalimumab was used to treat LP, patients initially received topical corticosteroids. While corticosteroids and other immunosuppressive agents are standard therapies, they often provide only temporary relief and may have an unfavorable side effect profile. Our review highlights the emerging role of adalimumab, a TNF-α inhibitor, in off-label management of LP subtypes, including cutaneous, mucosal, and vulvar LP and LPP. In several small case series and reports, patients treated with adalimumab experienced clinical improvement, including symptom resolution and quality-of-life enhancement, as well as complete remission, indicating a durable response.

The potential benefit of adalimumab in treating LP must be balanced with its paradoxical risk for inducing lichenoid eruptions as well as LP and its variants, as identified in our narrative review that included reports of patients receiving this biologic for other indications.^17-29 Since adalimumab is a fully humanized antibody, the development of neutralizing antibodies may not account for drug-induced LP and lichenoid eruptions. Given that it blocks TNF-α, adalimumab may induce these lesions through a cytokine imbalance. This is supported by data demonstrating enhanced type I IFN-related proteins in plaques of patients with psoriasiform lesions treated with TNF-α inhibitors.²⁶ These drug-induced eruptions often resolved or improved with topical corticosteroids after discontinuation, but their occurrence underscores the complexity of therapeutically targeting TNF-α in the management of LP. Our literature review suggests that adalimumab may offer therapeutic benefit in select cases of LP refractory to conventional therapy, especially when systemic control is required. Nonetheless, the risk for LP and lichenoid reactions necessitates cautious use and further investigation.

Conclusion

While the current evidence is limited to case reports and series, adalimumab shows promise as an effective and tolerable off-label treatment for LP, particularly in patients who are unresponsive to conventional immunosuppressive therapies. Remission or clinically significant improvement was achieved in several cases; however, the potential for adalimumab to induce LP and lichenoid eruptions underscores the need for careful patient selection and monitoring. Further prospective studies and larger cohorts are warranted to better define the safety and efficacy of adalimumab in treating LP lesions.

Lichen planus (LP) is a chronic inflammatory condition affecting the skin (cutaneous LP), mucous membranes (oral, ocular, or vulvar LP), hair (lichen planopilaris [LPP]), and nails that predominantly occurs in middle-aged adults. Although the true etiology remains unknown, the pathogenesis of LP is thought to involve multiple factors. Several human leukocyte antigen (HLA) alleles have been associated with LP and its variants, including HLA-B27, HLA-B51, HLA-DR1 (cutaneous and oral LP), HLA-DRB1*11, and HLA-DQB1*03 (LPP). Additionally, HLA-Bw57 has been reported to be associated with oral LP in a cohort of British patients.¹ In addition to HLA alleles, genetic polymorphisms in cytokines including IL-4, IL-6, IL-18, interferon (IFN) γ, and tumor necrosis factor (TNF) α and its receptor have been found to be associated with LP.² Beyond genetics, chronic viral infection has been implicated in the development of LP. Systemic infection with the hepatitis C virus has been linked to the development of oral LP by promoting the recruitment of hepatitis C virus–specific CD8+ T cells from peripheral blood to the oral lesions, where they exhibit a terminally differentiated effector status.³ Another report found an association between human herpesvirus 7 (HHV-7) and cutaneous LP; in this study, HHV-7 RNA was detected in plasmacytoid dendritic cells but not T cells and diminished after treatment, providing evidence for dendritic cells being involved in the HHV-7–mediated pathogenesis of cutaneous LP.⁴ These findings were further corroborated by another study of oral LP patients that found enhanced infiltration of plasmacytoid and myeloid dendritic cells and upregulation in toll-like receptor and IFN-γ signaling.⁴

In addition to immune cell dysregulation, LP and its variants have been linked to neurogenic inflammation. In oral LP lesions, neurokinin 1 receptor and substance P were highly expressed and demonstrated a positive correlation with the expression of apoptotic marker caspase-3 and proliferation marker Ki-67.⁵ These results suggest that neuropeptides may be involved in cell proliferation and turnover in oral LP. Similarly, in patients with LPP, substance P was more abundant in affected areas, whereas another neuropeptide, calcitonin gene-related peptide, was more highly expressed in unaffected areas,⁶ further supporting the pathogenic role of neurogenic inflammation in LP.

A mucosal variant that often goes undiagnosed is vulvar LP. Although no distinct pathologic mechanism for vulvar LP has been established, prior reports found an association with autoantibodies.^7,8 In patients with erosive vulvar LP, epidermal-binding basement membrane zone antibodies were detected in epidermal skin biopsies and in circulation with reactivity to bullous pemphigoid antigens 180 (9/11 [81.8%] patients) and 230 (2/11 [18.2%] patients).⁷ A similar study in patients with vulvar lichen sclerosus found similar proportions of circulating antibodies reactive to bullous pemphigoid antigens 180 (6/7 [85.7%] patients) and 230 (1/7 [14.3%] patients).⁸ Erosive vulvar LP has been shown to be associated with autoimmune disease (eg, alopecia areata, celiac disease and pernicious anemia),⁹ which suggests that the previously reported autoreactive antibodies^7,8 are secondary to autoimmunity rather than primary drivers of vulvar LP pathogenesis.

Certain medications also have been reported to cause cutaneous lichenoid drug eruptions. Although they can clinically and histologically mimic classic LP, lichenoid drug eruptions are a distinct entity. Common inciting medications include thiazide diuretics, angiotensin-converting enzyme inhibitors, anti-inflammatory drugs, antimalarials, checkpoint inhibitors, antimicrobials, antihypertensives, antidiabetics, and psychiatric drugs. The exact pathologic mechanism of lichenoid drug eruptions currently is unclear but is thought to involve the binding of drug molecules to the cell-surface proteins of the epidermis, creating an antigenic hapten stimulus for CD8+T cells and triggering apoptosis of keratinocytes.¹

The clinical severity of LP can range from mild localized disease to widespread and debilitating involvement. Multiple treatment modalities have been developed for management of LP, including topical and intralesional corticosteroids, phototherapy, Janus kinase inhibitors, phosphodiesterase-4 inhibitors, and anti–TNF-α inhibitors. Herein, we provide a narrative review and summary of the use of the TNF-α inhibitor adalimumab as a potential effective treatment for patients with LP.

Methods

We conducted a PubMed search of articles indexed for MEDLINE from 2005 to 2025 using the terms adalimumab AND lichen planus or adalimumab AND lichen. Articles that reported cases of oral LP, cutaneous LP, LPP, or lichenoid eruptions and adalimumab therapy were included in our review. Articles that used non-adalimumab TNF-α inhibitors were excluded. Using the search terms, 2 independent reviewers (M.G. and N.E.) conducted the literature review then screened the articles based on the inclusion and exclusion criteria. Our literature search yielded 40 articles, of which 20 met the criteria for inclusion in our narrative review.

Results

Our literature search yielded 11 patients with LP who were treated with adalimumab across studies (Table 1).^10-16 Prior LP treatments included topical corticosteroids (11/11 [100%]), disease-modifying antirheumatic drugs (6/11 [54.5%]), retinoids (4/11 [36.4%]), and psoralen plus UVA (1/11 [36.4%]). Adalimumab was administered subcutaneously following 4 treatment regimens: (1) 160 mg in week 1, then 80 mg in week 2, then 40 mg weekly for a median duration of 36 weeks (6/11 [54.5%]); (2) 80 mg in week 1, then 40 mg in week 2, 40 mg every 2 weeks for 20 weeks (1/11 [9.1%]); (3) 80 mg in week 1, then 40 mg every 2 weeks for a median duration of 12 weeks (2/11 [18.2%]); and (4) 40 mg every 2 weeks (2/11 [18.2%]). Adalimumab generally was well tolerated, with only 1 (9.1%) patient experiencing minor stress-related mucocutaneous flares on the tongue and extremities that resolved spontaneously.¹² Remission was achieved in 5 (45.5%) patients, with time to remission ranging from 2 to 4 months after adalimumab therapy, with a median of 2.5 months. In 1 (9.1%) patient with bullous LP, adalimumab therapy led to remission after 10 weeks. In both cases of oral and cutaneous LP (2/11 [18.2%]), remission was achieved after 2 months of treatment. Of the 2 LPP patients reported, 1 had hair regrowth after 9 months, and the other experienced remission after 3 months of adalimumab therapy. In the 1 (9.1%) case of annular LP, adalimumab treatment led to remission after 4 months. Five (45.5%) patients with vulvar LP treated with adalimumab for at least 9 months demonstrated improved Vulvar Quality of Life Index scores without improvement in their mucosal LP lesions. In 4 of the 5 (80.0%) patients who experienced remission after adalimumab treatment, remission lasted at least 6 to 10 months, with a median of 6 months; remission duration was not reported in 1 (20.0%) patient.

Paradoxically, our review of the literature yielded 12 patients in whom adalimumab was associated with lichenoid-type eruptions across 9 studies (Table 2).^17-29 The conditions for which these patients were undergoing treatment with adalimumab included ulcerative colitis,¹⁷ psoriasis,^18,19 Crohn disease,^20,26 rheumatoid arthritis,^21-23,26 oligoarthritis,²⁴ and ankylosing spondylitis.²⁵ Lichenoid drug eruptions occurred on the legs (5/12 [41.7%]), arms (3/12 [25%]), oral mucosa (2/12 [16.7%]), and forehead or scalp (2/12 [16.7%]). Onset of time to these lichenoid eruptions ranged from 2 weeks to 17 months, with a median of 4 months. Adalimumab was discontinued in 9 (75.0%) patients and was continued in 3 (25.0%). One patient who had an onset of their lichenoid eruption after 17 months of treatment with adalimumab continued to receive adalimumab therapy with the addition of topical corticosteroids, which led to resolution of their oral lesions and partial remission of their cutaneous lesions. In 1 (8.3%) patient with localized buccal lichenoid eruptions, discontinuation of adalimumab on its own was sufficient to completely clear the lesions. Seven patients (7/12 [58.3%]) received topical corticosteroids with minimal (2/12 [16.7%]) or moderate (4/12 [33.3%]) improvement, and 1 (8.3%) patient did not have reported outcomes data. Eosinophils were detected within the adalimumab-associated lichenoid eruptions in 3 (25.0%) patients.^17,20,22

In addition to its association with lichenoid drug eruptions, adalimumab also was reported to induce LPP in a patient who was being treated for Behçet disease,²⁹ oral LP in a patient being treated for Crohn disease,²⁷ and cutaneous LP in a patient being treated for Crohn disease (Table 2).²⁸ Time to onset ranged from 4 to 10 months, with a median of 6 months. Adalimumab was discontinued in 2 of 3 (66.7%) patients and was continued in the other patient (33.3%). After cessation of adalimumab therapy, administration of topical steroids led to complete resolution in the case of associated oral LP. In contrast, in adalimumab-induced cutaneous LP, initial topical corticosteroid treatment led to progression of lesions, which mostly resolved after adalimumab cessation. In 1 patient with LPP in whom adalimumab therapy could not be discontinued, topical corticosteroid and methotrexate therapy reduced the perifollicular erythema and stabilized the alopecia without full remission.

Comment

Conventional treatment modalities for LP often include topical corticosteroids as first-line therapy, with systemic corticosteroids, phototherapy, retinoids, or immunosuppressants (eg, cyclosporine or methotrexate) reserved for more severe or widespread disease. Historically, these approaches primarily have aimed to control symptoms rather than achieve long-term resolution; however, novel therapies including biologics and targeted immunomodulators show potential to induce sustained remission and improve quality of life for patients with refractory or mucosal LP.

In all reports where adalimumab was used to treat LP, patients initially received topical corticosteroids. While corticosteroids and other immunosuppressive agents are standard therapies, they often provide only temporary relief and may have an unfavorable side effect profile. Our review highlights the emerging role of adalimumab, a TNF-α inhibitor, in off-label management of LP subtypes, including cutaneous, mucosal, and vulvar LP and LPP. In several small case series and reports, patients treated with adalimumab experienced clinical improvement, including symptom resolution and quality-of-life enhancement, as well as complete remission, indicating a durable response.

The potential benefit of adalimumab in treating LP must be balanced with its paradoxical risk for inducing lichenoid eruptions as well as LP and its variants, as identified in our narrative review that included reports of patients receiving this biologic for other indications.^17-29 Since adalimumab is a fully humanized antibody, the development of neutralizing antibodies may not account for drug-induced LP and lichenoid eruptions. Given that it blocks TNF-α, adalimumab may induce these lesions through a cytokine imbalance. This is supported by data demonstrating enhanced type I IFN-related proteins in plaques of patients with psoriasiform lesions treated with TNF-α inhibitors.²⁶ These drug-induced eruptions often resolved or improved with topical corticosteroids after discontinuation, but their occurrence underscores the complexity of therapeutically targeting TNF-α in the management of LP. Our literature review suggests that adalimumab may offer therapeutic benefit in select cases of LP refractory to conventional therapy, especially when systemic control is required. Nonetheless, the risk for LP and lichenoid reactions necessitates cautious use and further investigation.

Conclusion

While the current evidence is limited to case reports and series, adalimumab shows promise as an effective and tolerable off-label treatment for LP, particularly in patients who are unresponsive to conventional immunosuppressive therapies. Remission or clinically significant improvement was achieved in several cases; however, the potential for adalimumab to induce LP and lichenoid eruptions underscores the need for careful patient selection and monitoring. Further prospective studies and larger cohorts are warranted to better define the safety and efficacy of adalimumab in treating LP lesions.

Extramammary Paget disease (EMPD) is a rare cutaneous malignancy typically seen in apocrine-rich areas, including the axillae and anogenital region. It presents as a slow-growing, erythematous patch or plaque that commonly is misdiagnosed as an infectious or inflammatory condition.^1,2 Primary EMPD occurs as a intraepithelial neoplasm, whereas secondary EMPD occurs due to epidermotropic metastases or direct extension of an underlying adenocarcinoma into the skin.¹ Most commonly, primary EMPD occurs in situ; however, when present, dermal invasion and metastases from the skin are associated with poorer outcomes.³ Given the rarity of metastatic disease, existing literature is limited to case reports and case series.

We present 2 patients with metastatic primary EMPD who had evidence of invasion on initial biopsy and died secondary to metastatic EMPD. We conducted a comprehensive review of the literature for invasive and metastatic EMPD to highlight key clinicopathologic features, treatment considerations, and the potential for rapid disease progression in cases of invasive EMPD.

Case Series

Patient 1—A 68-year-old White man with a history of breast cancer (in remission) presented to our clinic for further management of biopsy-proven scrotal EMPD. Prior to biopsy, he described a 6-month history of worsening scrotal rash treated with topical antifungals, oral antibiotics, and topical steroids due to presumed diagnosis of intertrigo, cellulitis, and dermatitis, respectively. Clinical examination showed indurated, erythematous, ulcerated plaques involving the bilateral groin, genitalia, and perineum (Figure 1). Skin biopsy confirmed a diagnosis of EMPD with both dermal and lymphovascular invasion. An immunohistochemical profile was positive for CK7 and carcinoembryonic antigen (CEA) and negative for CK20 (Figure 2).

At presentation, the patient had palpable lymphadenopathy and scrotal edema concerning for inguinal and iliac lymph node metastases. Workup for an underlying adenocarcinoma included computed tomography (CT) of the chest, abdomen, and pelvis; urologic consultation with cystoscopy; and a screening colonoscopy. The CT scan revealed multiple enlarged inguinal and external iliac lymph nodes. Fine-needle aspiration revealed CK7- and CEA-positive neoplastic cells consistent with metastatic EMPD. The patient was treated with 6 cycles of carboplatin-paclitaxel, palliative radiation therapy, and pembrolizumab with minimal response to treatment and development of osteolytic vertebral lesions concerning for disease progression. He died 1 year after the initial diagnosis secondary to the disease.

Patient 2—A 79-year-old White man presented for further management of an outside diagnosis of superficially invasive primary EMPD of the bilateral inguinal folds and scrotum that had been present for 5 months prior to biopsy and diagnosis. Clinical examination at initial presentation revealed erythematous patches of the bilateral inguinal folds and scrotum, as well as an erythematous scaling plaque in the right axilla. There was no palpable clinical lymphadenopathy. Biopsy of the axilla and groin were both consistent with invasive EMPD with positive staining for CK7 and negative staining for CK20 and CDX2. Workup for underlying adenocarcinoma with whole-body positron emission tomography/CT, mammography, esophagogastroduodenoscopy, serum CEA, colonoscopy, and cystoscopy were all negative for a metastatic adenocarcinoma. There was no imaging or clinical evidence of lymphadenopathy. Complete circumferential peripheral and deep-margin assessment was performed in a staged manner on both sites, and negative margins were obtained.

Surveillance imaging 6 months after surgery revealed suspicious hepatic lesions. Fine-needle aspiration of the hepatic lesions demonstrated positive staining for CK7 and negative staining for CK20, CDX2, prostate-specific antigen, and thyroid transcription factor 1, consistent with metastatic EMPD. Oncology recommended carboplatin and docetaxel or docetaxel monotherapy chemotherapy. The patient was further managed by an outside oncologist due to ease of travel but died secondary to the disease 15 months following the initial diagnosis.

Comment

Extramammary Paget disease is an uncommon cutaneous malignancy that manifests as pruritic erythematous plaques within apocrine-rich areas such as the genitalia, axillae, or anal region. It most commonly occurs in patients older than 65 years, with White women and Asian men being affected at disproportionately higher rates.^1,4 Delay in diagnosis is common, as EMPD can mimic other benign inflammatory or infectious conditions, including contact dermatitis, seborrheic dermatitis, tinea, candidiasis, and eczema.¹

Metastatic and multifocal cases of primary EMPD are especially rare. According to a search of PubMed articles indexed for MEDLINE published through December 2023 using the terms extramammary Paget disease, EMPD, neoplasm metastasis, invasive extramammary, and neoplasm invasiveness, we identified 5040 cases of invasive EMPD and 477 cases of metastatic EMPD.^5-37 Of the reports that disclosed patient demographic information, 3627 patients were female 1410 were male, and the mean age was 67 years. Sites of metastases included regional lymph nodes, liver, lungs, cervix, bladder, bone, brain, skin, kidney, and adrenal glands

Workup for EMPD—The initial steps for workup of EMPD include a thorough physical examination and lymph node assessment. A skin biopsy also should be performed for patients presenting with refractory, pruritic, and eczematous rashes in apocrine-rich areas to evaluate for EMPD.¹ Characterization of large and complex tumors is better achieved through multiple biopsies with particular focus on nodular or thickened areas, as these may indicate invasive disease.² Primary EMPD is characterized by pagetoid cells with abundant pale cytoplasm proliferating in a single-cell or nested pattern within the epidermis or dermis in invasive disease and often is accompanied by dermal lymphocytic inflammation.¹ Immunohistochemistry demonstrates positive staining for CEA, CK7, and CK8, with negative staining for indicators of secondary EMPD including CK20 and CDX2.^1,2

As part of the workup, it is critical to distinguish between primary disease and secondary EMPD.¹ Beyond skin and clinical lymph node examination, additional workup should be based on age-appropriate and location-directed malignant neoplasm screenings, including colonoscopy, cystoscopy, prostate examination, mammography, and Papanicolaou test. Advanced imaging such as CT, positron emission tomography, or magnetic resonance imaging can be used to assess for metastatic disease if internal malignant neoplasms are present on initial screening or clinical lymphadenopathy is identified.² Additionally, it can be helpful in the evaluation for nodal disease in cases of invasive EMPD.

The likelihood of associated underlying carcinomas varies depending on the site of involvement.^38,39 For example, vulvar involvement constitutes approximately 65% of EMPD cases, with 11% to 20% of cases being associated with underlying gastrointestinal or genitourinary carcinomas. Involvement of the male genitalia, as in our 2 patients, is rare, accounting for approximately 14% of cases, 11% of which are associated with prostate, testicular, and bladder carcinoma. Perianal involvement comprises 20% of EMPD cases and has the greatest risk for underlying malignancy with an incidence of 33% to 86%, the majority of which are rectal or tubo-ovarian cancers.^38,39 Consideration of the frequency and types of underlying carcinoma of respective sites of involvement can be helpful when ruling out secondary EMPD.

In both of our patients, palpable lymphadenopathy at the time of original diagnosis and histologic invasive disease on initial biopsy warranted thorough imaging and laboratory workup; there was no evidence of primary malignancy. Given the absence of an underlying carcinoma, both patients were classified as having metastatic primary EMPD.

Assessment of lymphadenopathy is an essential aspect of disease workup, as it is associated with a statistically higher rate of lymph node metastases. A study by Fujisawa et al²⁰ demonstrated that 80% of patients with lymphadenopathy had regional metastases compared to only 15% of patients without clinical lymphadenopathy. The presence of invasive disease also has been shown to correspond with lymph node metastases.⁴⁰ Ogata et al⁴⁰ showed that 0% of cases with in situ EMPD had a positive sentinel lymph node biopsy (SLNB) compared to 4% and 43% in cases that showed evidence of microinvasion and dermal invasion, respectively. Lymph node metastases are associated with poor prognosis, with increasingly worse prognosis when there are multiple lymph nodes affected.⁴¹ In our case series, patient 1 had lymphadenopathy and both patients had invasive EMPD; they both later developed metastases and died.

Lymphadenopathy should be further investigated with imaging and biopsy or fine-needle aspiration.⁴² Recent expert consensus guidelines recommended this method of investigation over routine use of SLNB, as there is no evidence that a positive SLNB affects treatment that changes disease-specific survival.²

Treatment of EMPD—Surgical excision of the primary lesion is the first-line treatment of EMPD,^1,2 which can be performed by wide local excision; however, studies have demonstrated higher recurrence-free survival with margin-controlled surgery (complete circumferential peripheral and deep margin assessment) or Mohs micrographic surgery (MMS), especially with CK7 immunostaining.^2,37,43 The literature on MMS of invasive EMPD is sparse, accounting for 57 patients.^25,37,44 Other reports describe management with surgical excision, wide local excision, regional resection, or vulvectomy, in addition to lymph node dissection, radiation therapy (RT), and/or chemotherapy.^{1-36,39,43-46} Despite the improved outcomes with MMS, the predominance of other surgical approaches in our search suggests that MMS may be currently underutilized for the treatment of invasive or locally advanced EMPD.

Among patients with unresectable disease or distant metastases, management includes RT with curative intent, chemotherapy, or a combination of both.^1,2 In our review, 267 cases were treated using RT and 77 with chemotherapy. Radiation therapy is an effective therapeutic option with a reported response rate of 62% to 100% and can be employed as either primary or adjuvant treatment.³ For patients with lymph node metastasis the combination of RT and lymph node dissection has been shown to have improved outcomes compared to lymph node dissection alone, with 1 study showing a 5-year survival of 75% for patients who received adjuvant RT compared to 0% for lymph node dissection alone.⁴⁵

There are currently no consensus guidelines on the best chemotherapeutic regimen for metastatic EMPD. Several regimens have been reported, including docetaxel monotherapy; low-dose 5-fluorouracil and cisplatin; combination chemotherapy FECOM (5-fluorouracil, epirubicin, carboplatin, vincristine, mitomycin); or combination therapy with cisplatin, epirubicin, and paclitaxel.¹

Prognosis of Metastatic EMPD—Because invasive and metastatic EMPD is rare, its natural history is hard to predict. Poor prognosis is associated with nodule formation, tumor thickness, perianal or vaginal involvement, lymphovascular invasion, nodal metastasis, and distant metastasis. The 5-year survival for metastatic EMPD has been reported to be less than 10%.⁴⁶ Our cases underscore the poor prognostic risk associated with metastatic EMPD.

For all cases of EMPD, close follow-up is warranted. Guidelines recommend physical examination with lymph node assessment every 3 to 6 months for 3 years and every 6 to 12 months for the subsequent 5 years.² Specific recommendations for follow-up in invasive disease have not yet been described, though the 20% probability of developing an internal malignancy within 5 years after diagnosis and poor prognostic outcomes associated with invasive and metastatic disease support the need for close monitoring.²

Conclusion

Although in situ EMPD often is a slow-growing tumor with good prognosis, invasive disease has high potential to behave aggressively with high morbidity and mortality. Increased awareness and prompt identification of invasive EMPD, expedited comprehensive workup, and early multidisciplinary management might impact patient outcomes.

Acknowledgment—The authors would like to thank Ellen Aaronson, MLIS, AHIP (Mayo Clinic Libraries [Jacksonville, FL]), for creating and conducting the narrative literature search in the MEDLINE database.

Extramammary Paget disease (EMPD) is a rare cutaneous malignancy typically seen in apocrine-rich areas, including the axillae and anogenital region. It presents as a slow-growing, erythematous patch or plaque that commonly is misdiagnosed as an infectious or inflammatory condition.^1,2 Primary EMPD occurs as a intraepithelial neoplasm, whereas secondary EMPD occurs due to epidermotropic metastases or direct extension of an underlying adenocarcinoma into the skin.¹ Most commonly, primary EMPD occurs in situ; however, when present, dermal invasion and metastases from the skin are associated with poorer outcomes.³ Given the rarity of metastatic disease, existing literature is limited to case reports and case series.

We present 2 patients with metastatic primary EMPD who had evidence of invasion on initial biopsy and died secondary to metastatic EMPD. We conducted a comprehensive review of the literature for invasive and metastatic EMPD to highlight key clinicopathologic features, treatment considerations, and the potential for rapid disease progression in cases of invasive EMPD.

Case Series

Patient 1—A 68-year-old White man with a history of breast cancer (in remission) presented to our clinic for further management of biopsy-proven scrotal EMPD. Prior to biopsy, he described a 6-month history of worsening scrotal rash treated with topical antifungals, oral antibiotics, and topical steroids due to presumed diagnosis of intertrigo, cellulitis, and dermatitis, respectively. Clinical examination showed indurated, erythematous, ulcerated plaques involving the bilateral groin, genitalia, and perineum (Figure 1). Skin biopsy confirmed a diagnosis of EMPD with both dermal and lymphovascular invasion. An immunohistochemical profile was positive for CK7 and carcinoembryonic antigen (CEA) and negative for CK20 (Figure 2).

At presentation, the patient had palpable lymphadenopathy and scrotal edema concerning for inguinal and iliac lymph node metastases. Workup for an underlying adenocarcinoma included computed tomography (CT) of the chest, abdomen, and pelvis; urologic consultation with cystoscopy; and a screening colonoscopy. The CT scan revealed multiple enlarged inguinal and external iliac lymph nodes. Fine-needle aspiration revealed CK7- and CEA-positive neoplastic cells consistent with metastatic EMPD. The patient was treated with 6 cycles of carboplatin-paclitaxel, palliative radiation therapy, and pembrolizumab with minimal response to treatment and development of osteolytic vertebral lesions concerning for disease progression. He died 1 year after the initial diagnosis secondary to the disease.

Patient 2—A 79-year-old White man presented for further management of an outside diagnosis of superficially invasive primary EMPD of the bilateral inguinal folds and scrotum that had been present for 5 months prior to biopsy and diagnosis. Clinical examination at initial presentation revealed erythematous patches of the bilateral inguinal folds and scrotum, as well as an erythematous scaling plaque in the right axilla. There was no palpable clinical lymphadenopathy. Biopsy of the axilla and groin were both consistent with invasive EMPD with positive staining for CK7 and negative staining for CK20 and CDX2. Workup for underlying adenocarcinoma with whole-body positron emission tomography/CT, mammography, esophagogastroduodenoscopy, serum CEA, colonoscopy, and cystoscopy were all negative for a metastatic adenocarcinoma. There was no imaging or clinical evidence of lymphadenopathy. Complete circumferential peripheral and deep-margin assessment was performed in a staged manner on both sites, and negative margins were obtained.

Surveillance imaging 6 months after surgery revealed suspicious hepatic lesions. Fine-needle aspiration of the hepatic lesions demonstrated positive staining for CK7 and negative staining for CK20, CDX2, prostate-specific antigen, and thyroid transcription factor 1, consistent with metastatic EMPD. Oncology recommended carboplatin and docetaxel or docetaxel monotherapy chemotherapy. The patient was further managed by an outside oncologist due to ease of travel but died secondary to the disease 15 months following the initial diagnosis.

Comment

Extramammary Paget disease is an uncommon cutaneous malignancy that manifests as pruritic erythematous plaques within apocrine-rich areas such as the genitalia, axillae, or anal region. It most commonly occurs in patients older than 65 years, with White women and Asian men being affected at disproportionately higher rates.^1,4 Delay in diagnosis is common, as EMPD can mimic other benign inflammatory or infectious conditions, including contact dermatitis, seborrheic dermatitis, tinea, candidiasis, and eczema.¹

Metastatic and multifocal cases of primary EMPD are especially rare. According to a search of PubMed articles indexed for MEDLINE published through December 2023 using the terms extramammary Paget disease, EMPD, neoplasm metastasis, invasive extramammary, and neoplasm invasiveness, we identified 5040 cases of invasive EMPD and 477 cases of metastatic EMPD.^5-37 Of the reports that disclosed patient demographic information, 3627 patients were female 1410 were male, and the mean age was 67 years. Sites of metastases included regional lymph nodes, liver, lungs, cervix, bladder, bone, brain, skin, kidney, and adrenal glands

Workup for EMPD—The initial steps for workup of EMPD include a thorough physical examination and lymph node assessment. A skin biopsy also should be performed for patients presenting with refractory, pruritic, and eczematous rashes in apocrine-rich areas to evaluate for EMPD.¹ Characterization of large and complex tumors is better achieved through multiple biopsies with particular focus on nodular or thickened areas, as these may indicate invasive disease.² Primary EMPD is characterized by pagetoid cells with abundant pale cytoplasm proliferating in a single-cell or nested pattern within the epidermis or dermis in invasive disease and often is accompanied by dermal lymphocytic inflammation.¹ Immunohistochemistry demonstrates positive staining for CEA, CK7, and CK8, with negative staining for indicators of secondary EMPD including CK20 and CDX2.^1,2

As part of the workup, it is critical to distinguish between primary disease and secondary EMPD.¹ Beyond skin and clinical lymph node examination, additional workup should be based on age-appropriate and location-directed malignant neoplasm screenings, including colonoscopy, cystoscopy, prostate examination, mammography, and Papanicolaou test. Advanced imaging such as CT, positron emission tomography, or magnetic resonance imaging can be used to assess for metastatic disease if internal malignant neoplasms are present on initial screening or clinical lymphadenopathy is identified.² Additionally, it can be helpful in the evaluation for nodal disease in cases of invasive EMPD.

The likelihood of associated underlying carcinomas varies depending on the site of involvement.^38,39 For example, vulvar involvement constitutes approximately 65% of EMPD cases, with 11% to 20% of cases being associated with underlying gastrointestinal or genitourinary carcinomas. Involvement of the male genitalia, as in our 2 patients, is rare, accounting for approximately 14% of cases, 11% of which are associated with prostate, testicular, and bladder carcinoma. Perianal involvement comprises 20% of EMPD cases and has the greatest risk for underlying malignancy with an incidence of 33% to 86%, the majority of which are rectal or tubo-ovarian cancers.^38,39 Consideration of the frequency and types of underlying carcinoma of respective sites of involvement can be helpful when ruling out secondary EMPD.

In both of our patients, palpable lymphadenopathy at the time of original diagnosis and histologic invasive disease on initial biopsy warranted thorough imaging and laboratory workup; there was no evidence of primary malignancy. Given the absence of an underlying carcinoma, both patients were classified as having metastatic primary EMPD.

Assessment of lymphadenopathy is an essential aspect of disease workup, as it is associated with a statistically higher rate of lymph node metastases. A study by Fujisawa et al²⁰ demonstrated that 80% of patients with lymphadenopathy had regional metastases compared to only 15% of patients without clinical lymphadenopathy. The presence of invasive disease also has been shown to correspond with lymph node metastases.⁴⁰ Ogata et al⁴⁰ showed that 0% of cases with in situ EMPD had a positive sentinel lymph node biopsy (SLNB) compared to 4% and 43% in cases that showed evidence of microinvasion and dermal invasion, respectively. Lymph node metastases are associated with poor prognosis, with increasingly worse prognosis when there are multiple lymph nodes affected.⁴¹ In our case series, patient 1 had lymphadenopathy and both patients had invasive EMPD; they both later developed metastases and died.

Lymphadenopathy should be further investigated with imaging and biopsy or fine-needle aspiration.⁴² Recent expert consensus guidelines recommended this method of investigation over routine use of SLNB, as there is no evidence that a positive SLNB affects treatment that changes disease-specific survival.²

Treatment of EMPD—Surgical excision of the primary lesion is the first-line treatment of EMPD,^1,2 which can be performed by wide local excision; however, studies have demonstrated higher recurrence-free survival with margin-controlled surgery (complete circumferential peripheral and deep margin assessment) or Mohs micrographic surgery (MMS), especially with CK7 immunostaining.^2,37,43 The literature on MMS of invasive EMPD is sparse, accounting for 57 patients.^25,37,44 Other reports describe management with surgical excision, wide local excision, regional resection, or vulvectomy, in addition to lymph node dissection, radiation therapy (RT), and/or chemotherapy.^{1-36,39,43-46} Despite the improved outcomes with MMS, the predominance of other surgical approaches in our search suggests that MMS may be currently underutilized for the treatment of invasive or locally advanced EMPD.

Among patients with unresectable disease or distant metastases, management includes RT with curative intent, chemotherapy, or a combination of both.^1,2 In our review, 267 cases were treated using RT and 77 with chemotherapy. Radiation therapy is an effective therapeutic option with a reported response rate of 62% to 100% and can be employed as either primary or adjuvant treatment.³ For patients with lymph node metastasis the combination of RT and lymph node dissection has been shown to have improved outcomes compared to lymph node dissection alone, with 1 study showing a 5-year survival of 75% for patients who received adjuvant RT compared to 0% for lymph node dissection alone.⁴⁵

There are currently no consensus guidelines on the best chemotherapeutic regimen for metastatic EMPD. Several regimens have been reported, including docetaxel monotherapy; low-dose 5-fluorouracil and cisplatin; combination chemotherapy FECOM (5-fluorouracil, epirubicin, carboplatin, vincristine, mitomycin); or combination therapy with cisplatin, epirubicin, and paclitaxel.¹

Prognosis of Metastatic EMPD—Because invasive and metastatic EMPD is rare, its natural history is hard to predict. Poor prognosis is associated with nodule formation, tumor thickness, perianal or vaginal involvement, lymphovascular invasion, nodal metastasis, and distant metastasis. The 5-year survival for metastatic EMPD has been reported to be less than 10%.⁴⁶ Our cases underscore the poor prognostic risk associated with metastatic EMPD.

For all cases of EMPD, close follow-up is warranted. Guidelines recommend physical examination with lymph node assessment every 3 to 6 months for 3 years and every 6 to 12 months for the subsequent 5 years.² Specific recommendations for follow-up in invasive disease have not yet been described, though the 20% probability of developing an internal malignancy within 5 years after diagnosis and poor prognostic outcomes associated with invasive and metastatic disease support the need for close monitoring.²

Conclusion

Although in situ EMPD often is a slow-growing tumor with good prognosis, invasive disease has high potential to behave aggressively with high morbidity and mortality. Increased awareness and prompt identification of invasive EMPD, expedited comprehensive workup, and early multidisciplinary management might impact patient outcomes.

Acknowledgment—The authors would like to thank Ellen Aaronson, MLIS, AHIP (Mayo Clinic Libraries [Jacksonville, FL]), for creating and conducting the narrative literature search in the MEDLINE database.

Extramammary Paget disease (EMPD) is a rare cutaneous malignancy typically seen in apocrine-rich areas, including the axillae and anogenital region. It presents as a slow-growing, erythematous patch or plaque that commonly is misdiagnosed as an infectious or inflammatory condition.^1,2 Primary EMPD occurs as a intraepithelial neoplasm, whereas secondary EMPD occurs due to epidermotropic metastases or direct extension of an underlying adenocarcinoma into the skin.¹ Most commonly, primary EMPD occurs in situ; however, when present, dermal invasion and metastases from the skin are associated with poorer outcomes.³ Given the rarity of metastatic disease, existing literature is limited to case reports and case series.

We present 2 patients with metastatic primary EMPD who had evidence of invasion on initial biopsy and died secondary to metastatic EMPD. We conducted a comprehensive review of the literature for invasive and metastatic EMPD to highlight key clinicopathologic features, treatment considerations, and the potential for rapid disease progression in cases of invasive EMPD.

Case Series

Patient 1—A 68-year-old White man with a history of breast cancer (in remission) presented to our clinic for further management of biopsy-proven scrotal EMPD. Prior to biopsy, he described a 6-month history of worsening scrotal rash treated with topical antifungals, oral antibiotics, and topical steroids due to presumed diagnosis of intertrigo, cellulitis, and dermatitis, respectively. Clinical examination showed indurated, erythematous, ulcerated plaques involving the bilateral groin, genitalia, and perineum (Figure 1). Skin biopsy confirmed a diagnosis of EMPD with both dermal and lymphovascular invasion. An immunohistochemical profile was positive for CK7 and carcinoembryonic antigen (CEA) and negative for CK20 (Figure 2).

At presentation, the patient had palpable lymphadenopathy and scrotal edema concerning for inguinal and iliac lymph node metastases. Workup for an underlying adenocarcinoma included computed tomography (CT) of the chest, abdomen, and pelvis; urologic consultation with cystoscopy; and a screening colonoscopy. The CT scan revealed multiple enlarged inguinal and external iliac lymph nodes. Fine-needle aspiration revealed CK7- and CEA-positive neoplastic cells consistent with metastatic EMPD. The patient was treated with 6 cycles of carboplatin-paclitaxel, palliative radiation therapy, and pembrolizumab with minimal response to treatment and development of osteolytic vertebral lesions concerning for disease progression. He died 1 year after the initial diagnosis secondary to the disease.

Patient 2—A 79-year-old White man presented for further management of an outside diagnosis of superficially invasive primary EMPD of the bilateral inguinal folds and scrotum that had been present for 5 months prior to biopsy and diagnosis. Clinical examination at initial presentation revealed erythematous patches of the bilateral inguinal folds and scrotum, as well as an erythematous scaling plaque in the right axilla. There was no palpable clinical lymphadenopathy. Biopsy of the axilla and groin were both consistent with invasive EMPD with positive staining for CK7 and negative staining for CK20 and CDX2. Workup for underlying adenocarcinoma with whole-body positron emission tomography/CT, mammography, esophagogastroduodenoscopy, serum CEA, colonoscopy, and cystoscopy were all negative for a metastatic adenocarcinoma. There was no imaging or clinical evidence of lymphadenopathy. Complete circumferential peripheral and deep-margin assessment was performed in a staged manner on both sites, and negative margins were obtained.

Surveillance imaging 6 months after surgery revealed suspicious hepatic lesions. Fine-needle aspiration of the hepatic lesions demonstrated positive staining for CK7 and negative staining for CK20, CDX2, prostate-specific antigen, and thyroid transcription factor 1, consistent with metastatic EMPD. Oncology recommended carboplatin and docetaxel or docetaxel monotherapy chemotherapy. The patient was further managed by an outside oncologist due to ease of travel but died secondary to the disease 15 months following the initial diagnosis.

Comment

Extramammary Paget disease is an uncommon cutaneous malignancy that manifests as pruritic erythematous plaques within apocrine-rich areas such as the genitalia, axillae, or anal region. It most commonly occurs in patients older than 65 years, with White women and Asian men being affected at disproportionately higher rates.^1,4 Delay in diagnosis is common, as EMPD can mimic other benign inflammatory or infectious conditions, including contact dermatitis, seborrheic dermatitis, tinea, candidiasis, and eczema.¹

Metastatic and multifocal cases of primary EMPD are especially rare. According to a search of PubMed articles indexed for MEDLINE published through December 2023 using the terms extramammary Paget disease, EMPD, neoplasm metastasis, invasive extramammary, and neoplasm invasiveness, we identified 5040 cases of invasive EMPD and 477 cases of metastatic EMPD.^5-37 Of the reports that disclosed patient demographic information, 3627 patients were female 1410 were male, and the mean age was 67 years. Sites of metastases included regional lymph nodes, liver, lungs, cervix, bladder, bone, brain, skin, kidney, and adrenal glands

Workup for EMPD—The initial steps for workup of EMPD include a thorough physical examination and lymph node assessment. A skin biopsy also should be performed for patients presenting with refractory, pruritic, and eczematous rashes in apocrine-rich areas to evaluate for EMPD.¹ Characterization of large and complex tumors is better achieved through multiple biopsies with particular focus on nodular or thickened areas, as these may indicate invasive disease.² Primary EMPD is characterized by pagetoid cells with abundant pale cytoplasm proliferating in a single-cell or nested pattern within the epidermis or dermis in invasive disease and often is accompanied by dermal lymphocytic inflammation.¹ Immunohistochemistry demonstrates positive staining for CEA, CK7, and CK8, with negative staining for indicators of secondary EMPD including CK20 and CDX2.^1,2

As part of the workup, it is critical to distinguish between primary disease and secondary EMPD.¹ Beyond skin and clinical lymph node examination, additional workup should be based on age-appropriate and location-directed malignant neoplasm screenings, including colonoscopy, cystoscopy, prostate examination, mammography, and Papanicolaou test. Advanced imaging such as CT, positron emission tomography, or magnetic resonance imaging can be used to assess for metastatic disease if internal malignant neoplasms are present on initial screening or clinical lymphadenopathy is identified.² Additionally, it can be helpful in the evaluation for nodal disease in cases of invasive EMPD.

The likelihood of associated underlying carcinomas varies depending on the site of involvement.^38,39 For example, vulvar involvement constitutes approximately 65% of EMPD cases, with 11% to 20% of cases being associated with underlying gastrointestinal or genitourinary carcinomas. Involvement of the male genitalia, as in our 2 patients, is rare, accounting for approximately 14% of cases, 11% of which are associated with prostate, testicular, and bladder carcinoma. Perianal involvement comprises 20% of EMPD cases and has the greatest risk for underlying malignancy with an incidence of 33% to 86%, the majority of which are rectal or tubo-ovarian cancers.^38,39 Consideration of the frequency and types of underlying carcinoma of respective sites of involvement can be helpful when ruling out secondary EMPD.

In both of our patients, palpable lymphadenopathy at the time of original diagnosis and histologic invasive disease on initial biopsy warranted thorough imaging and laboratory workup; there was no evidence of primary malignancy. Given the absence of an underlying carcinoma, both patients were classified as having metastatic primary EMPD.

Assessment of lymphadenopathy is an essential aspect of disease workup, as it is associated with a statistically higher rate of lymph node metastases. A study by Fujisawa et al²⁰ demonstrated that 80% of patients with lymphadenopathy had regional metastases compared to only 15% of patients without clinical lymphadenopathy. The presence of invasive disease also has been shown to correspond with lymph node metastases.⁴⁰ Ogata et al⁴⁰ showed that 0% of cases with in situ EMPD had a positive sentinel lymph node biopsy (SLNB) compared to 4% and 43% in cases that showed evidence of microinvasion and dermal invasion, respectively. Lymph node metastases are associated with poor prognosis, with increasingly worse prognosis when there are multiple lymph nodes affected.⁴¹ In our case series, patient 1 had lymphadenopathy and both patients had invasive EMPD; they both later developed metastases and died.

Lymphadenopathy should be further investigated with imaging and biopsy or fine-needle aspiration.⁴² Recent expert consensus guidelines recommended this method of investigation over routine use of SLNB, as there is no evidence that a positive SLNB affects treatment that changes disease-specific survival.²

Treatment of EMPD—Surgical excision of the primary lesion is the first-line treatment of EMPD,^1,2 which can be performed by wide local excision; however, studies have demonstrated higher recurrence-free survival with margin-controlled surgery (complete circumferential peripheral and deep margin assessment) or Mohs micrographic surgery (MMS), especially with CK7 immunostaining.^2,37,43 The literature on MMS of invasive EMPD is sparse, accounting for 57 patients.^25,37,44 Other reports describe management with surgical excision, wide local excision, regional resection, or vulvectomy, in addition to lymph node dissection, radiation therapy (RT), and/or chemotherapy.^{1-36,39,43-46} Despite the improved outcomes with MMS, the predominance of other surgical approaches in our search suggests that MMS may be currently underutilized for the treatment of invasive or locally advanced EMPD.

Among patients with unresectable disease or distant metastases, management includes RT with curative intent, chemotherapy, or a combination of both.^1,2 In our review, 267 cases were treated using RT and 77 with chemotherapy. Radiation therapy is an effective therapeutic option with a reported response rate of 62% to 100% and can be employed as either primary or adjuvant treatment.³ For patients with lymph node metastasis the combination of RT and lymph node dissection has been shown to have improved outcomes compared to lymph node dissection alone, with 1 study showing a 5-year survival of 75% for patients who received adjuvant RT compared to 0% for lymph node dissection alone.⁴⁵

There are currently no consensus guidelines on the best chemotherapeutic regimen for metastatic EMPD. Several regimens have been reported, including docetaxel monotherapy; low-dose 5-fluorouracil and cisplatin; combination chemotherapy FECOM (5-fluorouracil, epirubicin, carboplatin, vincristine, mitomycin); or combination therapy with cisplatin, epirubicin, and paclitaxel.¹

Prognosis of Metastatic EMPD—Because invasive and metastatic EMPD is rare, its natural history is hard to predict. Poor prognosis is associated with nodule formation, tumor thickness, perianal or vaginal involvement, lymphovascular invasion, nodal metastasis, and distant metastasis. The 5-year survival for metastatic EMPD has been reported to be less than 10%.⁴⁶ Our cases underscore the poor prognostic risk associated with metastatic EMPD.

For all cases of EMPD, close follow-up is warranted. Guidelines recommend physical examination with lymph node assessment every 3 to 6 months for 3 years and every 6 to 12 months for the subsequent 5 years.² Specific recommendations for follow-up in invasive disease have not yet been described, though the 20% probability of developing an internal malignancy within 5 years after diagnosis and poor prognostic outcomes associated with invasive and metastatic disease support the need for close monitoring.²

Conclusion

Although in situ EMPD often is a slow-growing tumor with good prognosis, invasive disease has high potential to behave aggressively with high morbidity and mortality. Increased awareness and prompt identification of invasive EMPD, expedited comprehensive workup, and early multidisciplinary management might impact patient outcomes.

Acknowledgment—The authors would like to thank Ellen Aaronson, MLIS, AHIP (Mayo Clinic Libraries [Jacksonville, FL]), for creating and conducting the narrative literature search in the MEDLINE database.

To the Editor:

Severe cutaneous adverse reactions (SCARs) are rare, life-threatening reactions that include acute generalized exanthematous pustulosis (AGEP), drug reaction with eosinophilia and systemic symptoms (DRESS), and Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN).¹ In addition to being associated with commonly implicated medications, SCARs also may occur in the setting of antineoplastic therapy.^2,3 Although ­antineoplastic-associated SCARs have been described, diagnosis can be difficult due to varying latency periods and atypical clinical features, such as those observed with BRAF inhibitor–related DRESS during immunotherapy.⁴ Severe cutaneous adverse reactions can increase morbidity and mortality in the oncologic patient population due to both the clinical sequelae from the cutaneous reaction and the potential to interrupt cancer treatment.

The aim of this study was to evaluate the clinical characteristics, outcomes, and impact on cancer treatment among patients diagnosed with a SCAR while receiving active therapy for malignancy. We conducted a retrospective chart review of electronic medical records at Yale New Haven Hospital (New Haven, Connecticut) from 2013 to 2023, identifying patients receiving antineoplastic therapy who were diagnosed with a SCAR. Cases were identified through a search of the electronic medical record performed by the joint data analytics team using the keywords DRESS, SJS, TEN, AGEP, and generalized bullous fixed drug eruption, along with spelling variations (both abbreviations and full terms), in addition to manual review by one of the authors (K.V.) of the inpatient dermatology consultation log and dermatopathology database. Only patients for whom an antineoplastic agent was identified as a high-probability culprit by the dermatology and/or oncology teams were included.

In total, 20 patients (11 female, 9 male) were identified as having an antineoplastic-associated SCAR. All patients had metastatic or advanced disease. We identified 2 (10%) cases of AGEP, 16 (80%) cases of DRESS, and 3 (15%) cases of SJS/TEN. One patient on immunotherapy had 2 distinct SCARs (AGEP, DRESS) at different time points. Table 1 describes patient and SCAR characteristics as well as impact on cancer treatment. The median (interquartile range [IQR]) latency period for AGEP was 7.5 (4-11) days. The median (IQR) latency period for 13 of the 16 (81%) DRESS cases was 14 (10-32) days. For 3 DRESS cases with a potential second-hit phenomenon in the setting of current or antecedent immunotherapy,⁵ the median (IQR) latency period was 122 (96-426) days for the immunotherapy drug and 28 (21-52) days for the drug culprit. The median (IQR) latency period for SJS/TEN was 23 (20-27) days.

Patients received treatment with combination systemic corticosteroids and topical corticosteroids in 13 (65%) cases, systemic corticosteroid monotherapy in 6 (30%) cases, or combination systemic corticosteroids and etanercept in 1 (5%) case. All patients experienced resolution of the SCAR and survived to hospital discharge. Most (17/20 [85%]) patients experienced interruption or discontinuation of cancer treatment. Table 2 describes the implicated antineoplastic therapies, which included chemotherapy (3 DRESS, 1 SJS/TEN), hormonal therapy (1 DRESS), immunotherapy (1 AGEP, 4 DRESS), and targeted therapy (1 AGEP, 8 DRESS, 2 SJS/TEN).

Limitations of this study include the retrospective study design, the small sample size, and the challenge of drug culprit identification in oncologic patients on multiple high-probability medications.

Though rare, SCARs can be encountered in patients on antineoplastic therapy with a wide range of drug culprits. In our cohort, SCARs occurred with various antineoplastic agents, including chemotherapy, hormonal therapy, immunotherapy, and targeted therapy. The most common antineoplastic-associated SCAR was DRESS, which had the widest latency period in the setting of a potential second-hit phenomenon with another drug culprit. Although we did not observe any cases of SJS/TEN in the immunotherapy category, it is important to consider progressive immunotherapy-related mucocutaneous eruption in the differential diagnosis. Fortunately, all patients survived to hospital discharge and experienced SCAR resolution with systemic treatment; however, most patients experienced interruption of cancer therapy, which has the potential to affect oncologic outcomes. This interruption is not uncommon, as rechallenge of an antineoplastic agent in patients with a therapy-related SCAR generally is not recommended. The awareness and prompt management of SCARs in a patient on treatment for malignancy are critical in order to minimize negative outcomes in this vulnerable patient population.

To the Editor:

Severe cutaneous adverse reactions (SCARs) are rare, life-threatening reactions that include acute generalized exanthematous pustulosis (AGEP), drug reaction with eosinophilia and systemic symptoms (DRESS), and Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN).¹ In addition to being associated with commonly implicated medications, SCARs also may occur in the setting of antineoplastic therapy.^2,3 Although ­antineoplastic-associated SCARs have been described, diagnosis can be difficult due to varying latency periods and atypical clinical features, such as those observed with BRAF inhibitor–related DRESS during immunotherapy.⁴ Severe cutaneous adverse reactions can increase morbidity and mortality in the oncologic patient population due to both the clinical sequelae from the cutaneous reaction and the potential to interrupt cancer treatment.

The aim of this study was to evaluate the clinical characteristics, outcomes, and impact on cancer treatment among patients diagnosed with a SCAR while receiving active therapy for malignancy. We conducted a retrospective chart review of electronic medical records at Yale New Haven Hospital (New Haven, Connecticut) from 2013 to 2023, identifying patients receiving antineoplastic therapy who were diagnosed with a SCAR. Cases were identified through a search of the electronic medical record performed by the joint data analytics team using the keywords DRESS, SJS, TEN, AGEP, and generalized bullous fixed drug eruption, along with spelling variations (both abbreviations and full terms), in addition to manual review by one of the authors (K.V.) of the inpatient dermatology consultation log and dermatopathology database. Only patients for whom an antineoplastic agent was identified as a high-probability culprit by the dermatology and/or oncology teams were included.

In total, 20 patients (11 female, 9 male) were identified as having an antineoplastic-associated SCAR. All patients had metastatic or advanced disease. We identified 2 (10%) cases of AGEP, 16 (80%) cases of DRESS, and 3 (15%) cases of SJS/TEN. One patient on immunotherapy had 2 distinct SCARs (AGEP, DRESS) at different time points. Table 1 describes patient and SCAR characteristics as well as impact on cancer treatment. The median (interquartile range [IQR]) latency period for AGEP was 7.5 (4-11) days. The median (IQR) latency period for 13 of the 16 (81%) DRESS cases was 14 (10-32) days. For 3 DRESS cases with a potential second-hit phenomenon in the setting of current or antecedent immunotherapy,⁵ the median (IQR) latency period was 122 (96-426) days for the immunotherapy drug and 28 (21-52) days for the drug culprit. The median (IQR) latency period for SJS/TEN was 23 (20-27) days.

Patients received treatment with combination systemic corticosteroids and topical corticosteroids in 13 (65%) cases, systemic corticosteroid monotherapy in 6 (30%) cases, or combination systemic corticosteroids and etanercept in 1 (5%) case. All patients experienced resolution of the SCAR and survived to hospital discharge. Most (17/20 [85%]) patients experienced interruption or discontinuation of cancer treatment. Table 2 describes the implicated antineoplastic therapies, which included chemotherapy (3 DRESS, 1 SJS/TEN), hormonal therapy (1 DRESS), immunotherapy (1 AGEP, 4 DRESS), and targeted therapy (1 AGEP, 8 DRESS, 2 SJS/TEN).

Limitations of this study include the retrospective study design, the small sample size, and the challenge of drug culprit identification in oncologic patients on multiple high-probability medications.

Though rare, SCARs can be encountered in patients on antineoplastic therapy with a wide range of drug culprits. In our cohort, SCARs occurred with various antineoplastic agents, including chemotherapy, hormonal therapy, immunotherapy, and targeted therapy. The most common antineoplastic-associated SCAR was DRESS, which had the widest latency period in the setting of a potential second-hit phenomenon with another drug culprit. Although we did not observe any cases of SJS/TEN in the immunotherapy category, it is important to consider progressive immunotherapy-related mucocutaneous eruption in the differential diagnosis. Fortunately, all patients survived to hospital discharge and experienced SCAR resolution with systemic treatment; however, most patients experienced interruption of cancer therapy, which has the potential to affect oncologic outcomes. This interruption is not uncommon, as rechallenge of an antineoplastic agent in patients with a therapy-related SCAR generally is not recommended. The awareness and prompt management of SCARs in a patient on treatment for malignancy are critical in order to minimize negative outcomes in this vulnerable patient population.

To the Editor:

Severe cutaneous adverse reactions (SCARs) are rare, life-threatening reactions that include acute generalized exanthematous pustulosis (AGEP), drug reaction with eosinophilia and systemic symptoms (DRESS), and Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN).¹ In addition to being associated with commonly implicated medications, SCARs also may occur in the setting of antineoplastic therapy.^2,3 Although ­antineoplastic-associated SCARs have been described, diagnosis can be difficult due to varying latency periods and atypical clinical features, such as those observed with BRAF inhibitor–related DRESS during immunotherapy.⁴ Severe cutaneous adverse reactions can increase morbidity and mortality in the oncologic patient population due to both the clinical sequelae from the cutaneous reaction and the potential to interrupt cancer treatment.

The aim of this study was to evaluate the clinical characteristics, outcomes, and impact on cancer treatment among patients diagnosed with a SCAR while receiving active therapy for malignancy. We conducted a retrospective chart review of electronic medical records at Yale New Haven Hospital (New Haven, Connecticut) from 2013 to 2023, identifying patients receiving antineoplastic therapy who were diagnosed with a SCAR. Cases were identified through a search of the electronic medical record performed by the joint data analytics team using the keywords DRESS, SJS, TEN, AGEP, and generalized bullous fixed drug eruption, along with spelling variations (both abbreviations and full terms), in addition to manual review by one of the authors (K.V.) of the inpatient dermatology consultation log and dermatopathology database. Only patients for whom an antineoplastic agent was identified as a high-probability culprit by the dermatology and/or oncology teams were included.

In total, 20 patients (11 female, 9 male) were identified as having an antineoplastic-associated SCAR. All patients had metastatic or advanced disease. We identified 2 (10%) cases of AGEP, 16 (80%) cases of DRESS, and 3 (15%) cases of SJS/TEN. One patient on immunotherapy had 2 distinct SCARs (AGEP, DRESS) at different time points. Table 1 describes patient and SCAR characteristics as well as impact on cancer treatment. The median (interquartile range [IQR]) latency period for AGEP was 7.5 (4-11) days. The median (IQR) latency period for 13 of the 16 (81%) DRESS cases was 14 (10-32) days. For 3 DRESS cases with a potential second-hit phenomenon in the setting of current or antecedent immunotherapy,⁵ the median (IQR) latency period was 122 (96-426) days for the immunotherapy drug and 28 (21-52) days for the drug culprit. The median (IQR) latency period for SJS/TEN was 23 (20-27) days.

Patients received treatment with combination systemic corticosteroids and topical corticosteroids in 13 (65%) cases, systemic corticosteroid monotherapy in 6 (30%) cases, or combination systemic corticosteroids and etanercept in 1 (5%) case. All patients experienced resolution of the SCAR and survived to hospital discharge. Most (17/20 [85%]) patients experienced interruption or discontinuation of cancer treatment. Table 2 describes the implicated antineoplastic therapies, which included chemotherapy (3 DRESS, 1 SJS/TEN), hormonal therapy (1 DRESS), immunotherapy (1 AGEP, 4 DRESS), and targeted therapy (1 AGEP, 8 DRESS, 2 SJS/TEN).

Limitations of this study include the retrospective study design, the small sample size, and the challenge of drug culprit identification in oncologic patients on multiple high-probability medications.

Though rare, SCARs can be encountered in patients on antineoplastic therapy with a wide range of drug culprits. In our cohort, SCARs occurred with various antineoplastic agents, including chemotherapy, hormonal therapy, immunotherapy, and targeted therapy. The most common antineoplastic-associated SCAR was DRESS, which had the widest latency period in the setting of a potential second-hit phenomenon with another drug culprit. Although we did not observe any cases of SJS/TEN in the immunotherapy category, it is important to consider progressive immunotherapy-related mucocutaneous eruption in the differential diagnosis. Fortunately, all patients survived to hospital discharge and experienced SCAR resolution with systemic treatment; however, most patients experienced interruption of cancer therapy, which has the potential to affect oncologic outcomes. This interruption is not uncommon, as rechallenge of an antineoplastic agent in patients with a therapy-related SCAR generally is not recommended. The awareness and prompt management of SCARs in a patient on treatment for malignancy are critical in order to minimize negative outcomes in this vulnerable patient population.

To the Editor:

At-home microcurrent facial devices have gained rapid popularity for cosmetic rejuvenation, promising improvements in skin tone, contour, and collagen production.¹ In particular, the post–COVID-19 era has seen a surge in at-home beauty practices driven by social media influence, with the global microcurrent facial market estimated at $372.9 million in 2022 and projected to grow at a compound annual growth rate of 7.3% through 2030.¹ Microcurrent devices deliver low-level electrical currents to the skin and underlying muscles. Given the limited exploration of the long-term safety, we aimed to collate existing data and identify trends in reports of adverse events (AEs) associated with these microcurrent devices.

On April 15, 2025, the US Food and Drug Administration’s Manufacturer and User Facility Device Experience (MAUDE) database was queried for medical device reports from January 1, 2013, through March 31, 2025, using product names and keywords including NuFACE, TheraFace, FOREO, and microcurrent device. Search terms were limited to brands for which complaint data existed in the MAUDE database at the time of query. To ensure accuracy, reports were manually reviewed to eliminate duplicates and irrelevant entries.

A total of 28 unique AE reports associated with at-home microcurrent devices were identified (eTable). The majority involved NuFACE devices (ie, NuFACE Trinity, NuFACE Mini, and NuFACE Trinity+)(NuFACE)(n=25), followed by the TheraFace PRO (Therabody, Inc)(n=2) and the FOREO BEAR (FOREO)(n=1). The most frequently documented AEs associated with the NuFACE devices included arrhythmia (7/25 [28%]), pain (6/25 [24%]), dizziness (4/25 [16%]), headache (4/25 [16%]), and inflammation (4/25 [16%]). There was 1 (4%) case of retinal detachment. The TheraFace PRO was associated with device overheating (2/2 [100%]), and the FOREO BEAR was associated with facial deformity/disfigurement (1/1 [100%]).

While microcurrent therapy is widely marketed to consumers through social media influencers and at-home beauty platforms,¹ randomized controlled trials (RCTs) evaluating AEs related to use of this technology are lacking, possibly due to nonstringent regulation of nonprescription cosmetic devices.² Contrary to our findings, RCTs of microcurrent devices have reported minimal or no AEs; for instance, an RCT evaluating 56 participants treated 5 times weekly for 12 weeks with a microcurrent device that was not included in our analysis reported only mild erythema in all experimental group participants.² In another RCT of 30 participants, 15 of whom were treated with a microcurrent device and 15 with placebo for 30 minutes once daily over a period of 10 days, no AEs were reported.³ A cohort analysis of 34 patients also provided preliminary evidence supporting the use of microcurrent therapy for chronic back and neck pain, beyond its cosmetic applications.⁴ Despite the lack of reported AEs in the literature, there is a notable absence of large-scale, rigorous studies on this topic.

Our analysis was subject to the limitations of the MAUDE database, in which reports of severe AEs are more likely to be reported than transient ones. Additionally, the small sample size and lack of a known denominator make it difficult to compare frequencies of AEs among different microcurrent tools. The products chosen for this study were the select few that reported complaint data, but there is a large existing market of devices that may be associated with AEs that have yet to be reported, potentially because of their novelty.

Our findings suggest that, despite their over-the-counter availability, microcurrent facial devices may carry major risks—particularly in at-home settings. While short-term studies have highlighted potential benefits, the small sample sizes and limited follow-up make it difficult to comprehensively characterize long-term safety risks. Among available studies on microcurrent beauty treatments, the longest follow-up was only 12 weeks.² Our findings support the need for further large-scale and longitudinal studies to evaluate both the efficacy and safety of at-home microcurrent therapy, especially with increasing consumer interest. The diversity of the products available adds to the challenge of broad safety guidelines, in addition to the lack of long-term clinical studies.

To the Editor:

At-home microcurrent facial devices have gained rapid popularity for cosmetic rejuvenation, promising improvements in skin tone, contour, and collagen production.¹ In particular, the post–COVID-19 era has seen a surge in at-home beauty practices driven by social media influence, with the global microcurrent facial market estimated at $372.9 million in 2022 and projected to grow at a compound annual growth rate of 7.3% through 2030.¹ Microcurrent devices deliver low-level electrical currents to the skin and underlying muscles. Given the limited exploration of the long-term safety, we aimed to collate existing data and identify trends in reports of adverse events (AEs) associated with these microcurrent devices.

On April 15, 2025, the US Food and Drug Administration’s Manufacturer and User Facility Device Experience (MAUDE) database was queried for medical device reports from January 1, 2013, through March 31, 2025, using product names and keywords including NuFACE, TheraFace, FOREO, and microcurrent device. Search terms were limited to brands for which complaint data existed in the MAUDE database at the time of query. To ensure accuracy, reports were manually reviewed to eliminate duplicates and irrelevant entries.

A total of 28 unique AE reports associated with at-home microcurrent devices were identified (eTable). The majority involved NuFACE devices (ie, NuFACE Trinity, NuFACE Mini, and NuFACE Trinity+)(NuFACE)(n=25), followed by the TheraFace PRO (Therabody, Inc)(n=2) and the FOREO BEAR (FOREO)(n=1). The most frequently documented AEs associated with the NuFACE devices included arrhythmia (7/25 [28%]), pain (6/25 [24%]), dizziness (4/25 [16%]), headache (4/25 [16%]), and inflammation (4/25 [16%]). There was 1 (4%) case of retinal detachment. The TheraFace PRO was associated with device overheating (2/2 [100%]), and the FOREO BEAR was associated with facial deformity/disfigurement (1/1 [100%]).

While microcurrent therapy is widely marketed to consumers through social media influencers and at-home beauty platforms,¹ randomized controlled trials (RCTs) evaluating AEs related to use of this technology are lacking, possibly due to nonstringent regulation of nonprescription cosmetic devices.² Contrary to our findings, RCTs of microcurrent devices have reported minimal or no AEs; for instance, an RCT evaluating 56 participants treated 5 times weekly for 12 weeks with a microcurrent device that was not included in our analysis reported only mild erythema in all experimental group participants.² In another RCT of 30 participants, 15 of whom were treated with a microcurrent device and 15 with placebo for 30 minutes once daily over a period of 10 days, no AEs were reported.³ A cohort analysis of 34 patients also provided preliminary evidence supporting the use of microcurrent therapy for chronic back and neck pain, beyond its cosmetic applications.⁴ Despite the lack of reported AEs in the literature, there is a notable absence of large-scale, rigorous studies on this topic.

Our analysis was subject to the limitations of the MAUDE database, in which reports of severe AEs are more likely to be reported than transient ones. Additionally, the small sample size and lack of a known denominator make it difficult to compare frequencies of AEs among different microcurrent tools. The products chosen for this study were the select few that reported complaint data, but there is a large existing market of devices that may be associated with AEs that have yet to be reported, potentially because of their novelty.

Our findings suggest that, despite their over-the-counter availability, microcurrent facial devices may carry major risks—particularly in at-home settings. While short-term studies have highlighted potential benefits, the small sample sizes and limited follow-up make it difficult to comprehensively characterize long-term safety risks. Among available studies on microcurrent beauty treatments, the longest follow-up was only 12 weeks.² Our findings support the need for further large-scale and longitudinal studies to evaluate both the efficacy and safety of at-home microcurrent therapy, especially with increasing consumer interest. The diversity of the products available adds to the challenge of broad safety guidelines, in addition to the lack of long-term clinical studies.

To the Editor:

At-home microcurrent facial devices have gained rapid popularity for cosmetic rejuvenation, promising improvements in skin tone, contour, and collagen production.¹ In particular, the post–COVID-19 era has seen a surge in at-home beauty practices driven by social media influence, with the global microcurrent facial market estimated at $372.9 million in 2022 and projected to grow at a compound annual growth rate of 7.3% through 2030.¹ Microcurrent devices deliver low-level electrical currents to the skin and underlying muscles. Given the limited exploration of the long-term safety, we aimed to collate existing data and identify trends in reports of adverse events (AEs) associated with these microcurrent devices.

On April 15, 2025, the US Food and Drug Administration’s Manufacturer and User Facility Device Experience (MAUDE) database was queried for medical device reports from January 1, 2013, through March 31, 2025, using product names and keywords including NuFACE, TheraFace, FOREO, and microcurrent device. Search terms were limited to brands for which complaint data existed in the MAUDE database at the time of query. To ensure accuracy, reports were manually reviewed to eliminate duplicates and irrelevant entries.

A total of 28 unique AE reports associated with at-home microcurrent devices were identified (eTable). The majority involved NuFACE devices (ie, NuFACE Trinity, NuFACE Mini, and NuFACE Trinity+)(NuFACE)(n=25), followed by the TheraFace PRO (Therabody, Inc)(n=2) and the FOREO BEAR (FOREO)(n=1). The most frequently documented AEs associated with the NuFACE devices included arrhythmia (7/25 [28%]), pain (6/25 [24%]), dizziness (4/25 [16%]), headache (4/25 [16%]), and inflammation (4/25 [16%]). There was 1 (4%) case of retinal detachment. The TheraFace PRO was associated with device overheating (2/2 [100%]), and the FOREO BEAR was associated with facial deformity/disfigurement (1/1 [100%]).

While microcurrent therapy is widely marketed to consumers through social media influencers and at-home beauty platforms,¹ randomized controlled trials (RCTs) evaluating AEs related to use of this technology are lacking, possibly due to nonstringent regulation of nonprescription cosmetic devices.² Contrary to our findings, RCTs of microcurrent devices have reported minimal or no AEs; for instance, an RCT evaluating 56 participants treated 5 times weekly for 12 weeks with a microcurrent device that was not included in our analysis reported only mild erythema in all experimental group participants.² In another RCT of 30 participants, 15 of whom were treated with a microcurrent device and 15 with placebo for 30 minutes once daily over a period of 10 days, no AEs were reported.³ A cohort analysis of 34 patients also provided preliminary evidence supporting the use of microcurrent therapy for chronic back and neck pain, beyond its cosmetic applications.⁴ Despite the lack of reported AEs in the literature, there is a notable absence of large-scale, rigorous studies on this topic.

Our analysis was subject to the limitations of the MAUDE database, in which reports of severe AEs are more likely to be reported than transient ones. Additionally, the small sample size and lack of a known denominator make it difficult to compare frequencies of AEs among different microcurrent tools. The products chosen for this study were the select few that reported complaint data, but there is a large existing market of devices that may be associated with AEs that have yet to be reported, potentially because of their novelty.

Our findings suggest that, despite their over-the-counter availability, microcurrent facial devices may carry major risks—particularly in at-home settings. While short-term studies have highlighted potential benefits, the small sample sizes and limited follow-up make it difficult to comprehensively characterize long-term safety risks. Among available studies on microcurrent beauty treatments, the longest follow-up was only 12 weeks.² Our findings support the need for further large-scale and longitudinal studies to evaluate both the efficacy and safety of at-home microcurrent therapy, especially with increasing consumer interest. The diversity of the products available adds to the challenge of broad safety guidelines, in addition to the lack of long-term clinical studies.

What evidence exists on the impact of systemic immunosuppressants, biologics, and small-molecule inhibitors on patch test sensitivity and specificity?

DR. ATWATER: Guidance on this topic recently was published by the North American Contact Dermatitis Group (NACDG) in the Journal of the American Academy of Dermatology in June 2025. The article outlined expert recommendations on whether systemic immunosuppressants, biologics, and small-molecule inhibitors should be held before patch testing, how long they should be withheld, and the maximum recommended doses that can be used during testing.

How can dermatologists perform patch testing or use alternative diagnostic strategies when systemic therapy cannot safely be withheld?

DR. ATWATER: When systemic therapy cannot safely be withheld and patch testing is needed for diagnostic purposes, I typically proceed with the understanding that there is risk of false-negative reactions. If the patient has dermatitis on systemic therapy, it suggests that an allergic response on patch testing is also possible. I generally follow the NACDG guidelines mentioned above, and I hold systemic medications during the week of testing, when possible. If the patient has diffuse dermatitis on systemic therapy and their skin is not clear enough to proceed, I prescribe a prednisone taper and patch test on 10 mg per day for the entire week of testing. In patients taking systemic medications, I typically consider doubtful (+/−) patch test reactions to be the equivalent of a positive (1+) reaction.

One alternative diagnostic strategy is to create a safe list that avoids common allergens and have the patient use only products on this list. If their skin clears with avoidance, it suggests that they may have a contact allergy, and you can proceed with patch testing.

In patients with a convincing history of contact dermatitis but a negative patch test, what are the most common causes of false negatives, and how do you distinguish those from true negatives?

DR. ATWATER: In this setting, the most common cause of a false-negative patch test is not testing the correct allergens. This may occur when too few allergens are tested or when relevant allergens are not tested. Other potential causes of false negatives are incorrect timing of allergen exposure and readings, inadequate allergen adherence, expired allergens, and testing with the incorrect vehicle or concentration of allergen. Some immunosuppressant medications also can cause a false-negative patch test. The only way to distinguish false negatives from true negatives is to be aware of these potential pitfalls and continuously work to avoid errors whenever possible.

What technical and practical factors most influence false negatives/positives, and what steps do you recommend to standardize and improve test yield?

DR. ATWATER: Not testing the correct allergens is a potential pitfall in patch testing. For example, when comparing the 35 allergens in the T.R.U.E. Test (thin layer rapid-use epicutaneous test) to the 80 allergens tested by the NACDG in 2021 to 2022, up to 48% of NACDG allergens are missed when testing with only the T.R.U.E. Test. This argues for comprehensive patch testing and testing of at least 80 to 90 allergens whenever possible. Another example is failure to test allergens relevant to occupational exposures, such as in the case of a hairdresser or nail technician. When patches are not applied for the correct period (48 hours) and the final reading isn’t completed in the recommended timeframe (96 to 168 hours), there is increased risk for false negatives and positives. Both false negatives and positives can occur if you complete your final reading too early, whereas false negatives may be more likely if you complete your final reading late. Poor allergen adherence, which can be caused by hair, sweat, poor tape application, water, and exercise, also can result in false negatives. Allergen concentration that is too low to elicit a reaction, as well as too little allergen placed into the chamber, also could increase the risk of false negatives. Too much allergen in the chamber or too high a concentration of the allergen can result in false positives.

Topical medications applied to the patch test site prior to or during patch testing, as well as phototherapy, sun exposure, intramuscular triamcinolone, immunosuppressants, biologics, and small-molecule inhibitors can suppress the immune response to allergen exposure.

To identify true positive patch test reactions, use side lighting and palpate the skin. Be aware of the appearance of irritant reactions, patch test reaction variants such as follicular reactions, and the poral reaction, which can be seen with cobalt. Strong knowledge of how to read patch test reactions will decrease your risk of false-positive and -negative reactions. Training and protocols are vital for standardization and accurate patch testing. We train our staff on the technicalities of patch testing and utilize patch test orders and checklists in our office. We take photos to confirm application sites and visually track reactions between visits. We also provide verbal and written patch test care instructions for our patients and reinforce instructions at each clinic visit.

What are your top practical tips for dermatologists to maximize diagnostic accuracy and patient safety?

DR. ATWATER: My first tip is to develop patch test protocols that are followed by staff and physicians—every time—for every patient. My second tip is to make sure you understand and are comfortable with the patch test process. There are several great patch test resources that can help, including Introduction to Patch Testing, a recently developed CME module in the AAD Learning Center (https://learning.aad.org/Listing/Introduction-to-Patch- Testing-20366). There also are patch test training courses and other resources offered by the American Contact Dermatitis Society (https://www.contactderm.org/).

What single guideline change would most improve patch testing?

DR. ATWATER: The single guideline change that would most improve the practice of patch testing is removal of payer limitations on the number of patches that can be applied per day. For many payers in the United States, this limit is 80 to 90 allergens, and it is sometimes lower. Limits on the number of allergens that can be applied per day may result in false-negative patch testing (when limits are applied), patient inconvenience (if testing is completed over 2 different application days), and insufficient reimbursement (if more allergens are tested than the limit allows).

What evidence exists on the impact of systemic immunosuppressants, biologics, and small-molecule inhibitors on patch test sensitivity and specificity?

DR. ATWATER: Guidance on this topic recently was published by the North American Contact Dermatitis Group (NACDG) in the Journal of the American Academy of Dermatology in June 2025. The article outlined expert recommendations on whether systemic immunosuppressants, biologics, and small-molecule inhibitors should be held before patch testing, how long they should be withheld, and the maximum recommended doses that can be used during testing.

How can dermatologists perform patch testing or use alternative diagnostic strategies when systemic therapy cannot safely be withheld?

DR. ATWATER: When systemic therapy cannot safely be withheld and patch testing is needed for diagnostic purposes, I typically proceed with the understanding that there is risk of false-negative reactions. If the patient has dermatitis on systemic therapy, it suggests that an allergic response on patch testing is also possible. I generally follow the NACDG guidelines mentioned above, and I hold systemic medications during the week of testing, when possible. If the patient has diffuse dermatitis on systemic therapy and their skin is not clear enough to proceed, I prescribe a prednisone taper and patch test on 10 mg per day for the entire week of testing. In patients taking systemic medications, I typically consider doubtful (+/−) patch test reactions to be the equivalent of a positive (1+) reaction.

One alternative diagnostic strategy is to create a safe list that avoids common allergens and have the patient use only products on this list. If their skin clears with avoidance, it suggests that they may have a contact allergy, and you can proceed with patch testing.

In patients with a convincing history of contact dermatitis but a negative patch test, what are the most common causes of false negatives, and how do you distinguish those from true negatives?

DR. ATWATER: In this setting, the most common cause of a false-negative patch test is not testing the correct allergens. This may occur when too few allergens are tested or when relevant allergens are not tested. Other potential causes of false negatives are incorrect timing of allergen exposure and readings, inadequate allergen adherence, expired allergens, and testing with the incorrect vehicle or concentration of allergen. Some immunosuppressant medications also can cause a false-negative patch test. The only way to distinguish false negatives from true negatives is to be aware of these potential pitfalls and continuously work to avoid errors whenever possible.

What technical and practical factors most influence false negatives/positives, and what steps do you recommend to standardize and improve test yield?

DR. ATWATER: Not testing the correct allergens is a potential pitfall in patch testing. For example, when comparing the 35 allergens in the T.R.U.E. Test (thin layer rapid-use epicutaneous test) to the 80 allergens tested by the NACDG in 2021 to 2022, up to 48% of NACDG allergens are missed when testing with only the T.R.U.E. Test. This argues for comprehensive patch testing and testing of at least 80 to 90 allergens whenever possible. Another example is failure to test allergens relevant to occupational exposures, such as in the case of a hairdresser or nail technician. When patches are not applied for the correct period (48 hours) and the final reading isn’t completed in the recommended timeframe (96 to 168 hours), there is increased risk for false negatives and positives. Both false negatives and positives can occur if you complete your final reading too early, whereas false negatives may be more likely if you complete your final reading late. Poor allergen adherence, which can be caused by hair, sweat, poor tape application, water, and exercise, also can result in false negatives. Allergen concentration that is too low to elicit a reaction, as well as too little allergen placed into the chamber, also could increase the risk of false negatives. Too much allergen in the chamber or too high a concentration of the allergen can result in false positives.

Topical medications applied to the patch test site prior to or during patch testing, as well as phototherapy, sun exposure, intramuscular triamcinolone, immunosuppressants, biologics, and small-molecule inhibitors can suppress the immune response to allergen exposure.

To identify true positive patch test reactions, use side lighting and palpate the skin. Be aware of the appearance of irritant reactions, patch test reaction variants such as follicular reactions, and the poral reaction, which can be seen with cobalt. Strong knowledge of how to read patch test reactions will decrease your risk of false-positive and -negative reactions. Training and protocols are vital for standardization and accurate patch testing. We train our staff on the technicalities of patch testing and utilize patch test orders and checklists in our office. We take photos to confirm application sites and visually track reactions between visits. We also provide verbal and written patch test care instructions for our patients and reinforce instructions at each clinic visit.

What are your top practical tips for dermatologists to maximize diagnostic accuracy and patient safety?

DR. ATWATER: My first tip is to develop patch test protocols that are followed by staff and physicians—every time—for every patient. My second tip is to make sure you understand and are comfortable with the patch test process. There are several great patch test resources that can help, including Introduction to Patch Testing, a recently developed CME module in the AAD Learning Center (https://learning.aad.org/Listing/Introduction-to-Patch- Testing-20366). There also are patch test training courses and other resources offered by the American Contact Dermatitis Society (https://www.contactderm.org/).

What single guideline change would most improve patch testing?

DR. ATWATER: The single guideline change that would most improve the practice of patch testing is removal of payer limitations on the number of patches that can be applied per day. For many payers in the United States, this limit is 80 to 90 allergens, and it is sometimes lower. Limits on the number of allergens that can be applied per day may result in false-negative patch testing (when limits are applied), patient inconvenience (if testing is completed over 2 different application days), and insufficient reimbursement (if more allergens are tested than the limit allows).

What evidence exists on the impact of systemic immunosuppressants, biologics, and small-molecule inhibitors on patch test sensitivity and specificity?

DR. ATWATER: Guidance on this topic recently was published by the North American Contact Dermatitis Group (NACDG) in the Journal of the American Academy of Dermatology in June 2025. The article outlined expert recommendations on whether systemic immunosuppressants, biologics, and small-molecule inhibitors should be held before patch testing, how long they should be withheld, and the maximum recommended doses that can be used during testing.

How can dermatologists perform patch testing or use alternative diagnostic strategies when systemic therapy cannot safely be withheld?

DR. ATWATER: When systemic therapy cannot safely be withheld and patch testing is needed for diagnostic purposes, I typically proceed with the understanding that there is risk of false-negative reactions. If the patient has dermatitis on systemic therapy, it suggests that an allergic response on patch testing is also possible. I generally follow the NACDG guidelines mentioned above, and I hold systemic medications during the week of testing, when possible. If the patient has diffuse dermatitis on systemic therapy and their skin is not clear enough to proceed, I prescribe a prednisone taper and patch test on 10 mg per day for the entire week of testing. In patients taking systemic medications, I typically consider doubtful (+/−) patch test reactions to be the equivalent of a positive (1+) reaction.

One alternative diagnostic strategy is to create a safe list that avoids common allergens and have the patient use only products on this list. If their skin clears with avoidance, it suggests that they may have a contact allergy, and you can proceed with patch testing.

In patients with a convincing history of contact dermatitis but a negative patch test, what are the most common causes of false negatives, and how do you distinguish those from true negatives?

DR. ATWATER: In this setting, the most common cause of a false-negative patch test is not testing the correct allergens. This may occur when too few allergens are tested or when relevant allergens are not tested. Other potential causes of false negatives are incorrect timing of allergen exposure and readings, inadequate allergen adherence, expired allergens, and testing with the incorrect vehicle or concentration of allergen. Some immunosuppressant medications also can cause a false-negative patch test. The only way to distinguish false negatives from true negatives is to be aware of these potential pitfalls and continuously work to avoid errors whenever possible.

What technical and practical factors most influence false negatives/positives, and what steps do you recommend to standardize and improve test yield?

DR. ATWATER: Not testing the correct allergens is a potential pitfall in patch testing. For example, when comparing the 35 allergens in the T.R.U.E. Test (thin layer rapid-use epicutaneous test) to the 80 allergens tested by the NACDG in 2021 to 2022, up to 48% of NACDG allergens are missed when testing with only the T.R.U.E. Test. This argues for comprehensive patch testing and testing of at least 80 to 90 allergens whenever possible. Another example is failure to test allergens relevant to occupational exposures, such as in the case of a hairdresser or nail technician. When patches are not applied for the correct period (48 hours) and the final reading isn’t completed in the recommended timeframe (96 to 168 hours), there is increased risk for false negatives and positives. Both false negatives and positives can occur if you complete your final reading too early, whereas false negatives may be more likely if you complete your final reading late. Poor allergen adherence, which can be caused by hair, sweat, poor tape application, water, and exercise, also can result in false negatives. Allergen concentration that is too low to elicit a reaction, as well as too little allergen placed into the chamber, also could increase the risk of false negatives. Too much allergen in the chamber or too high a concentration of the allergen can result in false positives.

Topical medications applied to the patch test site prior to or during patch testing, as well as phototherapy, sun exposure, intramuscular triamcinolone, immunosuppressants, biologics, and small-molecule inhibitors can suppress the immune response to allergen exposure.

To identify true positive patch test reactions, use side lighting and palpate the skin. Be aware of the appearance of irritant reactions, patch test reaction variants such as follicular reactions, and the poral reaction, which can be seen with cobalt. Strong knowledge of how to read patch test reactions will decrease your risk of false-positive and -negative reactions. Training and protocols are vital for standardization and accurate patch testing. We train our staff on the technicalities of patch testing and utilize patch test orders and checklists in our office. We take photos to confirm application sites and visually track reactions between visits. We also provide verbal and written patch test care instructions for our patients and reinforce instructions at each clinic visit.

What are your top practical tips for dermatologists to maximize diagnostic accuracy and patient safety?

DR. ATWATER: My first tip is to develop patch test protocols that are followed by staff and physicians—every time—for every patient. My second tip is to make sure you understand and are comfortable with the patch test process. There are several great patch test resources that can help, including Introduction to Patch Testing, a recently developed CME module in the AAD Learning Center (https://learning.aad.org/Listing/Introduction-to-Patch- Testing-20366). There also are patch test training courses and other resources offered by the American Contact Dermatitis Society (https://www.contactderm.org/).

What single guideline change would most improve patch testing?

DR. ATWATER: The single guideline change that would most improve the practice of patch testing is removal of payer limitations on the number of patches that can be applied per day. For many payers in the United States, this limit is 80 to 90 allergens, and it is sometimes lower. Limits on the number of allergens that can be applied per day may result in false-negative patch testing (when limits are applied), patient inconvenience (if testing is completed over 2 different application days), and insufficient reimbursement (if more allergens are tested than the limit allows).

Practice Gap

If not cared for properly, epidermal suture knots can cause discomfort, skin irritation, and an increased risk for infection. There is limited guidance on a simple adaptable method to reduce tram-track marks from epidermal sutures exerting pressure on the epidermis while still facilitating healing in dermatologic procedures such as excision of cysts or lipomas. We present a hybrid suture method that combines elements of traditional simple interrupted and retention sutures with a layer of sterile, absorbent rolled gauze or a dental roll placed beneath the suture knots.

The Technique

Traditional epidermal sutures concentrate pressure at the knot, increasing the risk for tram-track marks and patient discomfort. To address this, we developed a hybrid technique combining simple interrupted sutures with a sterile dental roll beneath the knots to reduce pressure, protect the wound, and promote comfortable wound healing.

After excision of a cyst, we approximated the wound edges with buried vertical mattress sutures for eversion (a set-back buried dermal suture also may be used). The sutures initially were placed loosely but were left untied (eFigure 1A). A sterile dental roll with sterile petrolatum on the underside was positioned over the wound before the knots were secured, similar to a bolster dressing (eFigures 1B and 1C). The dressing then was covered and left in place for 24 to 48 hours. After removal of the dressing, no bandage was needed because the wound was clean and hemostatic and the dental roll had absorbed minimal drainage and protected the incision edges during the initial healing period. The patient applied petrolatum daily to prevent the dental roll from drying out. Sutures and the bolster were removed at 14 days without complications or complaints.

Rolled gauze may be used as an alternative to the dental roll. To maintain a clean surgical field, nonsterile gauze may be soaked in a disinfectant (eg, alcohol) and wrung out to remove excess moisture before placement on the skin. The side of the gauze in contact with the skin also should be lubricated with petroleum jelly to prevent sticking. If the sutures slip during knot tying, one end can be secured with a needle driver or hemostat. Patients should be advised to keep the dental roll dry to prevent maceration and promote optimal wound healing, but minor dampness is permissible if followed by air-drying.

This suturing method is most suitable for low- to moderate-tension closures such as cyst or lipoma excisions. The serosanguinous drainage can be absorbed by the gauze or dental roll while pressure is simultaneously applied to the wound. We do not recommend this technique for high-tension wounds in which large surface areas are removed (eg, skin cancer excisions on the posterior shoulder that require wide margins). Close monitoring of the wound for dehiscence is needed. As the sutures stretch and swelling decreases, the pressure is distributed accordingly without excessive compression to the wound line. Depending on the location, the sutures and dental roll can be removed in 7 to 14 days.

Practice Implications

Placing a dental roll or rolled gauze beneath suture knots can prevent tram-track scarring by eliminating direct knot-to-skin contact (eFigure 2).^1,2 This technique distributes tension evenly, reduces the risk for wound edge necrosis, and absorbs serosanguinous drainage while providing hemostasis. The modification is quick, inexpensive, and especially beneficial for patients who may struggle with complex wound care, maintaining a clean environment until sutures are removed.

Practice Gap

If not cared for properly, epidermal suture knots can cause discomfort, skin irritation, and an increased risk for infection. There is limited guidance on a simple adaptable method to reduce tram-track marks from epidermal sutures exerting pressure on the epidermis while still facilitating healing in dermatologic procedures such as excision of cysts or lipomas. We present a hybrid suture method that combines elements of traditional simple interrupted and retention sutures with a layer of sterile, absorbent rolled gauze or a dental roll placed beneath the suture knots.

The Technique

Traditional epidermal sutures concentrate pressure at the knot, increasing the risk for tram-track marks and patient discomfort. To address this, we developed a hybrid technique combining simple interrupted sutures with a sterile dental roll beneath the knots to reduce pressure, protect the wound, and promote comfortable wound healing.

After excision of a cyst, we approximated the wound edges with buried vertical mattress sutures for eversion (a set-back buried dermal suture also may be used). The sutures initially were placed loosely but were left untied (eFigure 1A). A sterile dental roll with sterile petrolatum on the underside was positioned over the wound before the knots were secured, similar to a bolster dressing (eFigures 1B and 1C). The dressing then was covered and left in place for 24 to 48 hours. After removal of the dressing, no bandage was needed because the wound was clean and hemostatic and the dental roll had absorbed minimal drainage and protected the incision edges during the initial healing period. The patient applied petrolatum daily to prevent the dental roll from drying out. Sutures and the bolster were removed at 14 days without complications or complaints.

Rolled gauze may be used as an alternative to the dental roll. To maintain a clean surgical field, nonsterile gauze may be soaked in a disinfectant (eg, alcohol) and wrung out to remove excess moisture before placement on the skin. The side of the gauze in contact with the skin also should be lubricated with petroleum jelly to prevent sticking. If the sutures slip during knot tying, one end can be secured with a needle driver or hemostat. Patients should be advised to keep the dental roll dry to prevent maceration and promote optimal wound healing, but minor dampness is permissible if followed by air-drying.

This suturing method is most suitable for low- to moderate-tension closures such as cyst or lipoma excisions. The serosanguinous drainage can be absorbed by the gauze or dental roll while pressure is simultaneously applied to the wound. We do not recommend this technique for high-tension wounds in which large surface areas are removed (eg, skin cancer excisions on the posterior shoulder that require wide margins). Close monitoring of the wound for dehiscence is needed. As the sutures stretch and swelling decreases, the pressure is distributed accordingly without excessive compression to the wound line. Depending on the location, the sutures and dental roll can be removed in 7 to 14 days.

Practice Implications

Placing a dental roll or rolled gauze beneath suture knots can prevent tram-track scarring by eliminating direct knot-to-skin contact (eFigure 2).^1,2 This technique distributes tension evenly, reduces the risk for wound edge necrosis, and absorbs serosanguinous drainage while providing hemostasis. The modification is quick, inexpensive, and especially beneficial for patients who may struggle with complex wound care, maintaining a clean environment until sutures are removed.

Practice Gap

If not cared for properly, epidermal suture knots can cause discomfort, skin irritation, and an increased risk for infection. There is limited guidance on a simple adaptable method to reduce tram-track marks from epidermal sutures exerting pressure on the epidermis while still facilitating healing in dermatologic procedures such as excision of cysts or lipomas. We present a hybrid suture method that combines elements of traditional simple interrupted and retention sutures with a layer of sterile, absorbent rolled gauze or a dental roll placed beneath the suture knots.

The Technique

Traditional epidermal sutures concentrate pressure at the knot, increasing the risk for tram-track marks and patient discomfort. To address this, we developed a hybrid technique combining simple interrupted sutures with a sterile dental roll beneath the knots to reduce pressure, protect the wound, and promote comfortable wound healing.

After excision of a cyst, we approximated the wound edges with buried vertical mattress sutures for eversion (a set-back buried dermal suture also may be used). The sutures initially were placed loosely but were left untied (eFigure 1A). A sterile dental roll with sterile petrolatum on the underside was positioned over the wound before the knots were secured, similar to a bolster dressing (eFigures 1B and 1C). The dressing then was covered and left in place for 24 to 48 hours. After removal of the dressing, no bandage was needed because the wound was clean and hemostatic and the dental roll had absorbed minimal drainage and protected the incision edges during the initial healing period. The patient applied petrolatum daily to prevent the dental roll from drying out. Sutures and the bolster were removed at 14 days without complications or complaints.

Rolled gauze may be used as an alternative to the dental roll. To maintain a clean surgical field, nonsterile gauze may be soaked in a disinfectant (eg, alcohol) and wrung out to remove excess moisture before placement on the skin. The side of the gauze in contact with the skin also should be lubricated with petroleum jelly to prevent sticking. If the sutures slip during knot tying, one end can be secured with a needle driver or hemostat. Patients should be advised to keep the dental roll dry to prevent maceration and promote optimal wound healing, but minor dampness is permissible if followed by air-drying.

This suturing method is most suitable for low- to moderate-tension closures such as cyst or lipoma excisions. The serosanguinous drainage can be absorbed by the gauze or dental roll while pressure is simultaneously applied to the wound. We do not recommend this technique for high-tension wounds in which large surface areas are removed (eg, skin cancer excisions on the posterior shoulder that require wide margins). Close monitoring of the wound for dehiscence is needed. As the sutures stretch and swelling decreases, the pressure is distributed accordingly without excessive compression to the wound line. Depending on the location, the sutures and dental roll can be removed in 7 to 14 days.

Practice Implications

Placing a dental roll or rolled gauze beneath suture knots can prevent tram-track scarring by eliminating direct knot-to-skin contact (eFigure 2).^1,2 This technique distributes tension evenly, reduces the risk for wound edge necrosis, and absorbs serosanguinous drainage while providing hemostasis. The modification is quick, inexpensive, and especially beneficial for patients who may struggle with complex wound care, maintaining a clean environment until sutures are removed.

Infectious diseases historically have posed major challenges to the operations and health of military forces. In recent conflicts, nonbattle injuries including infections have caused more evacuations than combat trauma.¹ Deployment to endemic regions, poor sanitation, and trauma increase susceptibility to both common and rare infections, many of which have cutaneous manifestations.

Surveillance programs such as the Armed Forces Health Surveillance Division serve a critical role in monitoring outbreaks among deployed personnel.² Cutaneous manifestations of systemic disease often serve as early clinical indicators, especially in settings with limited diagnostic resources. This review describes rarely encountered infectious agents for which US military personnel are at increased risk and outlines management strategies for clinicians practicing in austere environments.

EPIDEMIOLOGIC RISK FACTORS IN MILITARY POPULATIONS

United States military personnel face an elevated risk for infectious diseases when deployed in tropical and subtropical regions where endemic pathogens are prevalent. Exposure to soil, water, and insect vectors facilitates transmission. Direct exposure during combat or training combined with high-density housing, combat-related trauma, and constraints on hygiene access during operations increases infection risk.³

REGION-SPECIFIC PATHOGENS

Middle East

Leishmania species—Leishmania, a protozoa transmitted via sand fly bites, has caused multiple documented outbreaks among US troops in Iraq and Afghanistan, with a reported incidence of 14%.⁴ Leishmaniasis can present as 3 main clinical variants: cutaneous, visceral, and mucocutaneous. Cutaneous leishmaniasis typically manifests as painless ulcers covered with hemorrhagic crusts on exposed regions of the body. While typically self-limited, lesions frequently result in irreversible scarring. Many Leishmania species respond well to antimonials such as sodium stibogluconate. Preventive measures include wearing protective clothing and sleeping inside insecticide-treated bed nets.⁵

Coxiella burnetii—Coxiella burnetii transmits through inhalation of aerosolized particles originating from the urine, feces, birth products, or milk of infected bovine. In 2003, a small number of cases were identified in US service members exposed to livestock while serving in Iraq.⁶ Outbreaks also occurred during World War II, but it is unclear whether they were caused by naturally occurring C burnetii or biowarfare.⁷ Though primarily a systemic illness with severe pneumonia, Q fever may manifest with an associated purpuric or morbilliform rash.⁸ Doxycycline is recommended both for treatment and empiric coverage.⁶

Acinetobacter baumannii—This multidrug-resistant organism is known to infect combat wounds and is associated with nosocomial outbreaks in military hospitals. Studies suggest environmental contamination and health care transmission contribute substantially to outbreaks in military hospitals.⁹ Cutaneous manifestations can include cellulitis with a peau d’orange appearance or necrotizing fasciitis; however, pneumonia and bacteremia have been reported. Prompt culture and antibiotic initiation with debridement are essential for treatment.¹⁰ Antibiotic stewardship and strict infection control are critical to prevent outbreaks and limit resistance.⁹

Africa

Plasmodium species—Malaria remains a life-threatening disease found in tropical and subtropical areas around the world. Despite preventive measures, 30 cases among US service members were reported in 2024.¹¹ Cutaneous findings include purpura fulminans, petechiae, acral necrosis, or reticulated erythema.¹² Service members stationed in endemic areas should take prophylactic antimalarials. Symptoms include fevers, headaches, and malaise, with possible rapid deterioration.¹³

Mycobacterium ulcerans—Mycobacterium ulcerans causes extensive necrotic ulcers—commonly known as Buruli ulcers—which generally begin as a nodule, plaque, papule, or edematous lesion, eventually progressing to extensive ulceration. Despite no documented cases of US personnel contracting Buruli ulcers, those stationed in endemic regions remain at risk. Environmental reservoirs of M ulcerans are unknown, but its DNA has been isolated from water sources.^14,15 These ulcers take months to heal, making wound management and antimycobacterial therapy essential. Primary preventive measures include avoidance of swimming in rivers or agricultural work in endemic areas.¹⁴

Mpox Virus—During the 2022 mpox outbreak, male service members who engaged in sexual activity with other men were at the highest risk, with 88.8% of infected service members reporting this practice.¹⁶ While the virus is endemic to Africa, 89.0% of cases were reported from service members stationed in the United States.¹⁷ Typical infection results in fever, headache, lymphadenopathy, and myalgias, followed by a facial rash that spreads over the body, palms, and soles. Safe-sex practices help prevent transmission, and there is a vaccine available for high-risk patients.¹⁶

Southeast Asia

Leptospira species—Leptospira is an aerobic spirochete found in tropical regions worldwide. Transmission occurs when water contaminated with urine from infected animals exposes humans to the organism. Infection manifests as a mild febrile illness, though approximately 10% of patients develop Weil syndrome, consisting of conjunctival suffusion, jaundice, and acute kidney injury. Treatment and prophylaxis include doxycycline, but severe disease warrants intravenous antibiotics.^17,18 A 2014 outbreak among Marines in Japan highlighted poor prophylactic compliance as a key risk factor.¹⁹ Proper education for those at risk is essential to prevent future outbreaks.

Mycobacterium leprae—Leprosy is an acid-fast mycobacterium that remains endemic in the Pacific Islands and Southeast Asia. Case reports of US service members diagnosed with leprosy exist, though only in patients who emigrated from endemic areas.²⁰ This disease has a spectrum of manifestations depending on the immune response, with tuberculoid leprosy showing a ­cell-mediated (T helper 1) response and lepromatous leprosy having more of a humoral (T helper 2) response.²¹ It manifests with hypopigmented anesthetic macules and peripheral neuropathy. Diagnosis is made by skin biopsy, which shows perineural lymphohistiocytic inflammation and non-necrotizing granulomas.²⁰ The infection typically is curable with a multidrug regimen.²¹

Strongyloides stercoralis—This nematode causes infection by transdermal penetration of bare feet. They then migrate to the lungs where the patient coughs and swallows the nematode into the gastrointestinal tract. Strongyloides stercoralis autoinfect by penetrating the intestinal wall, resulting in chronic digestive, respiratory, and cutaneous symptoms. Worldwide prevalence of S stercoralis infection is estimated to be 10% to 40%, with foreign-born US military members at increased risk compared to the general military population.^22,23 Larva currens may manifest with a pruritic erythematous plaque at the site of penetration that progresses to an intensely pruritic, creeping dermatitis as the nematode migrates under the skin. Avoidance of barefoot soil exposure and treatment with ivermectin are effective preventive and therapeutic measures.²³

South America

Ancylostoma braziliense—Found throughout the subtropical world, this hookworm primarily infects dogs and cats and is found in their stool. Larva currens has a similar manifestation and life cycle to cutaneous larva migrans, but autoinfection does not occur. Transmission occurs similarly to S stercoralis and responds well to oral albendazole or ivermectin; however, the infection is self-limited.²⁴ Military cases have been reported,²⁵ though overall morbidity remains poorly characterized.

Dengue Virus—An arbovirus transmitted by Aedes mosquitoes, dengue remains a major military threat. Service members in the Vietnam War experienced an attack rate as high as 80%.^26,27 Infection often manifests with retro-orbital pain and a morbilliform rash that occurs 2 to 5 days after fever, though severe cases may progress to hemorrhagic dengue with skin petechiae or ecchymosis.²⁸ Immediate intervention is essential in symptomatic patients to prevent life-threatening progression. There are no dengue vaccines approved by the US Food and Drug Administration for adults, thus military personnel in endemic areas remain at risk.²⁷

Trypanosoma cruzi—Chagas disease is transmitted when a reduviid infected with T cruzi bites and defecates on the patient’s skin. A skin nodule (chagoma) or painless eyelid edema (Romaña sign) may appear at the site of parasite entry. Chronic disease may result in dilated cardiomyopathy.²⁹ Several cases of Chagas disease have been reported in South American military operations, including an outbreak in 9 Columbian military personnel.³⁰ Cases in the southwestern United States have recently emerged, emphasizing the need for increased awareness.³¹ Proper insect repellent helps to ward off reduviid bugs. Nifurtimox and benznidazole are the only drugs with proven efficacy against T cruzi.²⁹

Continental United States of America

Coccidioides immitis—The first reported case of coccidiomycosis was described in 1892 in a service member with debilitating masses and ulcers.³² Endemic to arid regions of the western United States, coccidioidomycosis affects military trainees at rates up to 32% annually in high-risk settings.³³ Primary infection occurs in the lungs and may spread hematologically. The fungi prefer dry desert soils, which may aerosolize during military maneuvers. Coccidioidomycosis occasionally causes erythema nodosum, and diffuse infection shows verrucous plaques, ulcers, or abscesses. Dust avoidance and mask wearing are advised for those in endemic regions. Ketoconazole and amphotericin B are the only treatments approved by the US Food and Drug Administration.³² When starting immunosuppressive drugs, clinicians should inquire if patients have previously been stationed in Coccidioides-endemic areas, such as Fort Irwin, California, to avoid reactivation of the fungi.³³

Francisella tularensis—Acquired via ticks or contact with wild animals, tularemia causes an ulceroglandular disease with regional lymphadenopathy. Inoculation requires as few as 10 to 25 organisms; thus it is considered a Category A agent for bioterror.³⁴ Natural outbreaks have occurred during war times, most recently during the civil wars in Bosnia and Kosovo.³⁵ Patients may present with a painful ulcer that enlarges to form a plaque with raised borders. Personnel in wooded areas should use tick precautions and handle wild animals cautiously. Treatment includes gentamicin for severe disease, with tetracyclines effective in mild cases.³⁴

PREVENTION AND MANAGEMENT STRATEGIES IN AUSTERE SETTINGS

For health care professionals practicing in military settings, austere environments can provide a challenge for diagnosis of neglected diseases. Despite a lack of advanced diagnostic tools, practical options can be applied to the diagnostic process; for example, teledermatology is utilized for treatment of service members deployed to remote environments.³⁶

Management of uncommon infectious diseases in military personnel often requires treatments outside those practiced in domestic clinics. Field management may indicate prompt empiric therapy while balancing the risks of overtreatment against those of missed diagnoses³⁷; however, medical evacuation to a higher level of care may be indicated in patients with severe presentations to expedite diagnosis and treatment.³⁸

Prevention remains the primary goal to avoid local outbreaks. Long-sleeved uniforms, DEET (N, ­N-diethyl-meta-toluamide)–based repellents, permethrin-impregnated clothing, and bed nets are effective for vector protection. Prophylactic medications and vaccinations often are provided when personnel are deployed to endemic locations.³⁹

Onsite entomology teams also can provide surveillance of the local insect populations. They may contribute to vector control through insecticide application and environmental modification. The Armed Forces Health Surveillance Division and the Global Emerging Infections Surveillance Program monitor infectious threats in real time to locate any potential outbreaks, guiding operational responses.⁴⁰

FINAL THOUGHTS

Dermatologic signs often provide early evidence of infection in military personnel. With increasing antimicrobial resistance and the emergence of new pathogens, it is imperative for clinicians treating members of the military to recognize cutaneous signs, employ efficient diagnostic strategies, and encourage proactive prevention. A collaborative approach spanning dermatology, infectious disease, and public health is essential to protect the modern service member.

Infectious diseases historically have posed major challenges to the operations and health of military forces. In recent conflicts, nonbattle injuries including infections have caused more evacuations than combat trauma.¹ Deployment to endemic regions, poor sanitation, and trauma increase susceptibility to both common and rare infections, many of which have cutaneous manifestations.

Surveillance programs such as the Armed Forces Health Surveillance Division serve a critical role in monitoring outbreaks among deployed personnel.² Cutaneous manifestations of systemic disease often serve as early clinical indicators, especially in settings with limited diagnostic resources. This review describes rarely encountered infectious agents for which US military personnel are at increased risk and outlines management strategies for clinicians practicing in austere environments.

EPIDEMIOLOGIC RISK FACTORS IN MILITARY POPULATIONS

United States military personnel face an elevated risk for infectious diseases when deployed in tropical and subtropical regions where endemic pathogens are prevalent. Exposure to soil, water, and insect vectors facilitates transmission. Direct exposure during combat or training combined with high-density housing, combat-related trauma, and constraints on hygiene access during operations increases infection risk.³

REGION-SPECIFIC PATHOGENS

Middle East

Leishmania species—Leishmania, a protozoa transmitted via sand fly bites, has caused multiple documented outbreaks among US troops in Iraq and Afghanistan, with a reported incidence of 14%.⁴ Leishmaniasis can present as 3 main clinical variants: cutaneous, visceral, and mucocutaneous. Cutaneous leishmaniasis typically manifests as painless ulcers covered with hemorrhagic crusts on exposed regions of the body. While typically self-limited, lesions frequently result in irreversible scarring. Many Leishmania species respond well to antimonials such as sodium stibogluconate. Preventive measures include wearing protective clothing and sleeping inside insecticide-treated bed nets.⁵

Coxiella burnetii—Coxiella burnetii transmits through inhalation of aerosolized particles originating from the urine, feces, birth products, or milk of infected bovine. In 2003, a small number of cases were identified in US service members exposed to livestock while serving in Iraq.⁶ Outbreaks also occurred during World War II, but it is unclear whether they were caused by naturally occurring C burnetii or biowarfare.⁷ Though primarily a systemic illness with severe pneumonia, Q fever may manifest with an associated purpuric or morbilliform rash.⁸ Doxycycline is recommended both for treatment and empiric coverage.⁶

Acinetobacter baumannii—This multidrug-resistant organism is known to infect combat wounds and is associated with nosocomial outbreaks in military hospitals. Studies suggest environmental contamination and health care transmission contribute substantially to outbreaks in military hospitals.⁹ Cutaneous manifestations can include cellulitis with a peau d’orange appearance or necrotizing fasciitis; however, pneumonia and bacteremia have been reported. Prompt culture and antibiotic initiation with debridement are essential for treatment.¹⁰ Antibiotic stewardship and strict infection control are critical to prevent outbreaks and limit resistance.⁹

Africa

Plasmodium species—Malaria remains a life-threatening disease found in tropical and subtropical areas around the world. Despite preventive measures, 30 cases among US service members were reported in 2024.¹¹ Cutaneous findings include purpura fulminans, petechiae, acral necrosis, or reticulated erythema.¹² Service members stationed in endemic areas should take prophylactic antimalarials. Symptoms include fevers, headaches, and malaise, with possible rapid deterioration.¹³

Mycobacterium ulcerans—Mycobacterium ulcerans causes extensive necrotic ulcers—commonly known as Buruli ulcers—which generally begin as a nodule, plaque, papule, or edematous lesion, eventually progressing to extensive ulceration. Despite no documented cases of US personnel contracting Buruli ulcers, those stationed in endemic regions remain at risk. Environmental reservoirs of M ulcerans are unknown, but its DNA has been isolated from water sources.^14,15 These ulcers take months to heal, making wound management and antimycobacterial therapy essential. Primary preventive measures include avoidance of swimming in rivers or agricultural work in endemic areas.¹⁴

Mpox Virus—During the 2022 mpox outbreak, male service members who engaged in sexual activity with other men were at the highest risk, with 88.8% of infected service members reporting this practice.¹⁶ While the virus is endemic to Africa, 89.0% of cases were reported from service members stationed in the United States.¹⁷ Typical infection results in fever, headache, lymphadenopathy, and myalgias, followed by a facial rash that spreads over the body, palms, and soles. Safe-sex practices help prevent transmission, and there is a vaccine available for high-risk patients.¹⁶

Southeast Asia

Leptospira species—Leptospira is an aerobic spirochete found in tropical regions worldwide. Transmission occurs when water contaminated with urine from infected animals exposes humans to the organism. Infection manifests as a mild febrile illness, though approximately 10% of patients develop Weil syndrome, consisting of conjunctival suffusion, jaundice, and acute kidney injury. Treatment and prophylaxis include doxycycline, but severe disease warrants intravenous antibiotics.^17,18 A 2014 outbreak among Marines in Japan highlighted poor prophylactic compliance as a key risk factor.¹⁹ Proper education for those at risk is essential to prevent future outbreaks.

Mycobacterium leprae—Leprosy is an acid-fast mycobacterium that remains endemic in the Pacific Islands and Southeast Asia. Case reports of US service members diagnosed with leprosy exist, though only in patients who emigrated from endemic areas.²⁰ This disease has a spectrum of manifestations depending on the immune response, with tuberculoid leprosy showing a ­cell-mediated (T helper 1) response and lepromatous leprosy having more of a humoral (T helper 2) response.²¹ It manifests with hypopigmented anesthetic macules and peripheral neuropathy. Diagnosis is made by skin biopsy, which shows perineural lymphohistiocytic inflammation and non-necrotizing granulomas.²⁰ The infection typically is curable with a multidrug regimen.²¹

Strongyloides stercoralis—This nematode causes infection by transdermal penetration of bare feet. They then migrate to the lungs where the patient coughs and swallows the nematode into the gastrointestinal tract. Strongyloides stercoralis autoinfect by penetrating the intestinal wall, resulting in chronic digestive, respiratory, and cutaneous symptoms. Worldwide prevalence of S stercoralis infection is estimated to be 10% to 40%, with foreign-born US military members at increased risk compared to the general military population.^22,23 Larva currens may manifest with a pruritic erythematous plaque at the site of penetration that progresses to an intensely pruritic, creeping dermatitis as the nematode migrates under the skin. Avoidance of barefoot soil exposure and treatment with ivermectin are effective preventive and therapeutic measures.²³

South America

Ancylostoma braziliense—Found throughout the subtropical world, this hookworm primarily infects dogs and cats and is found in their stool. Larva currens has a similar manifestation and life cycle to cutaneous larva migrans, but autoinfection does not occur. Transmission occurs similarly to S stercoralis and responds well to oral albendazole or ivermectin; however, the infection is self-limited.²⁴ Military cases have been reported,²⁵ though overall morbidity remains poorly characterized.

Dengue Virus—An arbovirus transmitted by Aedes mosquitoes, dengue remains a major military threat. Service members in the Vietnam War experienced an attack rate as high as 80%.^26,27 Infection often manifests with retro-orbital pain and a morbilliform rash that occurs 2 to 5 days after fever, though severe cases may progress to hemorrhagic dengue with skin petechiae or ecchymosis.²⁸ Immediate intervention is essential in symptomatic patients to prevent life-threatening progression. There are no dengue vaccines approved by the US Food and Drug Administration for adults, thus military personnel in endemic areas remain at risk.²⁷

Trypanosoma cruzi—Chagas disease is transmitted when a reduviid infected with T cruzi bites and defecates on the patient’s skin. A skin nodule (chagoma) or painless eyelid edema (Romaña sign) may appear at the site of parasite entry. Chronic disease may result in dilated cardiomyopathy.²⁹ Several cases of Chagas disease have been reported in South American military operations, including an outbreak in 9 Columbian military personnel.³⁰ Cases in the southwestern United States have recently emerged, emphasizing the need for increased awareness.³¹ Proper insect repellent helps to ward off reduviid bugs. Nifurtimox and benznidazole are the only drugs with proven efficacy against T cruzi.²⁹

Continental United States of America

Coccidioides immitis—The first reported case of coccidiomycosis was described in 1892 in a service member with debilitating masses and ulcers.³² Endemic to arid regions of the western United States, coccidioidomycosis affects military trainees at rates up to 32% annually in high-risk settings.³³ Primary infection occurs in the lungs and may spread hematologically. The fungi prefer dry desert soils, which may aerosolize during military maneuvers. Coccidioidomycosis occasionally causes erythema nodosum, and diffuse infection shows verrucous plaques, ulcers, or abscesses. Dust avoidance and mask wearing are advised for those in endemic regions. Ketoconazole and amphotericin B are the only treatments approved by the US Food and Drug Administration.³² When starting immunosuppressive drugs, clinicians should inquire if patients have previously been stationed in Coccidioides-endemic areas, such as Fort Irwin, California, to avoid reactivation of the fungi.³³

Francisella tularensis—Acquired via ticks or contact with wild animals, tularemia causes an ulceroglandular disease with regional lymphadenopathy. Inoculation requires as few as 10 to 25 organisms; thus it is considered a Category A agent for bioterror.³⁴ Natural outbreaks have occurred during war times, most recently during the civil wars in Bosnia and Kosovo.³⁵ Patients may present with a painful ulcer that enlarges to form a plaque with raised borders. Personnel in wooded areas should use tick precautions and handle wild animals cautiously. Treatment includes gentamicin for severe disease, with tetracyclines effective in mild cases.³⁴

PREVENTION AND MANAGEMENT STRATEGIES IN AUSTERE SETTINGS

For health care professionals practicing in military settings, austere environments can provide a challenge for diagnosis of neglected diseases. Despite a lack of advanced diagnostic tools, practical options can be applied to the diagnostic process; for example, teledermatology is utilized for treatment of service members deployed to remote environments.³⁶

Management of uncommon infectious diseases in military personnel often requires treatments outside those practiced in domestic clinics. Field management may indicate prompt empiric therapy while balancing the risks of overtreatment against those of missed diagnoses³⁷; however, medical evacuation to a higher level of care may be indicated in patients with severe presentations to expedite diagnosis and treatment.³⁸

Prevention remains the primary goal to avoid local outbreaks. Long-sleeved uniforms, DEET (N, ­N-diethyl-meta-toluamide)–based repellents, permethrin-impregnated clothing, and bed nets are effective for vector protection. Prophylactic medications and vaccinations often are provided when personnel are deployed to endemic locations.³⁹

Onsite entomology teams also can provide surveillance of the local insect populations. They may contribute to vector control through insecticide application and environmental modification. The Armed Forces Health Surveillance Division and the Global Emerging Infections Surveillance Program monitor infectious threats in real time to locate any potential outbreaks, guiding operational responses.⁴⁰

FINAL THOUGHTS

Dermatologic signs often provide early evidence of infection in military personnel. With increasing antimicrobial resistance and the emergence of new pathogens, it is imperative for clinicians treating members of the military to recognize cutaneous signs, employ efficient diagnostic strategies, and encourage proactive prevention. A collaborative approach spanning dermatology, infectious disease, and public health is essential to protect the modern service member.

Infectious diseases historically have posed major challenges to the operations and health of military forces. In recent conflicts, nonbattle injuries including infections have caused more evacuations than combat trauma.¹ Deployment to endemic regions, poor sanitation, and trauma increase susceptibility to both common and rare infections, many of which have cutaneous manifestations.

Surveillance programs such as the Armed Forces Health Surveillance Division serve a critical role in monitoring outbreaks among deployed personnel.² Cutaneous manifestations of systemic disease often serve as early clinical indicators, especially in settings with limited diagnostic resources. This review describes rarely encountered infectious agents for which US military personnel are at increased risk and outlines management strategies for clinicians practicing in austere environments.

EPIDEMIOLOGIC RISK FACTORS IN MILITARY POPULATIONS

United States military personnel face an elevated risk for infectious diseases when deployed in tropical and subtropical regions where endemic pathogens are prevalent. Exposure to soil, water, and insect vectors facilitates transmission. Direct exposure during combat or training combined with high-density housing, combat-related trauma, and constraints on hygiene access during operations increases infection risk.³

REGION-SPECIFIC PATHOGENS

Middle East

Leishmania species—Leishmania, a protozoa transmitted via sand fly bites, has caused multiple documented outbreaks among US troops in Iraq and Afghanistan, with a reported incidence of 14%.⁴ Leishmaniasis can present as 3 main clinical variants: cutaneous, visceral, and mucocutaneous. Cutaneous leishmaniasis typically manifests as painless ulcers covered with hemorrhagic crusts on exposed regions of the body. While typically self-limited, lesions frequently result in irreversible scarring. Many Leishmania species respond well to antimonials such as sodium stibogluconate. Preventive measures include wearing protective clothing and sleeping inside insecticide-treated bed nets.⁵

Coxiella burnetii—Coxiella burnetii transmits through inhalation of aerosolized particles originating from the urine, feces, birth products, or milk of infected bovine. In 2003, a small number of cases were identified in US service members exposed to livestock while serving in Iraq.⁶ Outbreaks also occurred during World War II, but it is unclear whether they were caused by naturally occurring C burnetii or biowarfare.⁷ Though primarily a systemic illness with severe pneumonia, Q fever may manifest with an associated purpuric or morbilliform rash.⁸ Doxycycline is recommended both for treatment and empiric coverage.⁶

Acinetobacter baumannii—This multidrug-resistant organism is known to infect combat wounds and is associated with nosocomial outbreaks in military hospitals. Studies suggest environmental contamination and health care transmission contribute substantially to outbreaks in military hospitals.⁹ Cutaneous manifestations can include cellulitis with a peau d’orange appearance or necrotizing fasciitis; however, pneumonia and bacteremia have been reported. Prompt culture and antibiotic initiation with debridement are essential for treatment.¹⁰ Antibiotic stewardship and strict infection control are critical to prevent outbreaks and limit resistance.⁹

Africa

Plasmodium species—Malaria remains a life-threatening disease found in tropical and subtropical areas around the world. Despite preventive measures, 30 cases among US service members were reported in 2024.¹¹ Cutaneous findings include purpura fulminans, petechiae, acral necrosis, or reticulated erythema.¹² Service members stationed in endemic areas should take prophylactic antimalarials. Symptoms include fevers, headaches, and malaise, with possible rapid deterioration.¹³

Mycobacterium ulcerans—Mycobacterium ulcerans causes extensive necrotic ulcers—commonly known as Buruli ulcers—which generally begin as a nodule, plaque, papule, or edematous lesion, eventually progressing to extensive ulceration. Despite no documented cases of US personnel contracting Buruli ulcers, those stationed in endemic regions remain at risk. Environmental reservoirs of M ulcerans are unknown, but its DNA has been isolated from water sources.^14,15 These ulcers take months to heal, making wound management and antimycobacterial therapy essential. Primary preventive measures include avoidance of swimming in rivers or agricultural work in endemic areas.¹⁴

Mpox Virus—During the 2022 mpox outbreak, male service members who engaged in sexual activity with other men were at the highest risk, with 88.8% of infected service members reporting this practice.¹⁶ While the virus is endemic to Africa, 89.0% of cases were reported from service members stationed in the United States.¹⁷ Typical infection results in fever, headache, lymphadenopathy, and myalgias, followed by a facial rash that spreads over the body, palms, and soles. Safe-sex practices help prevent transmission, and there is a vaccine available for high-risk patients.¹⁶

Southeast Asia

Leptospira species—Leptospira is an aerobic spirochete found in tropical regions worldwide. Transmission occurs when water contaminated with urine from infected animals exposes humans to the organism. Infection manifests as a mild febrile illness, though approximately 10% of patients develop Weil syndrome, consisting of conjunctival suffusion, jaundice, and acute kidney injury. Treatment and prophylaxis include doxycycline, but severe disease warrants intravenous antibiotics.^17,18 A 2014 outbreak among Marines in Japan highlighted poor prophylactic compliance as a key risk factor.¹⁹ Proper education for those at risk is essential to prevent future outbreaks.

Mycobacterium leprae—Leprosy is an acid-fast mycobacterium that remains endemic in the Pacific Islands and Southeast Asia. Case reports of US service members diagnosed with leprosy exist, though only in patients who emigrated from endemic areas.²⁰ This disease has a spectrum of manifestations depending on the immune response, with tuberculoid leprosy showing a ­cell-mediated (T helper 1) response and lepromatous leprosy having more of a humoral (T helper 2) response.²¹ It manifests with hypopigmented anesthetic macules and peripheral neuropathy. Diagnosis is made by skin biopsy, which shows perineural lymphohistiocytic inflammation and non-necrotizing granulomas.²⁰ The infection typically is curable with a multidrug regimen.²¹

Strongyloides stercoralis—This nematode causes infection by transdermal penetration of bare feet. They then migrate to the lungs where the patient coughs and swallows the nematode into the gastrointestinal tract. Strongyloides stercoralis autoinfect by penetrating the intestinal wall, resulting in chronic digestive, respiratory, and cutaneous symptoms. Worldwide prevalence of S stercoralis infection is estimated to be 10% to 40%, with foreign-born US military members at increased risk compared to the general military population.^22,23 Larva currens may manifest with a pruritic erythematous plaque at the site of penetration that progresses to an intensely pruritic, creeping dermatitis as the nematode migrates under the skin. Avoidance of barefoot soil exposure and treatment with ivermectin are effective preventive and therapeutic measures.²³

South America

Ancylostoma braziliense—Found throughout the subtropical world, this hookworm primarily infects dogs and cats and is found in their stool. Larva currens has a similar manifestation and life cycle to cutaneous larva migrans, but autoinfection does not occur. Transmission occurs similarly to S stercoralis and responds well to oral albendazole or ivermectin; however, the infection is self-limited.²⁴ Military cases have been reported,²⁵ though overall morbidity remains poorly characterized.

Dengue Virus—An arbovirus transmitted by Aedes mosquitoes, dengue remains a major military threat. Service members in the Vietnam War experienced an attack rate as high as 80%.^26,27 Infection often manifests with retro-orbital pain and a morbilliform rash that occurs 2 to 5 days after fever, though severe cases may progress to hemorrhagic dengue with skin petechiae or ecchymosis.²⁸ Immediate intervention is essential in symptomatic patients to prevent life-threatening progression. There are no dengue vaccines approved by the US Food and Drug Administration for adults, thus military personnel in endemic areas remain at risk.²⁷

Trypanosoma cruzi—Chagas disease is transmitted when a reduviid infected with T cruzi bites and defecates on the patient’s skin. A skin nodule (chagoma) or painless eyelid edema (Romaña sign) may appear at the site of parasite entry. Chronic disease may result in dilated cardiomyopathy.²⁹ Several cases of Chagas disease have been reported in South American military operations, including an outbreak in 9 Columbian military personnel.³⁰ Cases in the southwestern United States have recently emerged, emphasizing the need for increased awareness.³¹ Proper insect repellent helps to ward off reduviid bugs. Nifurtimox and benznidazole are the only drugs with proven efficacy against T cruzi.²⁹

Continental United States of America

Coccidioides immitis—The first reported case of coccidiomycosis was described in 1892 in a service member with debilitating masses and ulcers.³² Endemic to arid regions of the western United States, coccidioidomycosis affects military trainees at rates up to 32% annually in high-risk settings.³³ Primary infection occurs in the lungs and may spread hematologically. The fungi prefer dry desert soils, which may aerosolize during military maneuvers. Coccidioidomycosis occasionally causes erythema nodosum, and diffuse infection shows verrucous plaques, ulcers, or abscesses. Dust avoidance and mask wearing are advised for those in endemic regions. Ketoconazole and amphotericin B are the only treatments approved by the US Food and Drug Administration.³² When starting immunosuppressive drugs, clinicians should inquire if patients have previously been stationed in Coccidioides-endemic areas, such as Fort Irwin, California, to avoid reactivation of the fungi.³³

Francisella tularensis—Acquired via ticks or contact with wild animals, tularemia causes an ulceroglandular disease with regional lymphadenopathy. Inoculation requires as few as 10 to 25 organisms; thus it is considered a Category A agent for bioterror.³⁴ Natural outbreaks have occurred during war times, most recently during the civil wars in Bosnia and Kosovo.³⁵ Patients may present with a painful ulcer that enlarges to form a plaque with raised borders. Personnel in wooded areas should use tick precautions and handle wild animals cautiously. Treatment includes gentamicin for severe disease, with tetracyclines effective in mild cases.³⁴

PREVENTION AND MANAGEMENT STRATEGIES IN AUSTERE SETTINGS

For health care professionals practicing in military settings, austere environments can provide a challenge for diagnosis of neglected diseases. Despite a lack of advanced diagnostic tools, practical options can be applied to the diagnostic process; for example, teledermatology is utilized for treatment of service members deployed to remote environments.³⁶

Management of uncommon infectious diseases in military personnel often requires treatments outside those practiced in domestic clinics. Field management may indicate prompt empiric therapy while balancing the risks of overtreatment against those of missed diagnoses³⁷; however, medical evacuation to a higher level of care may be indicated in patients with severe presentations to expedite diagnosis and treatment.³⁸

Prevention remains the primary goal to avoid local outbreaks. Long-sleeved uniforms, DEET (N, ­N-diethyl-meta-toluamide)–based repellents, permethrin-impregnated clothing, and bed nets are effective for vector protection. Prophylactic medications and vaccinations often are provided when personnel are deployed to endemic locations.³⁹

Onsite entomology teams also can provide surveillance of the local insect populations. They may contribute to vector control through insecticide application and environmental modification. The Armed Forces Health Surveillance Division and the Global Emerging Infections Surveillance Program monitor infectious threats in real time to locate any potential outbreaks, guiding operational responses.⁴⁰

FINAL THOUGHTS

Dermatologic signs often provide early evidence of infection in military personnel. With increasing antimicrobial resistance and the emergence of new pathogens, it is imperative for clinicians treating members of the military to recognize cutaneous signs, employ efficient diagnostic strategies, and encourage proactive prevention. A collaborative approach spanning dermatology, infectious disease, and public health is essential to protect the modern service member.

THE DIAGNOSIS: Plexiform Palisaded Encapsulated Neuroma

Microscopically, there was a superficial to deep dermal proliferation of tapered spindle cells in fascicles that were well circumscribed in nodules throughout the dermis with pale background stroma, mild mucin, and a thin capsule. The tapered spindle cells stained positive for SOX-10 and negative for Melan-A (Figure 1A). Staining for epithelial membrane antigen highlighted delicate cells around the periphery of the nodules, consistent with perineurium (Figure 1B). A diagnosis of plexiform palisaded encapsulated neuroma was made. No additional treatment was pursued due to the benign nature of the condition.

Palisaded encapsulated neuroma (PEN), also referred to as solitary circumscribed neuroma,¹ is a benign, generally solitary neurogenic tumor that manifests predominantly on the skin, particularly in areas of frequent outside trauma such as the face. Lesions also may occur on mucosal and acral sites.² First described by Reed et al³ in 1972, PEN characteristically manifests as a well-circumscribed, dermal nodule with a distinctive palisading pattern of Schwann cells and axons within a delicate perineurial capsule, the latter of which may be incomplete.³ Palisaded encapsulated neuroma frequently exhibits clefting between the tumor and the surrounding dermis. While PEN generally is sporadic, rare cases have been reported in association with Cowden syndrome and neurofibromatosis type 2.^4,5

While the nodular growth pattern is most common, PEN also may present in epithelioid, plexiform, multinodular, or fungating subtypes.⁶ The plexiform subtype of PEN is rare. It has a complex growth pattern and a tendency to involve multiple adjacent nerve bundles in a plexiform arrangement.^6,7 In two independent reviews characterizing the predominant growth patterns of PEN, nonnodular growth patterns were observed in a minority of the 85 cases: 18.8% (16/85) were plexiform, 7.1% (6/85) were multinodular or multilobular, and 7.1% (6/85) were fungating.^6,7

The clinical presentation of plexiform PEN often includes a painless, slow-growing mass, and it predominantly occurs in middle-aged adults.² Immunohistochemical staining reveals diffuse positivity for SOX-10 and S-100, which highlights the neural origin of the tumor.⁶ This variant, like conventional PEN, lacks notable atypia or mitotic activity.

Palisaded encapsulated neuroma, regardless of subtype, has an excellent prognosis, with no known cases of malignant transformation, and surgical excision with clear margins is curative.⁸

The differential diagnosis for plexiform PEN includes plexiform variants of neurofibroma and schwannoma, traumatic neuroma, and malignant peripheral nerve sheath tumor.

Neurofibromas are nonencapsulated lesions composed of spindle cells with wavy nuclei dispersed in a myxoid background.⁸ Neurofibromas can manifest in various locations throughout the body, including the skin, subcutaneous tissues, and internal organs. They are slow-growing tumors but may accelerate during periods of hormonal changes, such as pregnancy and puberty, or in cases of malignant transformation.⁸ Although plexiform neurofibromas are benign, malignant transformation can occur, particularly in patients with neurofibromatosis type 1 (NF1).^8,9 Neurofibromas may assume one of 3 growth patterns: localized, diffuse, or plexiform.⁸ Plexiform neurofibromas exhibit a multinodular, ropelike growth pattern with a mix of Schwann cells and fibroblasts (Figure 2).^8,9 These lesions are pathognomonic for NF1 and can infiltrate the surrounding tissue. They may involve large nerve trunks, leading to a more complex growth pattern compared to solitary neurofibromas.^8,9 The plexiform variants of both neurofibromas and PEN demonstrate a multinodular growth pattern; however, plexiform neurofibromas are nonencapsulated and show a more diffuse infiltrative nature, whereas plexiform PEN remains well circumscribed. Additionally, plexiform neurofibromas are associated with NF1, while plexiform PEN lacks this genetic association.

Schwannomas are encapsulated tumors that originate from the outer sheath of peripheral nerves, usually positioned eccentrically to the nerve fibers. Schwannomas are characterized by Antoni A and Antoni B areas, which usually are absent in PEN. Antoni A areas are composed of compact spindle cells arranged in palisades with Verocay bodies, while Antoni B areas are more loosely arranged and have a myxoid background (Figure 3).^8,9 Schwannomas stain positive for S-100 and often show degenerative changes such as cystic degeneration or calcification, particularly in larger lesions.^8,9 Plexiform schwannoma is a rare variant of schwannoma, and while it carries a substantial risk for local recurrence with rates as high as 50%, it has not been shown to possess malignant or metastatic potential.¹⁰ Unlike PEN, schwannomas have a consistent capsule but share S-100 positivity with PEN. Verocay bodies occasionally can be observed in PENs, with studies reporting their presence in 20% to 36% of cases.^7,11,12 Additionally, some schwannomas may exhibit few Verocay bodies or poorly developed forms, which can make histopathologic distinction more challenging.^7,11,12

Traumatic neuromas result from nerve regeneration following any type of outside trauma that is deep enough to cause nerve injury. The lesion often is painful and associated with prior trauma or surgery. Under optimal conditions, the severed ends of a nerve reconnect through the orderly growth of axons from the proximal stump to the distal stump, guided by tubes formed by proliferating Schwann cells. If the nerve ends are not properly aligned or if the distal stump is absent, the axons may proliferate in a disorganized manner at the proximal stump, resulting in the formation of a traumatic neuroma.⁸ Histologically, these lesions exhibit disorganized, proliferating nerve fibers intermixed with fibrous stroma.^8,13 The nerve fibers are not encapsulated, and there is an irregular arrangement of axons and Schwann cells (Figure 4).^8,13 Unlike PEN, which usually is encapsulated and well organized with fascicular architecture, traumatic neuromas exhibit a disorganized, haphazard arrangement of neural elements and lack a capsule.⁸ Clinically, traumatic neuromas also are more likely to be painful.

Malignant peripheral nerve sheath tumors are aggressive malignant spindle-cell tumors that may be associated with NF1 or occur sporadically.^9,14 The spindle cells are arranged in fascicles, and these tumors can have areas of necrosis, hemorrhage, and high mitotic activity.^9,15 The spindle cells may be arranged in a herringbone pattern, and alternating areas of hypocellularity and hypercellularity impart a marbled appearance (Figure 5).¹⁶ Malignant peripheral nerve sheath tumors frequently exhibit inactivation of the SWI/SNF-related, matrix- associated, actin-dependent regulator of chromatin subfamily B member 1 gene and loss of integrase interactor 1 protein. Transformation from plexiform neurofibroma to malignant peripheral nerve sheath tumor frequently is accompanied by progressive genomic changes.¹⁷ Malignant peripheral nerve sheath tumors differ substantially from PEN in their aggressive histologic features, including nuclear atypia and mitotic figures, which are absent in PEN.

THE DIAGNOSIS: Plexiform Palisaded Encapsulated Neuroma

Microscopically, there was a superficial to deep dermal proliferation of tapered spindle cells in fascicles that were well circumscribed in nodules throughout the dermis with pale background stroma, mild mucin, and a thin capsule. The tapered spindle cells stained positive for SOX-10 and negative for Melan-A (Figure 1A). Staining for epithelial membrane antigen highlighted delicate cells around the periphery of the nodules, consistent with perineurium (Figure 1B). A diagnosis of plexiform palisaded encapsulated neuroma was made. No additional treatment was pursued due to the benign nature of the condition.

Palisaded encapsulated neuroma (PEN), also referred to as solitary circumscribed neuroma,¹ is a benign, generally solitary neurogenic tumor that manifests predominantly on the skin, particularly in areas of frequent outside trauma such as the face. Lesions also may occur on mucosal and acral sites.² First described by Reed et al³ in 1972, PEN characteristically manifests as a well-circumscribed, dermal nodule with a distinctive palisading pattern of Schwann cells and axons within a delicate perineurial capsule, the latter of which may be incomplete.³ Palisaded encapsulated neuroma frequently exhibits clefting between the tumor and the surrounding dermis. While PEN generally is sporadic, rare cases have been reported in association with Cowden syndrome and neurofibromatosis type 2.^4,5

While the nodular growth pattern is most common, PEN also may present in epithelioid, plexiform, multinodular, or fungating subtypes.⁶ The plexiform subtype of PEN is rare. It has a complex growth pattern and a tendency to involve multiple adjacent nerve bundles in a plexiform arrangement.^6,7 In two independent reviews characterizing the predominant growth patterns of PEN, nonnodular growth patterns were observed in a minority of the 85 cases: 18.8% (16/85) were plexiform, 7.1% (6/85) were multinodular or multilobular, and 7.1% (6/85) were fungating.^6,7

The clinical presentation of plexiform PEN often includes a painless, slow-growing mass, and it predominantly occurs in middle-aged adults.² Immunohistochemical staining reveals diffuse positivity for SOX-10 and S-100, which highlights the neural origin of the tumor.⁶ This variant, like conventional PEN, lacks notable atypia or mitotic activity.

Palisaded encapsulated neuroma, regardless of subtype, has an excellent prognosis, with no known cases of malignant transformation, and surgical excision with clear margins is curative.⁸

The differential diagnosis for plexiform PEN includes plexiform variants of neurofibroma and schwannoma, traumatic neuroma, and malignant peripheral nerve sheath tumor.

Neurofibromas are nonencapsulated lesions composed of spindle cells with wavy nuclei dispersed in a myxoid background.⁸ Neurofibromas can manifest in various locations throughout the body, including the skin, subcutaneous tissues, and internal organs. They are slow-growing tumors but may accelerate during periods of hormonal changes, such as pregnancy and puberty, or in cases of malignant transformation.⁸ Although plexiform neurofibromas are benign, malignant transformation can occur, particularly in patients with neurofibromatosis type 1 (NF1).^8,9 Neurofibromas may assume one of 3 growth patterns: localized, diffuse, or plexiform.⁸ Plexiform neurofibromas exhibit a multinodular, ropelike growth pattern with a mix of Schwann cells and fibroblasts (Figure 2).^8,9 These lesions are pathognomonic for NF1 and can infiltrate the surrounding tissue. They may involve large nerve trunks, leading to a more complex growth pattern compared to solitary neurofibromas.^8,9 The plexiform variants of both neurofibromas and PEN demonstrate a multinodular growth pattern; however, plexiform neurofibromas are nonencapsulated and show a more diffuse infiltrative nature, whereas plexiform PEN remains well circumscribed. Additionally, plexiform neurofibromas are associated with NF1, while plexiform PEN lacks this genetic association.

Schwannomas are encapsulated tumors that originate from the outer sheath of peripheral nerves, usually positioned eccentrically to the nerve fibers. Schwannomas are characterized by Antoni A and Antoni B areas, which usually are absent in PEN. Antoni A areas are composed of compact spindle cells arranged in palisades with Verocay bodies, while Antoni B areas are more loosely arranged and have a myxoid background (Figure 3).^8,9 Schwannomas stain positive for S-100 and often show degenerative changes such as cystic degeneration or calcification, particularly in larger lesions.^8,9 Plexiform schwannoma is a rare variant of schwannoma, and while it carries a substantial risk for local recurrence with rates as high as 50%, it has not been shown to possess malignant or metastatic potential.¹⁰ Unlike PEN, schwannomas have a consistent capsule but share S-100 positivity with PEN. Verocay bodies occasionally can be observed in PENs, with studies reporting their presence in 20% to 36% of cases.^7,11,12 Additionally, some schwannomas may exhibit few Verocay bodies or poorly developed forms, which can make histopathologic distinction more challenging.^7,11,12

Traumatic neuromas result from nerve regeneration following any type of outside trauma that is deep enough to cause nerve injury. The lesion often is painful and associated with prior trauma or surgery. Under optimal conditions, the severed ends of a nerve reconnect through the orderly growth of axons from the proximal stump to the distal stump, guided by tubes formed by proliferating Schwann cells. If the nerve ends are not properly aligned or if the distal stump is absent, the axons may proliferate in a disorganized manner at the proximal stump, resulting in the formation of a traumatic neuroma.⁸ Histologically, these lesions exhibit disorganized, proliferating nerve fibers intermixed with fibrous stroma.^8,13 The nerve fibers are not encapsulated, and there is an irregular arrangement of axons and Schwann cells (Figure 4).^8,13 Unlike PEN, which usually is encapsulated and well organized with fascicular architecture, traumatic neuromas exhibit a disorganized, haphazard arrangement of neural elements and lack a capsule.⁸ Clinically, traumatic neuromas also are more likely to be painful.

Malignant peripheral nerve sheath tumors are aggressive malignant spindle-cell tumors that may be associated with NF1 or occur sporadically.^9,14 The spindle cells are arranged in fascicles, and these tumors can have areas of necrosis, hemorrhage, and high mitotic activity.^9,15 The spindle cells may be arranged in a herringbone pattern, and alternating areas of hypocellularity and hypercellularity impart a marbled appearance (Figure 5).¹⁶ Malignant peripheral nerve sheath tumors frequently exhibit inactivation of the SWI/SNF-related, matrix- associated, actin-dependent regulator of chromatin subfamily B member 1 gene and loss of integrase interactor 1 protein. Transformation from plexiform neurofibroma to malignant peripheral nerve sheath tumor frequently is accompanied by progressive genomic changes.¹⁷ Malignant peripheral nerve sheath tumors differ substantially from PEN in their aggressive histologic features, including nuclear atypia and mitotic figures, which are absent in PEN.

THE DIAGNOSIS: Plexiform Palisaded Encapsulated Neuroma

Microscopically, there was a superficial to deep dermal proliferation of tapered spindle cells in fascicles that were well circumscribed in nodules throughout the dermis with pale background stroma, mild mucin, and a thin capsule. The tapered spindle cells stained positive for SOX-10 and negative for Melan-A (Figure 1A). Staining for epithelial membrane antigen highlighted delicate cells around the periphery of the nodules, consistent with perineurium (Figure 1B). A diagnosis of plexiform palisaded encapsulated neuroma was made. No additional treatment was pursued due to the benign nature of the condition.

Palisaded encapsulated neuroma (PEN), also referred to as solitary circumscribed neuroma,¹ is a benign, generally solitary neurogenic tumor that manifests predominantly on the skin, particularly in areas of frequent outside trauma such as the face. Lesions also may occur on mucosal and acral sites.² First described by Reed et al³ in 1972, PEN characteristically manifests as a well-circumscribed, dermal nodule with a distinctive palisading pattern of Schwann cells and axons within a delicate perineurial capsule, the latter of which may be incomplete.³ Palisaded encapsulated neuroma frequently exhibits clefting between the tumor and the surrounding dermis. While PEN generally is sporadic, rare cases have been reported in association with Cowden syndrome and neurofibromatosis type 2.^4,5

While the nodular growth pattern is most common, PEN also may present in epithelioid, plexiform, multinodular, or fungating subtypes.⁶ The plexiform subtype of PEN is rare. It has a complex growth pattern and a tendency to involve multiple adjacent nerve bundles in a plexiform arrangement.^6,7 In two independent reviews characterizing the predominant growth patterns of PEN, nonnodular growth patterns were observed in a minority of the 85 cases: 18.8% (16/85) were plexiform, 7.1% (6/85) were multinodular or multilobular, and 7.1% (6/85) were fungating.^6,7

The clinical presentation of plexiform PEN often includes a painless, slow-growing mass, and it predominantly occurs in middle-aged adults.² Immunohistochemical staining reveals diffuse positivity for SOX-10 and S-100, which highlights the neural origin of the tumor.⁶ This variant, like conventional PEN, lacks notable atypia or mitotic activity.

Palisaded encapsulated neuroma, regardless of subtype, has an excellent prognosis, with no known cases of malignant transformation, and surgical excision with clear margins is curative.⁸

The differential diagnosis for plexiform PEN includes plexiform variants of neurofibroma and schwannoma, traumatic neuroma, and malignant peripheral nerve sheath tumor.

Neurofibromas are nonencapsulated lesions composed of spindle cells with wavy nuclei dispersed in a myxoid background.⁸ Neurofibromas can manifest in various locations throughout the body, including the skin, subcutaneous tissues, and internal organs. They are slow-growing tumors but may accelerate during periods of hormonal changes, such as pregnancy and puberty, or in cases of malignant transformation.⁸ Although plexiform neurofibromas are benign, malignant transformation can occur, particularly in patients with neurofibromatosis type 1 (NF1).^8,9 Neurofibromas may assume one of 3 growth patterns: localized, diffuse, or plexiform.⁸ Plexiform neurofibromas exhibit a multinodular, ropelike growth pattern with a mix of Schwann cells and fibroblasts (Figure 2).^8,9 These lesions are pathognomonic for NF1 and can infiltrate the surrounding tissue. They may involve large nerve trunks, leading to a more complex growth pattern compared to solitary neurofibromas.^8,9 The plexiform variants of both neurofibromas and PEN demonstrate a multinodular growth pattern; however, plexiform neurofibromas are nonencapsulated and show a more diffuse infiltrative nature, whereas plexiform PEN remains well circumscribed. Additionally, plexiform neurofibromas are associated with NF1, while plexiform PEN lacks this genetic association.

Schwannomas are encapsulated tumors that originate from the outer sheath of peripheral nerves, usually positioned eccentrically to the nerve fibers. Schwannomas are characterized by Antoni A and Antoni B areas, which usually are absent in PEN. Antoni A areas are composed of compact spindle cells arranged in palisades with Verocay bodies, while Antoni B areas are more loosely arranged and have a myxoid background (Figure 3).^8,9 Schwannomas stain positive for S-100 and often show degenerative changes such as cystic degeneration or calcification, particularly in larger lesions.^8,9 Plexiform schwannoma is a rare variant of schwannoma, and while it carries a substantial risk for local recurrence with rates as high as 50%, it has not been shown to possess malignant or metastatic potential.¹⁰ Unlike PEN, schwannomas have a consistent capsule but share S-100 positivity with PEN. Verocay bodies occasionally can be observed in PENs, with studies reporting their presence in 20% to 36% of cases.^7,11,12 Additionally, some schwannomas may exhibit few Verocay bodies or poorly developed forms, which can make histopathologic distinction more challenging.^7,11,12

Traumatic neuromas result from nerve regeneration following any type of outside trauma that is deep enough to cause nerve injury. The lesion often is painful and associated with prior trauma or surgery. Under optimal conditions, the severed ends of a nerve reconnect through the orderly growth of axons from the proximal stump to the distal stump, guided by tubes formed by proliferating Schwann cells. If the nerve ends are not properly aligned or if the distal stump is absent, the axons may proliferate in a disorganized manner at the proximal stump, resulting in the formation of a traumatic neuroma.⁸ Histologically, these lesions exhibit disorganized, proliferating nerve fibers intermixed with fibrous stroma.^8,13 The nerve fibers are not encapsulated, and there is an irregular arrangement of axons and Schwann cells (Figure 4).^8,13 Unlike PEN, which usually is encapsulated and well organized with fascicular architecture, traumatic neuromas exhibit a disorganized, haphazard arrangement of neural elements and lack a capsule.⁸ Clinically, traumatic neuromas also are more likely to be painful.

Malignant peripheral nerve sheath tumors are aggressive malignant spindle-cell tumors that may be associated with NF1 or occur sporadically.^9,14 The spindle cells are arranged in fascicles, and these tumors can have areas of necrosis, hemorrhage, and high mitotic activity.^9,15 The spindle cells may be arranged in a herringbone pattern, and alternating areas of hypocellularity and hypercellularity impart a marbled appearance (Figure 5).¹⁶ Malignant peripheral nerve sheath tumors frequently exhibit inactivation of the SWI/SNF-related, matrix- associated, actin-dependent regulator of chromatin subfamily B member 1 gene and loss of integrase interactor 1 protein. Transformation from plexiform neurofibroma to malignant peripheral nerve sheath tumor frequently is accompanied by progressive genomic changes.¹⁷ Malignant peripheral nerve sheath tumors differ substantially from PEN in their aggressive histologic features, including nuclear atypia and mitotic figures, which are absent in PEN.