Mixed Topics

Genetic sequencing of peptides in rebound virus in individuals with HIV who had analytic treatment interruptions (ATIs) confirmed the peptides’ expression in HIV-1 infection, according to data presented at the International AIDS Society Conference on HIV Science. 

Previous research has shown that HIV-specific CD8 T-cell responses directed against five genetically conserved HIV-1 protein regions (Gag, Pol, Vif, Vpr, and Env) are associated with viral control, Josefina Marín-Rojas, PhD, Faculty of Medicine and Health, University of Sydney, and colleagues wrote in their abstract.

However, data on whether these peptides are expressed in rebound virus among individuals with HIV who experienced ATI are limited, they wrote.

The researchers applied an immunoinformatics analysis pipeline (IMAP) to select 182 peptides (IMAP-peptides) from structurally important and mutation-intolerant regions of HIV-1 proteins, senior author Sarah Palmer, PhD, co-director of the Centre for Virus Research at the Westmead Institute for Medical Research and professor in the Faculty of Medicine and Health at the University of Sydney, said in an interview.

“Our studies indicate if the immune system targets these structurally important and mutation-intolerant regions of HIV-1 proteins, this can contribute to virological control in the absence of HIV-1 therapy,” she explained.

The researchers reviewed data from the PULSE clinical trial, which included 68 men who have sex with men living with HIV in Australia. The men underwent three consecutive ATIs. A total of seven participants’ transiently controlled HIV rebound during the third ATI. The researchers examined whether the IMAP peptides were present in the HIV-1 RNA sequences of the rebound virus in four noncontrollers (patients who had viral rebound in all three ATIs) and five of the seven transient controllers who showed viral control during the third ATI.

The technique of near full-length HIV-1 RNA sequencing of rebound virus from three noncontrollers and two transient controllers identified the Gag, Pol, Vif, Vpr, and Env IMAP-peptides in 52%-100% of the viral sequences obtained from these participants across three ATI timepoints.

“We assumed that cells from people living with HIV that experience virological control after treatment interruption would have the immune response to our IMAP-peptides that we observed; however, we are amazed and encouraged by the level and extent of this immune response,” Palmer told this news organization.

The researchers also compared CD8 T-cell response between the IMAP peptides and a control peptide pool without the IMAP peptides.

The CD8 T-cells from three transient controllers had a 15- to 53-fold higher effector response to the IMAP-peptides than the CD8 T-cells from two noncontrollers, the researchers wrote in their abstract. The relative response to the IMAP-peptides in noncontrollers was 20 times lower than that to the control peptides, but the IMAP-peptide response in the transient controllers group was similar to that in the control group, the authors noted.

The results highlight the potential of IMAP in developing treatment strategies. Although the results are too preliminary to impact clinical practice at this time, the findings from the current study could lead to the development of an mRNA vaccine to clear HIV-infected cells from people living with HIV, Palmer told this news organization.

“Our next steps include developing and testing mRNA vaccine constructs that contain our IMAP-peptides to assess the immune response of cells from people living with HIV to these vaccines,” Palmer said. “From there we will conduct studies of the most promising mRNA vaccine constructs in a humanized mouse model,” she said.

 

Data Enhance Understanding of Immunity

The current study may provide information that can significantly impact understanding of the immune responses to HIV, David J. Cennimo, MD, associate professor of medicine and pediatrics in the Division of Infectious Disease at Rutgers New Jersey Medical School, Newark, New Jersey, said in an interview.

“The investigators looked at highly conserved regions of multiple HIV proteins,” said Cennimo, who was not involved in the study. “Conserved regions and antibody responses to them may play a role in controlling HIV viral replication and rebound,” Cennimo told this news organization. “The investigators showed these regions were present in rebounding viremia, and individuals that exhibited greater immune recognition of these regions suppressed rebound viremia longer, and perhaps targeting these regions could impact HIV prevention or cure strategies,” he said.

Secondarily, the study showed the success of the novel technique (IMAP) to identify conserved peptides, said Cennimo. The technique could potentially be applied to other viruses that mutate to escape host response, he said.The study was funded by the U.S. National Institutes of Health, the Foundation for AIDS Research, the Australian National Health and Medical Research Council, and Sandra and David Ansley. The researchers and Cennimo disclosed no financial conflicts of interest.

A version of this article first appeared on Medscape.com.

Genetic sequencing of peptides in rebound virus in individuals with HIV who had analytic treatment interruptions (ATIs) confirmed the peptides’ expression in HIV-1 infection, according to data presented at the International AIDS Society Conference on HIV Science. 

Previous research has shown that HIV-specific CD8 T-cell responses directed against five genetically conserved HIV-1 protein regions (Gag, Pol, Vif, Vpr, and Env) are associated with viral control, Josefina Marín-Rojas, PhD, Faculty of Medicine and Health, University of Sydney, and colleagues wrote in their abstract.

However, data on whether these peptides are expressed in rebound virus among individuals with HIV who experienced ATI are limited, they wrote.

The researchers applied an immunoinformatics analysis pipeline (IMAP) to select 182 peptides (IMAP-peptides) from structurally important and mutation-intolerant regions of HIV-1 proteins, senior author Sarah Palmer, PhD, co-director of the Centre for Virus Research at the Westmead Institute for Medical Research and professor in the Faculty of Medicine and Health at the University of Sydney, said in an interview.

“Our studies indicate if the immune system targets these structurally important and mutation-intolerant regions of HIV-1 proteins, this can contribute to virological control in the absence of HIV-1 therapy,” she explained.

The researchers reviewed data from the PULSE clinical trial, which included 68 men who have sex with men living with HIV in Australia. The men underwent three consecutive ATIs. A total of seven participants’ transiently controlled HIV rebound during the third ATI. The researchers examined whether the IMAP peptides were present in the HIV-1 RNA sequences of the rebound virus in four noncontrollers (patients who had viral rebound in all three ATIs) and five of the seven transient controllers who showed viral control during the third ATI.

The technique of near full-length HIV-1 RNA sequencing of rebound virus from three noncontrollers and two transient controllers identified the Gag, Pol, Vif, Vpr, and Env IMAP-peptides in 52%-100% of the viral sequences obtained from these participants across three ATI timepoints.

“We assumed that cells from people living with HIV that experience virological control after treatment interruption would have the immune response to our IMAP-peptides that we observed; however, we are amazed and encouraged by the level and extent of this immune response,” Palmer told this news organization.

The researchers also compared CD8 T-cell response between the IMAP peptides and a control peptide pool without the IMAP peptides.

The CD8 T-cells from three transient controllers had a 15- to 53-fold higher effector response to the IMAP-peptides than the CD8 T-cells from two noncontrollers, the researchers wrote in their abstract. The relative response to the IMAP-peptides in noncontrollers was 20 times lower than that to the control peptides, but the IMAP-peptide response in the transient controllers group was similar to that in the control group, the authors noted.

The results highlight the potential of IMAP in developing treatment strategies. Although the results are too preliminary to impact clinical practice at this time, the findings from the current study could lead to the development of an mRNA vaccine to clear HIV-infected cells from people living with HIV, Palmer told this news organization.

“Our next steps include developing and testing mRNA vaccine constructs that contain our IMAP-peptides to assess the immune response of cells from people living with HIV to these vaccines,” Palmer said. “From there we will conduct studies of the most promising mRNA vaccine constructs in a humanized mouse model,” she said.

 

Data Enhance Understanding of Immunity

The current study may provide information that can significantly impact understanding of the immune responses to HIV, David J. Cennimo, MD, associate professor of medicine and pediatrics in the Division of Infectious Disease at Rutgers New Jersey Medical School, Newark, New Jersey, said in an interview.

“The investigators looked at highly conserved regions of multiple HIV proteins,” said Cennimo, who was not involved in the study. “Conserved regions and antibody responses to them may play a role in controlling HIV viral replication and rebound,” Cennimo told this news organization. “The investigators showed these regions were present in rebounding viremia, and individuals that exhibited greater immune recognition of these regions suppressed rebound viremia longer, and perhaps targeting these regions could impact HIV prevention or cure strategies,” he said.

Secondarily, the study showed the success of the novel technique (IMAP) to identify conserved peptides, said Cennimo. The technique could potentially be applied to other viruses that mutate to escape host response, he said.The study was funded by the U.S. National Institutes of Health, the Foundation for AIDS Research, the Australian National Health and Medical Research Council, and Sandra and David Ansley. The researchers and Cennimo disclosed no financial conflicts of interest.

A version of this article first appeared on Medscape.com.

Genetic sequencing of peptides in rebound virus in individuals with HIV who had analytic treatment interruptions (ATIs) confirmed the peptides’ expression in HIV-1 infection, according to data presented at the International AIDS Society Conference on HIV Science. 

Previous research has shown that HIV-specific CD8 T-cell responses directed against five genetically conserved HIV-1 protein regions (Gag, Pol, Vif, Vpr, and Env) are associated with viral control, Josefina Marín-Rojas, PhD, Faculty of Medicine and Health, University of Sydney, and colleagues wrote in their abstract.

However, data on whether these peptides are expressed in rebound virus among individuals with HIV who experienced ATI are limited, they wrote.

The researchers applied an immunoinformatics analysis pipeline (IMAP) to select 182 peptides (IMAP-peptides) from structurally important and mutation-intolerant regions of HIV-1 proteins, senior author Sarah Palmer, PhD, co-director of the Centre for Virus Research at the Westmead Institute for Medical Research and professor in the Faculty of Medicine and Health at the University of Sydney, said in an interview.

“Our studies indicate if the immune system targets these structurally important and mutation-intolerant regions of HIV-1 proteins, this can contribute to virological control in the absence of HIV-1 therapy,” she explained.

The researchers reviewed data from the PULSE clinical trial, which included 68 men who have sex with men living with HIV in Australia. The men underwent three consecutive ATIs. A total of seven participants’ transiently controlled HIV rebound during the third ATI. The researchers examined whether the IMAP peptides were present in the HIV-1 RNA sequences of the rebound virus in four noncontrollers (patients who had viral rebound in all three ATIs) and five of the seven transient controllers who showed viral control during the third ATI.

The technique of near full-length HIV-1 RNA sequencing of rebound virus from three noncontrollers and two transient controllers identified the Gag, Pol, Vif, Vpr, and Env IMAP-peptides in 52%-100% of the viral sequences obtained from these participants across three ATI timepoints.

“We assumed that cells from people living with HIV that experience virological control after treatment interruption would have the immune response to our IMAP-peptides that we observed; however, we are amazed and encouraged by the level and extent of this immune response,” Palmer told this news organization.

The researchers also compared CD8 T-cell response between the IMAP peptides and a control peptide pool without the IMAP peptides.

The CD8 T-cells from three transient controllers had a 15- to 53-fold higher effector response to the IMAP-peptides than the CD8 T-cells from two noncontrollers, the researchers wrote in their abstract. The relative response to the IMAP-peptides in noncontrollers was 20 times lower than that to the control peptides, but the IMAP-peptide response in the transient controllers group was similar to that in the control group, the authors noted.

The results highlight the potential of IMAP in developing treatment strategies. Although the results are too preliminary to impact clinical practice at this time, the findings from the current study could lead to the development of an mRNA vaccine to clear HIV-infected cells from people living with HIV, Palmer told this news organization.

“Our next steps include developing and testing mRNA vaccine constructs that contain our IMAP-peptides to assess the immune response of cells from people living with HIV to these vaccines,” Palmer said. “From there we will conduct studies of the most promising mRNA vaccine constructs in a humanized mouse model,” she said.

 

Data Enhance Understanding of Immunity

The current study may provide information that can significantly impact understanding of the immune responses to HIV, David J. Cennimo, MD, associate professor of medicine and pediatrics in the Division of Infectious Disease at Rutgers New Jersey Medical School, Newark, New Jersey, said in an interview.

“The investigators looked at highly conserved regions of multiple HIV proteins,” said Cennimo, who was not involved in the study. “Conserved regions and antibody responses to them may play a role in controlling HIV viral replication and rebound,” Cennimo told this news organization. “The investigators showed these regions were present in rebounding viremia, and individuals that exhibited greater immune recognition of these regions suppressed rebound viremia longer, and perhaps targeting these regions could impact HIV prevention or cure strategies,” he said.

Secondarily, the study showed the success of the novel technique (IMAP) to identify conserved peptides, said Cennimo. The technique could potentially be applied to other viruses that mutate to escape host response, he said.The study was funded by the U.S. National Institutes of Health, the Foundation for AIDS Research, the Australian National Health and Medical Research Council, and Sandra and David Ansley. The researchers and Cennimo disclosed no financial conflicts of interest.

A version of this article first appeared on Medscape.com.

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare, life-threatening conditions that involve widespread necrosis of the skin and mucous membranes.¹ Guidelines for SJS and TEN recommend management in hospitals with access to inpatient dermatology to provide immediate interventions that are necessary for achieving optimal patient outcomes.² A delay in admission of 5 days or more after onset of symptoms has been associated with increases in overall mortality, bacteremia, intensive care unit (ICU) admission, and length of stay.³ Patients who are not directly admitted to specialized facilities and require transfer from other hospitals may experience delays in receiving critical interventions, further increasing the risk for mortality and complications. In this study, we analyzed the clinical outcomes of patients with SJS/TEN in relation to their admission pathway.

Methods

A single-center retrospective chart review was performed at Atrium Health Wake Forest Baptist Medical Center (AHWFBMC) in Winston-Salem, North Carolina. Participants were identified using i2b2, an informatics tool compliant with the Health Insurance Portability and Accountability Act for integrating biology and the bedside. Inclusion criteria were having a diagnosis of SJS (International Classification of Diseases, Tenth Revision, code L51.1; International Classification of Diseases, Ninth Revision, code 695.13), TEN (International Classification of Diseases, Tenth Revision, code L51.2; International Classification of Diseases, Ninth Revision, code 695.15) or Lyell syndrome from January 2012 to December 2024. Patients with erythema multiforme or bullous drug eruption were excluded, as these conditions initially were misdiagnosed as SJS or TEN. Patients with only a reported history of prior SJS or TEN also were excluded.

The following clinical outcomes were assessed: demographics, comorbidities, age at disease onset, outside hospital transfer status, complications during admission, inpatient length of stay in days, age of mortality (if applicable), culprit medications, interventions received, Severity-of-Illness Score for Toxic Epidermal Necrolysis (SCORTEN) upon admission, site of admission (eg, floor bed, ICU, medical ICU, burn unit), and length of disease process prior to hospital admission. Patients then were categorized as either direct or transfer admissions based on the initial point of care and admission process. Direct admissions included patients who presented to the AHWFBMC emergency department and were subsequently admitted. Transfer patients included patients who initially presented to an outside hospital and were transferred to AHWFBMC. Data regarding the wait time for Physician Access Line requests and the time elapsed from the initial transfer call to arrival at the tertiary hospital also were collected—this is a method that outside hospitals can use to contact physicians at the tertiary hospital for a possible transfer. Statistical analysis was performed using unpaired t tests and X² tests as necessary using GraphPad By Dotmatics Prism.

Results

A total of 112 patients were included in the analysis; of these, 71 had a diagnosis with biopsy confirmation of SJS, SJS/TEN overlap, or TEN (Table 1). Forty-one patients were excluded due to having a diagnosis of erythema multiforme or bullous drug eruption or a reported history of prior SJS or TEN without hospitalization. All biopsies were performed at AHWFBMC. Of the 71 confirmed patients with SJS/TEN, 54 (76%) were female with a mean age of 44 years. The majority of patients identified as Black (35 [49%]) or White (27 [38%]), along with Asian (7 [10%]) and other (2 [3%]). The most common comorbidity was cardiovascular disease in 42 (59%) patients, followed by type 2 diabetes in 36 (51%) patients. Among these 71 patients with SJS/TEN, 29 (41%) were directly admitted to the tertiary hospital, while 42 (59%) were transferred from outside hospitals.

Of the 71 confirmed patients with SJS/TEN, sulfonamides were identified as the most common inciting drug in 25 (41%) patients, followed by beta-lactam antibiotics in 16 (23%) patients (Table 2). This is consistent with previous literature of sulfamethoxazole with trimethoprim as the primary causative drug for SJS and TEN in the United States.¹

Clinical Outcomes—Of the 71 patients, there were 23 (32%) cases of SJS, 29 (41%) cases of SJS/TEN overlap, and 19 (27%) cases of TEN (eTable). The initial and maximum affected body surface area (BSA) was higher in transfer admissions, with a mean maximum BSA of 38.55% in the transfer group compared to 19.14% in the direct admissions. The mean SCORTEN (range, 0-5) was 1.6 overall, with a higher mean score of 1.92 in the transfer group compared to 1.07 in the direct admissions.

Transfer patients had a longer mean stay at the tertiary hospital (13.71 d) compared to direct admissions (7.17 d). The mean time from symptom onset until tertiary hospital admission was 8.5 days; transfer and direct admission patients had similar mean time from symptom onset of 9.02 days and 7.86 days, respectively. Although the duration of cutaneous symptoms from onset until tertiary hospital admission was similar (P=.283) between direct admissions (7.86 d) and transfer patients (9.02 d), the transfer group presented with greater disease severity at the time of admission. Transfer patients had a higher mean maximum BSA involvement (38.55% vs 19.14% [P=.005]), elevated SCORTEN (1.92 vs 1.07 [P=.029]), and longer mean hospital stays (13.71 d vs 7.17 d [P<.0001]) compared to direct admissions.

Despite the absence of mortality in both groups, transfer patients showed a higher number of ICU admissions (19 vs 5 [P=.014]) and burn unit admissions (9 vs 2 [P=.096]), bacteremia (16 vs 4 [P=.025]), acute kidney injury (13 vs 10 [P=.755]), acute respiratory failure (12 vs 5 [P=.272]), and transaminitis (8 vs 3 [P=.319]).

Outside Hospital Treatments—All outside hospitals provided supportive care with intravenous fluids and acetaminophen; however, further care provided at outside hospitals varied (Table 3), with transfer patients most frequently being treated with diphenhydramine (69% [29/42]), antimicrobial medications (57% [24/42]), steroids (40%), and epinephrine (10% [4/42]). Some patients may have received more than one of these treatments. Based on outside hospital treatments, the primary care teams’ main clinical concerns were allergic reactions and infection, as 33 (79%) patients received diphenhydramine (29 [89%]) or epinephrine (4 [12%]) and 24 (52%) received antimicrobial medications. Of the 42 transfer patients, 24 (57%) received or continued these medications before transfer; the medications were promptly discontinued upon tertiary hospital admission.

Once the outside hospitals contacted the tertiary hospital for a referral, the mean length of time between the transfer request and Physician Access Line call was 17.13 minutes (Table 4). Following the transfer request, the mean length of time for arrival at the tertiary hospital was 6.22 hours. The mean length of stay at the outside hospital prior to the patient being transferred was 3.84 days.

Comment

This retrospective study examined 71 patients with biopsy-confirmed SJS, SJS/TEN overlap, or TEN to evaluate differences in clinical outcomes between direct and transfer admissions. Transfer patients had a higher mean maximum affected BSA (38.55% vs 19.14% [P=.005]) and elevated SCORTEN (1.92 vs 1.07 [P=.029]); a higher number of transfer patients were admitted to the ICU (19 vs 5 [P=.014]) and burn unit (9 vs 2 [P=.096]), and this group also demonstrated longer hospitalization stays (13.71 vs 7.17 [P<.0001]). There were more complications among transfer patients, including bacteremia (16 vs 4 [P=.025]), which is consistent with findings from the existing literature.³

Once the decision for transfer of the patients included in our study was initiated and accepted, there was a prompt response and transfer of care; the mean length of time for Physician Access Line request was 17.13 minutes, and the mean transfer time to arrive at the tertiary hospital was 6.22 hours; however, patients spent an average of 3.84 days at outside hospitals, reflecting that transfer calls frequently were initiated due to urgent clinical decline of the patient rather than as an early intervention strategy. The management at outside hospitals often included the continuation of antimicrobial medications, which were discontinued upon transfer to AHWFBMC. Causative agents were either previously prescribed for a new medical condition or initiated for the management of suspected infections at outside hospitals. This may reflect the difficulty in correctly diagnosing SJS/TEN and initiating appropriate management at hospital facilities without an inpatient dermatologist.

The presence of inpatient dermatologists can improve the diagnostic accuracy and treatment of various conditions.^4,5 Dermatology consultations added or changed 77% of treatment plans for 271 hospitalized patients.⁴ The impact of this intervention is reflected by the success of early dermatology consultations in reducing the length of hospitalization and use of inappropriate treatments in the care of skin diseases.^6-8

Access to dermatologic care has been an identified need in inpatient hospitals that may limit the ability of hospitals to promptly treat serious conditions such as SJS/TEN.⁹ From an inpatient dermatology study from 2013 through 2019, 98.2% of 782 inpatient dermatologists reside in metropolitan areas, limiting the availability of care for rural patients; this study also found a decreasing number of facilities with inpatient dermatologists.¹⁰

The limitations of our study include a small sample size of 71 patients, which restricted the generalizability of our results. Our study also was based at a single tertiary center, which thereby limited the findings to this geographic area. It also was difficult to match patients by their demographic and comorbid conditions. The retrospective study design depended on the accuracy and completeness of medical records, which can introduce information bias. Future studies should compare the clinical outcomes of SJS/TEN based on burn unit and ICU admissions.

Conclusion

Prompt identification of SJS/TEN and rapid transfer to hospitals with inpatient dermatology are essential to optimize patient outcomes. Developing and validating SJS/TEN diagnosis and transfer protocols across multiple institutions may be helpful.

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare, life-threatening conditions that involve widespread necrosis of the skin and mucous membranes.¹ Guidelines for SJS and TEN recommend management in hospitals with access to inpatient dermatology to provide immediate interventions that are necessary for achieving optimal patient outcomes.² A delay in admission of 5 days or more after onset of symptoms has been associated with increases in overall mortality, bacteremia, intensive care unit (ICU) admission, and length of stay.³ Patients who are not directly admitted to specialized facilities and require transfer from other hospitals may experience delays in receiving critical interventions, further increasing the risk for mortality and complications. In this study, we analyzed the clinical outcomes of patients with SJS/TEN in relation to their admission pathway.

Methods

A single-center retrospective chart review was performed at Atrium Health Wake Forest Baptist Medical Center (AHWFBMC) in Winston-Salem, North Carolina. Participants were identified using i2b2, an informatics tool compliant with the Health Insurance Portability and Accountability Act for integrating biology and the bedside. Inclusion criteria were having a diagnosis of SJS (International Classification of Diseases, Tenth Revision, code L51.1; International Classification of Diseases, Ninth Revision, code 695.13), TEN (International Classification of Diseases, Tenth Revision, code L51.2; International Classification of Diseases, Ninth Revision, code 695.15) or Lyell syndrome from January 2012 to December 2024. Patients with erythema multiforme or bullous drug eruption were excluded, as these conditions initially were misdiagnosed as SJS or TEN. Patients with only a reported history of prior SJS or TEN also were excluded.

The following clinical outcomes were assessed: demographics, comorbidities, age at disease onset, outside hospital transfer status, complications during admission, inpatient length of stay in days, age of mortality (if applicable), culprit medications, interventions received, Severity-of-Illness Score for Toxic Epidermal Necrolysis (SCORTEN) upon admission, site of admission (eg, floor bed, ICU, medical ICU, burn unit), and length of disease process prior to hospital admission. Patients then were categorized as either direct or transfer admissions based on the initial point of care and admission process. Direct admissions included patients who presented to the AHWFBMC emergency department and were subsequently admitted. Transfer patients included patients who initially presented to an outside hospital and were transferred to AHWFBMC. Data regarding the wait time for Physician Access Line requests and the time elapsed from the initial transfer call to arrival at the tertiary hospital also were collected—this is a method that outside hospitals can use to contact physicians at the tertiary hospital for a possible transfer. Statistical analysis was performed using unpaired t tests and X² tests as necessary using GraphPad By Dotmatics Prism.

Results

A total of 112 patients were included in the analysis; of these, 71 had a diagnosis with biopsy confirmation of SJS, SJS/TEN overlap, or TEN (Table 1). Forty-one patients were excluded due to having a diagnosis of erythema multiforme or bullous drug eruption or a reported history of prior SJS or TEN without hospitalization. All biopsies were performed at AHWFBMC. Of the 71 confirmed patients with SJS/TEN, 54 (76%) were female with a mean age of 44 years. The majority of patients identified as Black (35 [49%]) or White (27 [38%]), along with Asian (7 [10%]) and other (2 [3%]). The most common comorbidity was cardiovascular disease in 42 (59%) patients, followed by type 2 diabetes in 36 (51%) patients. Among these 71 patients with SJS/TEN, 29 (41%) were directly admitted to the tertiary hospital, while 42 (59%) were transferred from outside hospitals.

Of the 71 confirmed patients with SJS/TEN, sulfonamides were identified as the most common inciting drug in 25 (41%) patients, followed by beta-lactam antibiotics in 16 (23%) patients (Table 2). This is consistent with previous literature of sulfamethoxazole with trimethoprim as the primary causative drug for SJS and TEN in the United States.¹

Clinical Outcomes—Of the 71 patients, there were 23 (32%) cases of SJS, 29 (41%) cases of SJS/TEN overlap, and 19 (27%) cases of TEN (eTable). The initial and maximum affected body surface area (BSA) was higher in transfer admissions, with a mean maximum BSA of 38.55% in the transfer group compared to 19.14% in the direct admissions. The mean SCORTEN (range, 0-5) was 1.6 overall, with a higher mean score of 1.92 in the transfer group compared to 1.07 in the direct admissions.

Transfer patients had a longer mean stay at the tertiary hospital (13.71 d) compared to direct admissions (7.17 d). The mean time from symptom onset until tertiary hospital admission was 8.5 days; transfer and direct admission patients had similar mean time from symptom onset of 9.02 days and 7.86 days, respectively. Although the duration of cutaneous symptoms from onset until tertiary hospital admission was similar (P=.283) between direct admissions (7.86 d) and transfer patients (9.02 d), the transfer group presented with greater disease severity at the time of admission. Transfer patients had a higher mean maximum BSA involvement (38.55% vs 19.14% [P=.005]), elevated SCORTEN (1.92 vs 1.07 [P=.029]), and longer mean hospital stays (13.71 d vs 7.17 d [P<.0001]) compared to direct admissions.

Despite the absence of mortality in both groups, transfer patients showed a higher number of ICU admissions (19 vs 5 [P=.014]) and burn unit admissions (9 vs 2 [P=.096]), bacteremia (16 vs 4 [P=.025]), acute kidney injury (13 vs 10 [P=.755]), acute respiratory failure (12 vs 5 [P=.272]), and transaminitis (8 vs 3 [P=.319]).

Outside Hospital Treatments—All outside hospitals provided supportive care with intravenous fluids and acetaminophen; however, further care provided at outside hospitals varied (Table 3), with transfer patients most frequently being treated with diphenhydramine (69% [29/42]), antimicrobial medications (57% [24/42]), steroids (40%), and epinephrine (10% [4/42]). Some patients may have received more than one of these treatments. Based on outside hospital treatments, the primary care teams’ main clinical concerns were allergic reactions and infection, as 33 (79%) patients received diphenhydramine (29 [89%]) or epinephrine (4 [12%]) and 24 (52%) received antimicrobial medications. Of the 42 transfer patients, 24 (57%) received or continued these medications before transfer; the medications were promptly discontinued upon tertiary hospital admission.

Once the outside hospitals contacted the tertiary hospital for a referral, the mean length of time between the transfer request and Physician Access Line call was 17.13 minutes (Table 4). Following the transfer request, the mean length of time for arrival at the tertiary hospital was 6.22 hours. The mean length of stay at the outside hospital prior to the patient being transferred was 3.84 days.

Comment

This retrospective study examined 71 patients with biopsy-confirmed SJS, SJS/TEN overlap, or TEN to evaluate differences in clinical outcomes between direct and transfer admissions. Transfer patients had a higher mean maximum affected BSA (38.55% vs 19.14% [P=.005]) and elevated SCORTEN (1.92 vs 1.07 [P=.029]); a higher number of transfer patients were admitted to the ICU (19 vs 5 [P=.014]) and burn unit (9 vs 2 [P=.096]), and this group also demonstrated longer hospitalization stays (13.71 vs 7.17 [P<.0001]). There were more complications among transfer patients, including bacteremia (16 vs 4 [P=.025]), which is consistent with findings from the existing literature.³

Once the decision for transfer of the patients included in our study was initiated and accepted, there was a prompt response and transfer of care; the mean length of time for Physician Access Line request was 17.13 minutes, and the mean transfer time to arrive at the tertiary hospital was 6.22 hours; however, patients spent an average of 3.84 days at outside hospitals, reflecting that transfer calls frequently were initiated due to urgent clinical decline of the patient rather than as an early intervention strategy. The management at outside hospitals often included the continuation of antimicrobial medications, which were discontinued upon transfer to AHWFBMC. Causative agents were either previously prescribed for a new medical condition or initiated for the management of suspected infections at outside hospitals. This may reflect the difficulty in correctly diagnosing SJS/TEN and initiating appropriate management at hospital facilities without an inpatient dermatologist.

The presence of inpatient dermatologists can improve the diagnostic accuracy and treatment of various conditions.^4,5 Dermatology consultations added or changed 77% of treatment plans for 271 hospitalized patients.⁴ The impact of this intervention is reflected by the success of early dermatology consultations in reducing the length of hospitalization and use of inappropriate treatments in the care of skin diseases.^6-8

Access to dermatologic care has been an identified need in inpatient hospitals that may limit the ability of hospitals to promptly treat serious conditions such as SJS/TEN.⁹ From an inpatient dermatology study from 2013 through 2019, 98.2% of 782 inpatient dermatologists reside in metropolitan areas, limiting the availability of care for rural patients; this study also found a decreasing number of facilities with inpatient dermatologists.¹⁰

The limitations of our study include a small sample size of 71 patients, which restricted the generalizability of our results. Our study also was based at a single tertiary center, which thereby limited the findings to this geographic area. It also was difficult to match patients by their demographic and comorbid conditions. The retrospective study design depended on the accuracy and completeness of medical records, which can introduce information bias. Future studies should compare the clinical outcomes of SJS/TEN based on burn unit and ICU admissions.

Conclusion

Prompt identification of SJS/TEN and rapid transfer to hospitals with inpatient dermatology are essential to optimize patient outcomes. Developing and validating SJS/TEN diagnosis and transfer protocols across multiple institutions may be helpful.

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare, life-threatening conditions that involve widespread necrosis of the skin and mucous membranes.¹ Guidelines for SJS and TEN recommend management in hospitals with access to inpatient dermatology to provide immediate interventions that are necessary for achieving optimal patient outcomes.² A delay in admission of 5 days or more after onset of symptoms has been associated with increases in overall mortality, bacteremia, intensive care unit (ICU) admission, and length of stay.³ Patients who are not directly admitted to specialized facilities and require transfer from other hospitals may experience delays in receiving critical interventions, further increasing the risk for mortality and complications. In this study, we analyzed the clinical outcomes of patients with SJS/TEN in relation to their admission pathway.

Methods

A single-center retrospective chart review was performed at Atrium Health Wake Forest Baptist Medical Center (AHWFBMC) in Winston-Salem, North Carolina. Participants were identified using i2b2, an informatics tool compliant with the Health Insurance Portability and Accountability Act for integrating biology and the bedside. Inclusion criteria were having a diagnosis of SJS (International Classification of Diseases, Tenth Revision, code L51.1; International Classification of Diseases, Ninth Revision, code 695.13), TEN (International Classification of Diseases, Tenth Revision, code L51.2; International Classification of Diseases, Ninth Revision, code 695.15) or Lyell syndrome from January 2012 to December 2024. Patients with erythema multiforme or bullous drug eruption were excluded, as these conditions initially were misdiagnosed as SJS or TEN. Patients with only a reported history of prior SJS or TEN also were excluded.

The following clinical outcomes were assessed: demographics, comorbidities, age at disease onset, outside hospital transfer status, complications during admission, inpatient length of stay in days, age of mortality (if applicable), culprit medications, interventions received, Severity-of-Illness Score for Toxic Epidermal Necrolysis (SCORTEN) upon admission, site of admission (eg, floor bed, ICU, medical ICU, burn unit), and length of disease process prior to hospital admission. Patients then were categorized as either direct or transfer admissions based on the initial point of care and admission process. Direct admissions included patients who presented to the AHWFBMC emergency department and were subsequently admitted. Transfer patients included patients who initially presented to an outside hospital and were transferred to AHWFBMC. Data regarding the wait time for Physician Access Line requests and the time elapsed from the initial transfer call to arrival at the tertiary hospital also were collected—this is a method that outside hospitals can use to contact physicians at the tertiary hospital for a possible transfer. Statistical analysis was performed using unpaired t tests and X² tests as necessary using GraphPad By Dotmatics Prism.

Results

A total of 112 patients were included in the analysis; of these, 71 had a diagnosis with biopsy confirmation of SJS, SJS/TEN overlap, or TEN (Table 1). Forty-one patients were excluded due to having a diagnosis of erythema multiforme or bullous drug eruption or a reported history of prior SJS or TEN without hospitalization. All biopsies were performed at AHWFBMC. Of the 71 confirmed patients with SJS/TEN, 54 (76%) were female with a mean age of 44 years. The majority of patients identified as Black (35 [49%]) or White (27 [38%]), along with Asian (7 [10%]) and other (2 [3%]). The most common comorbidity was cardiovascular disease in 42 (59%) patients, followed by type 2 diabetes in 36 (51%) patients. Among these 71 patients with SJS/TEN, 29 (41%) were directly admitted to the tertiary hospital, while 42 (59%) were transferred from outside hospitals.

Of the 71 confirmed patients with SJS/TEN, sulfonamides were identified as the most common inciting drug in 25 (41%) patients, followed by beta-lactam antibiotics in 16 (23%) patients (Table 2). This is consistent with previous literature of sulfamethoxazole with trimethoprim as the primary causative drug for SJS and TEN in the United States.¹

Clinical Outcomes—Of the 71 patients, there were 23 (32%) cases of SJS, 29 (41%) cases of SJS/TEN overlap, and 19 (27%) cases of TEN (eTable). The initial and maximum affected body surface area (BSA) was higher in transfer admissions, with a mean maximum BSA of 38.55% in the transfer group compared to 19.14% in the direct admissions. The mean SCORTEN (range, 0-5) was 1.6 overall, with a higher mean score of 1.92 in the transfer group compared to 1.07 in the direct admissions.

Transfer patients had a longer mean stay at the tertiary hospital (13.71 d) compared to direct admissions (7.17 d). The mean time from symptom onset until tertiary hospital admission was 8.5 days; transfer and direct admission patients had similar mean time from symptom onset of 9.02 days and 7.86 days, respectively. Although the duration of cutaneous symptoms from onset until tertiary hospital admission was similar (P=.283) between direct admissions (7.86 d) and transfer patients (9.02 d), the transfer group presented with greater disease severity at the time of admission. Transfer patients had a higher mean maximum BSA involvement (38.55% vs 19.14% [P=.005]), elevated SCORTEN (1.92 vs 1.07 [P=.029]), and longer mean hospital stays (13.71 d vs 7.17 d [P<.0001]) compared to direct admissions.

Despite the absence of mortality in both groups, transfer patients showed a higher number of ICU admissions (19 vs 5 [P=.014]) and burn unit admissions (9 vs 2 [P=.096]), bacteremia (16 vs 4 [P=.025]), acute kidney injury (13 vs 10 [P=.755]), acute respiratory failure (12 vs 5 [P=.272]), and transaminitis (8 vs 3 [P=.319]).

Outside Hospital Treatments—All outside hospitals provided supportive care with intravenous fluids and acetaminophen; however, further care provided at outside hospitals varied (Table 3), with transfer patients most frequently being treated with diphenhydramine (69% [29/42]), antimicrobial medications (57% [24/42]), steroids (40%), and epinephrine (10% [4/42]). Some patients may have received more than one of these treatments. Based on outside hospital treatments, the primary care teams’ main clinical concerns were allergic reactions and infection, as 33 (79%) patients received diphenhydramine (29 [89%]) or epinephrine (4 [12%]) and 24 (52%) received antimicrobial medications. Of the 42 transfer patients, 24 (57%) received or continued these medications before transfer; the medications were promptly discontinued upon tertiary hospital admission.

Once the outside hospitals contacted the tertiary hospital for a referral, the mean length of time between the transfer request and Physician Access Line call was 17.13 minutes (Table 4). Following the transfer request, the mean length of time for arrival at the tertiary hospital was 6.22 hours. The mean length of stay at the outside hospital prior to the patient being transferred was 3.84 days.

Comment

This retrospective study examined 71 patients with biopsy-confirmed SJS, SJS/TEN overlap, or TEN to evaluate differences in clinical outcomes between direct and transfer admissions. Transfer patients had a higher mean maximum affected BSA (38.55% vs 19.14% [P=.005]) and elevated SCORTEN (1.92 vs 1.07 [P=.029]); a higher number of transfer patients were admitted to the ICU (19 vs 5 [P=.014]) and burn unit (9 vs 2 [P=.096]), and this group also demonstrated longer hospitalization stays (13.71 vs 7.17 [P<.0001]). There were more complications among transfer patients, including bacteremia (16 vs 4 [P=.025]), which is consistent with findings from the existing literature.³

Once the decision for transfer of the patients included in our study was initiated and accepted, there was a prompt response and transfer of care; the mean length of time for Physician Access Line request was 17.13 minutes, and the mean transfer time to arrive at the tertiary hospital was 6.22 hours; however, patients spent an average of 3.84 days at outside hospitals, reflecting that transfer calls frequently were initiated due to urgent clinical decline of the patient rather than as an early intervention strategy. The management at outside hospitals often included the continuation of antimicrobial medications, which were discontinued upon transfer to AHWFBMC. Causative agents were either previously prescribed for a new medical condition or initiated for the management of suspected infections at outside hospitals. This may reflect the difficulty in correctly diagnosing SJS/TEN and initiating appropriate management at hospital facilities without an inpatient dermatologist.

The presence of inpatient dermatologists can improve the diagnostic accuracy and treatment of various conditions.^4,5 Dermatology consultations added or changed 77% of treatment plans for 271 hospitalized patients.⁴ The impact of this intervention is reflected by the success of early dermatology consultations in reducing the length of hospitalization and use of inappropriate treatments in the care of skin diseases.^6-8

Access to dermatologic care has been an identified need in inpatient hospitals that may limit the ability of hospitals to promptly treat serious conditions such as SJS/TEN.⁹ From an inpatient dermatology study from 2013 through 2019, 98.2% of 782 inpatient dermatologists reside in metropolitan areas, limiting the availability of care for rural patients; this study also found a decreasing number of facilities with inpatient dermatologists.¹⁰

The limitations of our study include a small sample size of 71 patients, which restricted the generalizability of our results. Our study also was based at a single tertiary center, which thereby limited the findings to this geographic area. It also was difficult to match patients by their demographic and comorbid conditions. The retrospective study design depended on the accuracy and completeness of medical records, which can introduce information bias. Future studies should compare the clinical outcomes of SJS/TEN based on burn unit and ICU admissions.

Conclusion

Prompt identification of SJS/TEN and rapid transfer to hospitals with inpatient dermatology are essential to optimize patient outcomes. Developing and validating SJS/TEN diagnosis and transfer protocols across multiple institutions may be helpful.

RAPID CITY, S.D. — Cassandra Palmier had been meaning to get her son the second and final dose of the measles vaccine. But car problems made it difficult to get to the doctor.

So she pounced on the opportunity to get him vaccinated after learning that a mobile clinic would be visiting her neighborhood.

“I was definitely concerned about the epidemic and the measles,” Palmier, a member of the Oglala Sioux Tribe, said at the June event. “I wanted to do my part.”

So did her son, Makaito Cuny.

“I’m not going to be scared,” the 5-year-old announced as he walked onto the bus containing the clinic and hopped into an exam chair.

Makaito sat still as a nurse gave him the shot in his arm. “I did it!” he said while smiling at his mother.

The vaccine clinic was hosted by the Great Plains Tribal Leaders’ Health Board, which serves tribes across Iowa, Nebraska, and the Dakotas. It’s one way Native American tribes and organizations are responding to concerns about low measles vaccination rates and patients’ difficulty accessing health care as the disease spreads across the country.

Meghan O’Connell, the board’s chief public health officer, said it is also working with tribes that want to host vaccine clinics.

Elsewhere, tribal health organizations have launched social media campaigns, are making sure health providers are vaccinated, and are reaching out to the parents of unvaccinated children.

This spring, Project ECHO at the University of New Mexico hosted an online video series about measles aimed at health care professionals and organizations that serve Native American communities. The presenters outlined the basics of measles diagnosis and treatment, discussed culturally relevant communication strategies, and shared how tribes are responding to the outbreak.

Participants also strategized about ways to improve vaccination rates, said Harry Brown, a physician and an epidemiologist for the United South and Eastern Tribes, a nonprofit that works with 33 tribes in the Atlantic Coast and Southeast regions.

“It’s a pretty hot topic right now in Indian Country and I think a lot of people are being proactive,” he said.

Measles can survive for up to two hours in the air in a space where an infected person has been, sickening up to 90% of people who aren’t vaccinated, according to the Centers for Disease Control and Prevention.

The U.S. has had 1,319 confirmed cases of measles this year as of July 23, according to the CDC. It’s the largest outbreak in the U.S. since 1992. Ninety-two percent of the 2025 cases involve unvaccinated patients or people with an unknown vaccination status. Three people had died in the U.S. and 165 had been hospitalized as of July 23.

O’Connell said data on Native Americans’ vaccination rates is imperfect but that it suggests a lower percentage of them have received measles shots than the overall U.S. population.

The limited national data on measles vaccination rates for Native Americans is based on small surveys of people who self-identify as Native American. Some show that Native Americans have slightly lower measles vaccination rates, while others show significant gaps.

Data from some states, including South Dakota and Montana, shows that Native Americans are less likely than white children to be vaccinated on schedule.

The national measles vaccination rate is significantly lower for Native Americans who use the mostly rural Indian Health Service. About 76% of children 16 to 27 months old had gotten the first shot, according to data collected by the agency during recent patient visits at 156 clinics. That’s a 10-percentage-point drop from 10 years ago.

But the IHS data shows that its patients are at least as likely as other children to have received both recommended measles shots by the time they’re 17. O’Connell said it’s unclear if currently unvaccinated patients will continue the trend of eventually getting up to date on their shots or if they will remain unvaccinated.

The immunization rate is probably higher for older children since schools require students to get vaccinated unless they have an exemption, Brown said. He said it’s important that parents get their children vaccinated on time, when they’re young and more at risk of being hospitalized or dying from the disease.

Native Americans may have lower vaccination rates due to the challenges they face in accessing shots and other health care, O’Connell said. Those on rural reservations may be an hour or more from a clinic. Or, like Palmier, they may not have reliable transportation.

Another reason, O’Connell said, is that some Native Americans distrust the Indian Health Service, which is chronically underfunded and understaffed. If the only nearby health care facility is run by the agency, patients may delay or skip care.

O’Connell and Brown said vaccine skepticism and mistrust of the entire health care system are growing in Native American communities, as has occurred elsewhere nationwide.

“Prior to social media, I think our population was pretty trustful of childhood vaccination. And American Indians have a long history of being severely impacted by infectious disease,” he said.

European colonizers’ arrival in the late 1400s brought new diseases, including measles, that killed tens of millions of Indigenous people in North and South America by the early 1600s. Native Americans have also had high mortality rates in modern pandemics, including the 1918-20 Spanish flu and COVID-19.

The Great Plains Tribal Leaders’ Health Board reacted quickly when measles cases began showing up near its headquarters in South Dakota this year. Nebraska health officials announced in late May that a child had measles in a rural part of the state, close to the Pine Ridge Indian Reservation. Then, four people from the Rapid City area got sick later that month and into the middle of June.

“Our phones really rang off the hook” once that news came out, said Darren Crowe, a vice president at the board’s Oyate Health Center in Rapid City. He said parents wanted to know if their children were up to date on their measles vaccines.

Crowe said the health board ordered extra masks, created a measles command team that meets daily, and called parents when its online database showed their children needed a shot.

Brown praised that approach.

“It takes a concerted outreach effort that goes individual to individual,” he said, adding that his organization helped the Mississippi Band of Choctaw Indians and the Alabama-Coushatta Tribe of Texas with similar efforts.

Brown said reaching specific families can be a challenge in some low-income Native American communities, where many people’s phone numbers frequently change since they use temporary prepaid plans.

Once a health worker reaches a parent, Brown said, they should listen and ask questions before sharing the importance of the vaccine against measles, mumps, and rubella.

“Rather than trying to preach to somebody and beat them over the head with data or whatever to convince them that this is what they need to do, you start out by finding out where they are,” he said. “So, ‘Tell me about your experience with vaccination. Tell me what you know about vaccination.’”

Most people agree to immunize their children when presented with helpful information in a nonjudgmental way, Brown said.

KFF Health News is a national newsroom that produces in-depth journalism about health issues and is one of the core operating programs at KFF—an independent source of health policy research, polling, and journalism. Learn more about KFF.

RAPID CITY, S.D. — Cassandra Palmier had been meaning to get her son the second and final dose of the measles vaccine. But car problems made it difficult to get to the doctor.

So she pounced on the opportunity to get him vaccinated after learning that a mobile clinic would be visiting her neighborhood.

“I was definitely concerned about the epidemic and the measles,” Palmier, a member of the Oglala Sioux Tribe, said at the June event. “I wanted to do my part.”

So did her son, Makaito Cuny.

“I’m not going to be scared,” the 5-year-old announced as he walked onto the bus containing the clinic and hopped into an exam chair.

Makaito sat still as a nurse gave him the shot in his arm. “I did it!” he said while smiling at his mother.

The vaccine clinic was hosted by the Great Plains Tribal Leaders’ Health Board, which serves tribes across Iowa, Nebraska, and the Dakotas. It’s one way Native American tribes and organizations are responding to concerns about low measles vaccination rates and patients’ difficulty accessing health care as the disease spreads across the country.

Meghan O’Connell, the board’s chief public health officer, said it is also working with tribes that want to host vaccine clinics.

Elsewhere, tribal health organizations have launched social media campaigns, are making sure health providers are vaccinated, and are reaching out to the parents of unvaccinated children.

This spring, Project ECHO at the University of New Mexico hosted an online video series about measles aimed at health care professionals and organizations that serve Native American communities. The presenters outlined the basics of measles diagnosis and treatment, discussed culturally relevant communication strategies, and shared how tribes are responding to the outbreak.

Participants also strategized about ways to improve vaccination rates, said Harry Brown, a physician and an epidemiologist for the United South and Eastern Tribes, a nonprofit that works with 33 tribes in the Atlantic Coast and Southeast regions.

“It’s a pretty hot topic right now in Indian Country and I think a lot of people are being proactive,” he said.

Measles can survive for up to two hours in the air in a space where an infected person has been, sickening up to 90% of people who aren’t vaccinated, according to the Centers for Disease Control and Prevention.

The U.S. has had 1,319 confirmed cases of measles this year as of July 23, according to the CDC. It’s the largest outbreak in the U.S. since 1992. Ninety-two percent of the 2025 cases involve unvaccinated patients or people with an unknown vaccination status. Three people had died in the U.S. and 165 had been hospitalized as of July 23.

O’Connell said data on Native Americans’ vaccination rates is imperfect but that it suggests a lower percentage of them have received measles shots than the overall U.S. population.

The limited national data on measles vaccination rates for Native Americans is based on small surveys of people who self-identify as Native American. Some show that Native Americans have slightly lower measles vaccination rates, while others show significant gaps.

Data from some states, including South Dakota and Montana, shows that Native Americans are less likely than white children to be vaccinated on schedule.

The national measles vaccination rate is significantly lower for Native Americans who use the mostly rural Indian Health Service. About 76% of children 16 to 27 months old had gotten the first shot, according to data collected by the agency during recent patient visits at 156 clinics. That’s a 10-percentage-point drop from 10 years ago.

But the IHS data shows that its patients are at least as likely as other children to have received both recommended measles shots by the time they’re 17. O’Connell said it’s unclear if currently unvaccinated patients will continue the trend of eventually getting up to date on their shots or if they will remain unvaccinated.

The immunization rate is probably higher for older children since schools require students to get vaccinated unless they have an exemption, Brown said. He said it’s important that parents get their children vaccinated on time, when they’re young and more at risk of being hospitalized or dying from the disease.

Native Americans may have lower vaccination rates due to the challenges they face in accessing shots and other health care, O’Connell said. Those on rural reservations may be an hour or more from a clinic. Or, like Palmier, they may not have reliable transportation.

Another reason, O’Connell said, is that some Native Americans distrust the Indian Health Service, which is chronically underfunded and understaffed. If the only nearby health care facility is run by the agency, patients may delay or skip care.

O’Connell and Brown said vaccine skepticism and mistrust of the entire health care system are growing in Native American communities, as has occurred elsewhere nationwide.

“Prior to social media, I think our population was pretty trustful of childhood vaccination. And American Indians have a long history of being severely impacted by infectious disease,” he said.

European colonizers’ arrival in the late 1400s brought new diseases, including measles, that killed tens of millions of Indigenous people in North and South America by the early 1600s. Native Americans have also had high mortality rates in modern pandemics, including the 1918-20 Spanish flu and COVID-19.

The Great Plains Tribal Leaders’ Health Board reacted quickly when measles cases began showing up near its headquarters in South Dakota this year. Nebraska health officials announced in late May that a child had measles in a rural part of the state, close to the Pine Ridge Indian Reservation. Then, four people from the Rapid City area got sick later that month and into the middle of June.

“Our phones really rang off the hook” once that news came out, said Darren Crowe, a vice president at the board’s Oyate Health Center in Rapid City. He said parents wanted to know if their children were up to date on their measles vaccines.

Crowe said the health board ordered extra masks, created a measles command team that meets daily, and called parents when its online database showed their children needed a shot.

Brown praised that approach.

“It takes a concerted outreach effort that goes individual to individual,” he said, adding that his organization helped the Mississippi Band of Choctaw Indians and the Alabama-Coushatta Tribe of Texas with similar efforts.

Brown said reaching specific families can be a challenge in some low-income Native American communities, where many people’s phone numbers frequently change since they use temporary prepaid plans.

Once a health worker reaches a parent, Brown said, they should listen and ask questions before sharing the importance of the vaccine against measles, mumps, and rubella.

“Rather than trying to preach to somebody and beat them over the head with data or whatever to convince them that this is what they need to do, you start out by finding out where they are,” he said. “So, ‘Tell me about your experience with vaccination. Tell me what you know about vaccination.’”

Most people agree to immunize their children when presented with helpful information in a nonjudgmental way, Brown said.

KFF Health News is a national newsroom that produces in-depth journalism about health issues and is one of the core operating programs at KFF—an independent source of health policy research, polling, and journalism. Learn more about KFF.

RAPID CITY, S.D. — Cassandra Palmier had been meaning to get her son the second and final dose of the measles vaccine. But car problems made it difficult to get to the doctor.

So she pounced on the opportunity to get him vaccinated after learning that a mobile clinic would be visiting her neighborhood.

“I was definitely concerned about the epidemic and the measles,” Palmier, a member of the Oglala Sioux Tribe, said at the June event. “I wanted to do my part.”

So did her son, Makaito Cuny.

“I’m not going to be scared,” the 5-year-old announced as he walked onto the bus containing the clinic and hopped into an exam chair.

Makaito sat still as a nurse gave him the shot in his arm. “I did it!” he said while smiling at his mother.

The vaccine clinic was hosted by the Great Plains Tribal Leaders’ Health Board, which serves tribes across Iowa, Nebraska, and the Dakotas. It’s one way Native American tribes and organizations are responding to concerns about low measles vaccination rates and patients’ difficulty accessing health care as the disease spreads across the country.

Meghan O’Connell, the board’s chief public health officer, said it is also working with tribes that want to host vaccine clinics.

Elsewhere, tribal health organizations have launched social media campaigns, are making sure health providers are vaccinated, and are reaching out to the parents of unvaccinated children.

This spring, Project ECHO at the University of New Mexico hosted an online video series about measles aimed at health care professionals and organizations that serve Native American communities. The presenters outlined the basics of measles diagnosis and treatment, discussed culturally relevant communication strategies, and shared how tribes are responding to the outbreak.

Participants also strategized about ways to improve vaccination rates, said Harry Brown, a physician and an epidemiologist for the United South and Eastern Tribes, a nonprofit that works with 33 tribes in the Atlantic Coast and Southeast regions.

“It’s a pretty hot topic right now in Indian Country and I think a lot of people are being proactive,” he said.

Measles can survive for up to two hours in the air in a space where an infected person has been, sickening up to 90% of people who aren’t vaccinated, according to the Centers for Disease Control and Prevention.

The U.S. has had 1,319 confirmed cases of measles this year as of July 23, according to the CDC. It’s the largest outbreak in the U.S. since 1992. Ninety-two percent of the 2025 cases involve unvaccinated patients or people with an unknown vaccination status. Three people had died in the U.S. and 165 had been hospitalized as of July 23.

O’Connell said data on Native Americans’ vaccination rates is imperfect but that it suggests a lower percentage of them have received measles shots than the overall U.S. population.

The limited national data on measles vaccination rates for Native Americans is based on small surveys of people who self-identify as Native American. Some show that Native Americans have slightly lower measles vaccination rates, while others show significant gaps.

Data from some states, including South Dakota and Montana, shows that Native Americans are less likely than white children to be vaccinated on schedule.

The national measles vaccination rate is significantly lower for Native Americans who use the mostly rural Indian Health Service. About 76% of children 16 to 27 months old had gotten the first shot, according to data collected by the agency during recent patient visits at 156 clinics. That’s a 10-percentage-point drop from 10 years ago.

But the IHS data shows that its patients are at least as likely as other children to have received both recommended measles shots by the time they’re 17. O’Connell said it’s unclear if currently unvaccinated patients will continue the trend of eventually getting up to date on their shots or if they will remain unvaccinated.

The immunization rate is probably higher for older children since schools require students to get vaccinated unless they have an exemption, Brown said. He said it’s important that parents get their children vaccinated on time, when they’re young and more at risk of being hospitalized or dying from the disease.

Native Americans may have lower vaccination rates due to the challenges they face in accessing shots and other health care, O’Connell said. Those on rural reservations may be an hour or more from a clinic. Or, like Palmier, they may not have reliable transportation.

Another reason, O’Connell said, is that some Native Americans distrust the Indian Health Service, which is chronically underfunded and understaffed. If the only nearby health care facility is run by the agency, patients may delay or skip care.

O’Connell and Brown said vaccine skepticism and mistrust of the entire health care system are growing in Native American communities, as has occurred elsewhere nationwide.

“Prior to social media, I think our population was pretty trustful of childhood vaccination. And American Indians have a long history of being severely impacted by infectious disease,” he said.

European colonizers’ arrival in the late 1400s brought new diseases, including measles, that killed tens of millions of Indigenous people in North and South America by the early 1600s. Native Americans have also had high mortality rates in modern pandemics, including the 1918-20 Spanish flu and COVID-19.

The Great Plains Tribal Leaders’ Health Board reacted quickly when measles cases began showing up near its headquarters in South Dakota this year. Nebraska health officials announced in late May that a child had measles in a rural part of the state, close to the Pine Ridge Indian Reservation. Then, four people from the Rapid City area got sick later that month and into the middle of June.

“Our phones really rang off the hook” once that news came out, said Darren Crowe, a vice president at the board’s Oyate Health Center in Rapid City. He said parents wanted to know if their children were up to date on their measles vaccines.

Crowe said the health board ordered extra masks, created a measles command team that meets daily, and called parents when its online database showed their children needed a shot.

Brown praised that approach.

“It takes a concerted outreach effort that goes individual to individual,” he said, adding that his organization helped the Mississippi Band of Choctaw Indians and the Alabama-Coushatta Tribe of Texas with similar efforts.

Brown said reaching specific families can be a challenge in some low-income Native American communities, where many people’s phone numbers frequently change since they use temporary prepaid plans.

Once a health worker reaches a parent, Brown said, they should listen and ask questions before sharing the importance of the vaccine against measles, mumps, and rubella.

“Rather than trying to preach to somebody and beat them over the head with data or whatever to convince them that this is what they need to do, you start out by finding out where they are,” he said. “So, ‘Tell me about your experience with vaccination. Tell me what you know about vaccination.’”

Most people agree to immunize their children when presented with helpful information in a nonjudgmental way, Brown said.

KFF Health News is a national newsroom that produces in-depth journalism about health issues and is one of the core operating programs at KFF—an independent source of health policy research, polling, and journalism. Learn more about KFF.

Federal Health Care Data Trends is a special supplement to Federal Practitioner, showcasing the latest research in health care for veterans and active-duty military members via compelling infographics. 
Topics include:

• Veteran Health at a Glance
• Obesity
• Hepatology
• Diabetes
• Cardiology
• Pulmonology
• Neurology
• Mental Health
• Women's Health
• LGBTQ+ Care
• HIV
• Acute Pain
• Dermatology

Federal Health Care Data Trends is a special supplement to Federal Practitioner, showcasing the latest research in health care for veterans and active-duty military members via compelling infographics. 
Topics include:

• Veteran Health at a Glance
• Obesity
• Hepatology
• Diabetes
• Cardiology
• Pulmonology
• Neurology
• Mental Health
• Women's Health
• LGBTQ+ Care
• HIV
• Acute Pain
• Dermatology

Federal Health Care Data Trends is a special supplement to Federal Practitioner, showcasing the latest research in health care for veterans and active-duty military members via compelling infographics. 
Topics include:

• Veteran Health at a Glance
• Obesity
• Hepatology
• Diabetes
• Cardiology
• Pulmonology
• Neurology
• Mental Health
• Women's Health
• LGBTQ+ Care
• HIV
• Acute Pain
• Dermatology

THE DIAGNOSIS: Pedunculated Lipofibroma

Histopathology confirmed a pedunculated/polypoid lesion with intradermal lobules of adipocytes/mature adipose tissue admixed with connective tissue bundles and vascular ectasias. Overlying epidermal acanthosis with slight papillomatosis and hyperkeratosis was present (Figure 1). Masson trichrome staining highlighted admixed collagen bundles (Figure 2). Verhoeff–van Gieson staining showed marked reduction in elastic fibers (Figure 3). Immunostaining was negative for smooth muscle actin and desmin. A diagnosis of pedunculated lipofibroma on the nose was made based on both clinical and histopathologic findings.

Pedunculated lipofibroma (or solitary lipofibroma) is the solitary form of nevus lipomatosus cutaneous superficialis (NLCS).⁷ First described by Hoffmann and Zurhelle¹ in 1921, NLCS is an uncommon benign hamartomatous cutaneous lesion/connective tissue nevus that also has a classic multiple form.^1-13 The etiology of NLCS remains unclear, but several theories have been proposed to explain its pathogenesis, including deposition of adipocytes secondary to degenerative changes in dermal connective tissue, focal/local heterotopic development of adipose tissue, and derivation from differentiating lipoblasts (preadipose tissue) originating from precursor vascular or perivascular cells.^2-13

Pedunculated lipofibroma usually develops during the third to sixth decades of life and manifests as a single cutaneous lesion with a smooth surface, often on a non–pelvic girdle location.^7-13 No particular predilection sites are noted, with lesions reported on the arm, axilla, back, upper thigh, knee, and sole.^5,12 There are rare reports of this type of NLCS on the ear, scalp, forehead, or eyelid.^7-11

In the classic form of NLCS, multiple cutaneous lesions are present at birth or develop within the first 2 to 3 decades of life.^2-6 Lesions consist of soft, nontender, pedunculated, flesh-colored or yellowish papules and nodules with a verrucoid or cerebriform surface that may later coalesce to form plaques.^2-6 Predilection sites include the pelvic girdle, buttocks, sacral and coccygeal regions, and upper posterior thighs, with a linear or zosteriform pattern of distribution.^2-6 Rarely, the classic form can arise in elderly patients and/or at an atypical anatomic location (eg, clitoris,³ shoulder,⁵ thorax,⁵ abdomen⁵) and can demonstrate extension of lesions across the midline.⁴ Rare cases of classic NLCS on the scalp² and face^3-6 have been reported, including lesions localized to the nose³ and chin⁴ and others extending from the right mandible to the neck⁵ and right lower lip to the submandibular/posteriorateral cervical region.⁶ In some cases, lesions clinically resemble plane xanthoma⁴ and localized scleroderma.⁶

Adotama et al¹³ proposed a set of clinical features to differentiate classic NLCS, pedunculated lipofibroma (solitary NLCS), and fibroepithelial polyp with adipocytes (distinguished by their furrowed surface, hyperpigmentation, and anatomic predilection for the neck and axilla). Lesions are asymptomatic in both forms of NLCS.^2-13 Family history or predominant sex involvement have not been reported in either clinical type.^2-13 Reported associations with NLCS include a number of endocrinologic conditions including diabetes.⁷ Other coexisting skin findings can include café-au-lait macules, leukodermic (white) spots, overlying hypertrichosis, comedolike alterations, angiokeratoma, hemangioma, and folliculosebaceous cystic hamartoma.⁴ None of these were evident in our patient.

Lesions from both types of NLCS are indistinguishable on histopathology, characterized by the presence of a central core of ectopic mature adipocytes in the papillary/reticular dermis.^2-13 Additional light microscopic features (some seen in our case) have been described, including thickened collagen bundles, reduction of elastic fibers, increased numbers of fibroblasts and/or mast cells, increased (small-vessel) vascularity, focal mucin deposition/myxoid degeneration, a mild perivascular lymphocytic infiltrate, attenuation of adnexal structures, and abnormalities of the epidermis (eg, surface ulceration).^2-13

Prior to biopsy, the differential diagnosis in our patient included angiofibroma, pyogenic granuloma, and basal cell carcinoma given the exophytic, pink, papular appearance of the lesion; however, the histopathologic differential diagnosis included angiofibroma, angiomyolipoma, lymphangioma, nevus sebaceus, and spindle cell lipoma (SCL). In angiofibroma, a dermal proliferation of stellate fibroblasts, dilated blood vessels, and collagenous stroma are seen. Cutaneous angiomyolipoma demonstrates smooth muscle bundles in addition to thickened blood vessels and variable proportions of mature adipocytes. Lymphangioma is characterized by dilated lymph channels lined by flat endothelial cells. Nevus sebaceus shows superficial immature and abnormally formed pilosebaceous units, with epidermal papillomatosis.

Rare cases of SCL on the nose have been described.¹⁴ Similar to pedunculated lipofibroma, reported examples demonstrate mature univacuolar adipocytes with thick collagen fibers and bland uniform spindle cells. Unlike the lesion seen in our patient, nasal SCL may be clinically mobile and typically is localized to the subcutaneous tissue, although dermal tumors also occur.¹⁴ Variably reported histopathologic findings in nasal SCL include circumscription/encapsulation, spindle cells arranged in short fascicles with nuclear palisading, a myxoid/mucinous interstitial matrix, and/or multinucleated giant cells—all light microscopic features that were not identified in our case; however, variable proportions of adipocytic, fibrous, and myxoid components among reported examples of SCL on the nose¹⁴ can make distinction from pedunculated lipofibroma difficult, as both are benign lipomatous tumor variants.

Clinically, pedunculated lipofibroma may be confused with more common benign cutaneous lesions and must be distinguished from other fibrolipomatous lesions on the nose. Specifically, the differential diagnosis includes benign cutaneous papillomas such as acrochordon, angiofibroma, melanocytic nevi, neurofibroma, nevus sebaceus, lymphangioma, and eccrine poroma.^7-13 These all can be readily excluded on histopathology. Pedunculated lipofibroma on the nose, as in our patient, must be distinguished from fibrolipoma¹⁵ and dendritic myxofibrolipoma.¹⁶ Fibrolipoma is a subcutaneous proliferation of mature adipose tissue and fibrous tissue and comprises 1.6% of all facial lipomas reported worldwide.¹⁵ Dendritic myxofibrolipoma is a recently described benign soft-tissue tumor characterized by an admixture of mature adipose tissue, spindle and stellate cells, and an abundant myxoid stroma with prominent collagenization.¹⁶

Treatment of pedunculated lipofibroma on the nose is not indicated except for cosmetic reasons, in which case simple surgical excision would be considered satisfactory. Following biopsy, no further treatment was pursued in our patient.

THE DIAGNOSIS: Pedunculated Lipofibroma

Histopathology confirmed a pedunculated/polypoid lesion with intradermal lobules of adipocytes/mature adipose tissue admixed with connective tissue bundles and vascular ectasias. Overlying epidermal acanthosis with slight papillomatosis and hyperkeratosis was present (Figure 1). Masson trichrome staining highlighted admixed collagen bundles (Figure 2). Verhoeff–van Gieson staining showed marked reduction in elastic fibers (Figure 3). Immunostaining was negative for smooth muscle actin and desmin. A diagnosis of pedunculated lipofibroma on the nose was made based on both clinical and histopathologic findings.

Pedunculated lipofibroma (or solitary lipofibroma) is the solitary form of nevus lipomatosus cutaneous superficialis (NLCS).⁷ First described by Hoffmann and Zurhelle¹ in 1921, NLCS is an uncommon benign hamartomatous cutaneous lesion/connective tissue nevus that also has a classic multiple form.^1-13 The etiology of NLCS remains unclear, but several theories have been proposed to explain its pathogenesis, including deposition of adipocytes secondary to degenerative changes in dermal connective tissue, focal/local heterotopic development of adipose tissue, and derivation from differentiating lipoblasts (preadipose tissue) originating from precursor vascular or perivascular cells.^2-13

Pedunculated lipofibroma usually develops during the third to sixth decades of life and manifests as a single cutaneous lesion with a smooth surface, often on a non–pelvic girdle location.^7-13 No particular predilection sites are noted, with lesions reported on the arm, axilla, back, upper thigh, knee, and sole.^5,12 There are rare reports of this type of NLCS on the ear, scalp, forehead, or eyelid.^7-11

In the classic form of NLCS, multiple cutaneous lesions are present at birth or develop within the first 2 to 3 decades of life.^2-6 Lesions consist of soft, nontender, pedunculated, flesh-colored or yellowish papules and nodules with a verrucoid or cerebriform surface that may later coalesce to form plaques.^2-6 Predilection sites include the pelvic girdle, buttocks, sacral and coccygeal regions, and upper posterior thighs, with a linear or zosteriform pattern of distribution.^2-6 Rarely, the classic form can arise in elderly patients and/or at an atypical anatomic location (eg, clitoris,³ shoulder,⁵ thorax,⁵ abdomen⁵) and can demonstrate extension of lesions across the midline.⁴ Rare cases of classic NLCS on the scalp² and face^3-6 have been reported, including lesions localized to the nose³ and chin⁴ and others extending from the right mandible to the neck⁵ and right lower lip to the submandibular/posteriorateral cervical region.⁶ In some cases, lesions clinically resemble plane xanthoma⁴ and localized scleroderma.⁶

Adotama et al¹³ proposed a set of clinical features to differentiate classic NLCS, pedunculated lipofibroma (solitary NLCS), and fibroepithelial polyp with adipocytes (distinguished by their furrowed surface, hyperpigmentation, and anatomic predilection for the neck and axilla). Lesions are asymptomatic in both forms of NLCS.^2-13 Family history or predominant sex involvement have not been reported in either clinical type.^2-13 Reported associations with NLCS include a number of endocrinologic conditions including diabetes.⁷ Other coexisting skin findings can include café-au-lait macules, leukodermic (white) spots, overlying hypertrichosis, comedolike alterations, angiokeratoma, hemangioma, and folliculosebaceous cystic hamartoma.⁴ None of these were evident in our patient.

Lesions from both types of NLCS are indistinguishable on histopathology, characterized by the presence of a central core of ectopic mature adipocytes in the papillary/reticular dermis.^2-13 Additional light microscopic features (some seen in our case) have been described, including thickened collagen bundles, reduction of elastic fibers, increased numbers of fibroblasts and/or mast cells, increased (small-vessel) vascularity, focal mucin deposition/myxoid degeneration, a mild perivascular lymphocytic infiltrate, attenuation of adnexal structures, and abnormalities of the epidermis (eg, surface ulceration).^2-13

Prior to biopsy, the differential diagnosis in our patient included angiofibroma, pyogenic granuloma, and basal cell carcinoma given the exophytic, pink, papular appearance of the lesion; however, the histopathologic differential diagnosis included angiofibroma, angiomyolipoma, lymphangioma, nevus sebaceus, and spindle cell lipoma (SCL). In angiofibroma, a dermal proliferation of stellate fibroblasts, dilated blood vessels, and collagenous stroma are seen. Cutaneous angiomyolipoma demonstrates smooth muscle bundles in addition to thickened blood vessels and variable proportions of mature adipocytes. Lymphangioma is characterized by dilated lymph channels lined by flat endothelial cells. Nevus sebaceus shows superficial immature and abnormally formed pilosebaceous units, with epidermal papillomatosis.

Rare cases of SCL on the nose have been described.¹⁴ Similar to pedunculated lipofibroma, reported examples demonstrate mature univacuolar adipocytes with thick collagen fibers and bland uniform spindle cells. Unlike the lesion seen in our patient, nasal SCL may be clinically mobile and typically is localized to the subcutaneous tissue, although dermal tumors also occur.¹⁴ Variably reported histopathologic findings in nasal SCL include circumscription/encapsulation, spindle cells arranged in short fascicles with nuclear palisading, a myxoid/mucinous interstitial matrix, and/or multinucleated giant cells—all light microscopic features that were not identified in our case; however, variable proportions of adipocytic, fibrous, and myxoid components among reported examples of SCL on the nose¹⁴ can make distinction from pedunculated lipofibroma difficult, as both are benign lipomatous tumor variants.

Clinically, pedunculated lipofibroma may be confused with more common benign cutaneous lesions and must be distinguished from other fibrolipomatous lesions on the nose. Specifically, the differential diagnosis includes benign cutaneous papillomas such as acrochordon, angiofibroma, melanocytic nevi, neurofibroma, nevus sebaceus, lymphangioma, and eccrine poroma.^7-13 These all can be readily excluded on histopathology. Pedunculated lipofibroma on the nose, as in our patient, must be distinguished from fibrolipoma¹⁵ and dendritic myxofibrolipoma.¹⁶ Fibrolipoma is a subcutaneous proliferation of mature adipose tissue and fibrous tissue and comprises 1.6% of all facial lipomas reported worldwide.¹⁵ Dendritic myxofibrolipoma is a recently described benign soft-tissue tumor characterized by an admixture of mature adipose tissue, spindle and stellate cells, and an abundant myxoid stroma with prominent collagenization.¹⁶

Treatment of pedunculated lipofibroma on the nose is not indicated except for cosmetic reasons, in which case simple surgical excision would be considered satisfactory. Following biopsy, no further treatment was pursued in our patient.

THE DIAGNOSIS: Pedunculated Lipofibroma

Histopathology confirmed a pedunculated/polypoid lesion with intradermal lobules of adipocytes/mature adipose tissue admixed with connective tissue bundles and vascular ectasias. Overlying epidermal acanthosis with slight papillomatosis and hyperkeratosis was present (Figure 1). Masson trichrome staining highlighted admixed collagen bundles (Figure 2). Verhoeff–van Gieson staining showed marked reduction in elastic fibers (Figure 3). Immunostaining was negative for smooth muscle actin and desmin. A diagnosis of pedunculated lipofibroma on the nose was made based on both clinical and histopathologic findings.

Pedunculated lipofibroma (or solitary lipofibroma) is the solitary form of nevus lipomatosus cutaneous superficialis (NLCS).⁷ First described by Hoffmann and Zurhelle¹ in 1921, NLCS is an uncommon benign hamartomatous cutaneous lesion/connective tissue nevus that also has a classic multiple form.^1-13 The etiology of NLCS remains unclear, but several theories have been proposed to explain its pathogenesis, including deposition of adipocytes secondary to degenerative changes in dermal connective tissue, focal/local heterotopic development of adipose tissue, and derivation from differentiating lipoblasts (preadipose tissue) originating from precursor vascular or perivascular cells.^2-13

Pedunculated lipofibroma usually develops during the third to sixth decades of life and manifests as a single cutaneous lesion with a smooth surface, often on a non–pelvic girdle location.^7-13 No particular predilection sites are noted, with lesions reported on the arm, axilla, back, upper thigh, knee, and sole.^5,12 There are rare reports of this type of NLCS on the ear, scalp, forehead, or eyelid.^7-11

In the classic form of NLCS, multiple cutaneous lesions are present at birth or develop within the first 2 to 3 decades of life.^2-6 Lesions consist of soft, nontender, pedunculated, flesh-colored or yellowish papules and nodules with a verrucoid or cerebriform surface that may later coalesce to form plaques.^2-6 Predilection sites include the pelvic girdle, buttocks, sacral and coccygeal regions, and upper posterior thighs, with a linear or zosteriform pattern of distribution.^2-6 Rarely, the classic form can arise in elderly patients and/or at an atypical anatomic location (eg, clitoris,³ shoulder,⁵ thorax,⁵ abdomen⁵) and can demonstrate extension of lesions across the midline.⁴ Rare cases of classic NLCS on the scalp² and face^3-6 have been reported, including lesions localized to the nose³ and chin⁴ and others extending from the right mandible to the neck⁵ and right lower lip to the submandibular/posteriorateral cervical region.⁶ In some cases, lesions clinically resemble plane xanthoma⁴ and localized scleroderma.⁶

Adotama et al¹³ proposed a set of clinical features to differentiate classic NLCS, pedunculated lipofibroma (solitary NLCS), and fibroepithelial polyp with adipocytes (distinguished by their furrowed surface, hyperpigmentation, and anatomic predilection for the neck and axilla). Lesions are asymptomatic in both forms of NLCS.^2-13 Family history or predominant sex involvement have not been reported in either clinical type.^2-13 Reported associations with NLCS include a number of endocrinologic conditions including diabetes.⁷ Other coexisting skin findings can include café-au-lait macules, leukodermic (white) spots, overlying hypertrichosis, comedolike alterations, angiokeratoma, hemangioma, and folliculosebaceous cystic hamartoma.⁴ None of these were evident in our patient.

Lesions from both types of NLCS are indistinguishable on histopathology, characterized by the presence of a central core of ectopic mature adipocytes in the papillary/reticular dermis.^2-13 Additional light microscopic features (some seen in our case) have been described, including thickened collagen bundles, reduction of elastic fibers, increased numbers of fibroblasts and/or mast cells, increased (small-vessel) vascularity, focal mucin deposition/myxoid degeneration, a mild perivascular lymphocytic infiltrate, attenuation of adnexal structures, and abnormalities of the epidermis (eg, surface ulceration).^2-13

Prior to biopsy, the differential diagnosis in our patient included angiofibroma, pyogenic granuloma, and basal cell carcinoma given the exophytic, pink, papular appearance of the lesion; however, the histopathologic differential diagnosis included angiofibroma, angiomyolipoma, lymphangioma, nevus sebaceus, and spindle cell lipoma (SCL). In angiofibroma, a dermal proliferation of stellate fibroblasts, dilated blood vessels, and collagenous stroma are seen. Cutaneous angiomyolipoma demonstrates smooth muscle bundles in addition to thickened blood vessels and variable proportions of mature adipocytes. Lymphangioma is characterized by dilated lymph channels lined by flat endothelial cells. Nevus sebaceus shows superficial immature and abnormally formed pilosebaceous units, with epidermal papillomatosis.

Rare cases of SCL on the nose have been described.¹⁴ Similar to pedunculated lipofibroma, reported examples demonstrate mature univacuolar adipocytes with thick collagen fibers and bland uniform spindle cells. Unlike the lesion seen in our patient, nasal SCL may be clinically mobile and typically is localized to the subcutaneous tissue, although dermal tumors also occur.¹⁴ Variably reported histopathologic findings in nasal SCL include circumscription/encapsulation, spindle cells arranged in short fascicles with nuclear palisading, a myxoid/mucinous interstitial matrix, and/or multinucleated giant cells—all light microscopic features that were not identified in our case; however, variable proportions of adipocytic, fibrous, and myxoid components among reported examples of SCL on the nose¹⁴ can make distinction from pedunculated lipofibroma difficult, as both are benign lipomatous tumor variants.

Clinically, pedunculated lipofibroma may be confused with more common benign cutaneous lesions and must be distinguished from other fibrolipomatous lesions on the nose. Specifically, the differential diagnosis includes benign cutaneous papillomas such as acrochordon, angiofibroma, melanocytic nevi, neurofibroma, nevus sebaceus, lymphangioma, and eccrine poroma.^7-13 These all can be readily excluded on histopathology. Pedunculated lipofibroma on the nose, as in our patient, must be distinguished from fibrolipoma¹⁵ and dendritic myxofibrolipoma.¹⁶ Fibrolipoma is a subcutaneous proliferation of mature adipose tissue and fibrous tissue and comprises 1.6% of all facial lipomas reported worldwide.¹⁵ Dendritic myxofibrolipoma is a recently described benign soft-tissue tumor characterized by an admixture of mature adipose tissue, spindle and stellate cells, and an abundant myxoid stroma with prominent collagenization.¹⁶

Treatment of pedunculated lipofibroma on the nose is not indicated except for cosmetic reasons, in which case simple surgical excision would be considered satisfactory. Following biopsy, no further treatment was pursued in our patient.

Caring messages to veterans at risk for suicide come in many forms: cards, letters, phone calls, email, and text messages. Each message can have a major impact on the veteran’s mental health and their decision to use health care provided by the US Department of Veterans Affairs (VA). A recent study outlined ways to centralize that impact, ensuring the caring message reaches those who need it most.

The study examined the impact of the VA Veterans Crisis Line (VCL) caring letters intervention among veterans at increased psychiatric risk. It focused on veterans with ≥ 2 Veterans Health Administration (VHA) health service encounters within 24 months prior to VCL contact. The primary outcome was suicide-related events (SRE), including suicide attempts, intentional self-harm, and suicidal self-directed violence. Secondary outcomes included VHA health care use (all-cause inpatient and outpatient, mental health outpatient, mental health inpatient, and emergency department). 

Of 186,514 VCL callers, 8.3% had a psychiatric hospitalization, 4.8% were flagged as high-risk by the REACH VET program, 6.2% had an SRE, and 12.9% met any of these criteria in the year prior to initial VCL contact. There was no association between caring letters and all-cause mortality or SRE, even though caring letters is one of the only interventions to demonstrate a reduction in suicide mortality as a randomized controlled trial.

While reducing suicide has not been the expected result, caring letters have consistently been associated with increased use of outpatient mental health services. The analysis found that veterans with and without indicators of elevated psychiatric risk were using services more. That, the researchers suggest, is more evidence that caring letters might prompt engagement with VHA care, even among veterans not identified as high risk.

Psychiatrist Jerome A. Motto, MD believed long-term supportive but nondemanding contact could reduce a suicidal person’s sense of isolation and enhance feelings of connectedness. His 1976 intervention established a plan to “exert a suicide prevention influence on high-risk persons who decline to enter the health care system.” In Motto’s 5-year follow-up study of 3,006 psychiatric inpatients, half of those who were not following their postdischarge treatment plan received calls or letters expressing interest in their well-being. Suicidal deaths were found to “diverge progressively,” leading Motto to claim the study showed “tentative evidence” that a high-risk population for suicide can be identified and that risk might be reduced through a systematic approach.

Despite those findings, the results of studies on repeated follow-up contact have been mixed. One review outlined how 5 studies showed a statistically significant reduction in suicidal behavior, 4 showed mixed results with trends toward a preventive effect, and 2 studies did not show a preventive effect.

In 2020, the VA launched an intervention for veterans who contacted the VCL. In the first 12 months, CLs were sent to > 100,000 veterans. In feedback interviews, participants described feeling appreciated, cared for, encouraged, and connected. They also said that the CLs helped them engage with community resources and made them more likely to seek VA care. Even veterans who were skeptical of the utility of the caring letters sometimes admitted keeping them.

Finding effective ways to prevent suicide among veterans has been a top priority for the VA. In 2021, then-US Surgeon General Jerome Adams issued a Call to Action that recommended using caring letters when gaps in care may exist, including following crisis line calls.

Caring messages to veterans at risk for suicide come in many forms: cards, letters, phone calls, email, and text messages. Each message can have a major impact on the veteran’s mental health and their decision to use health care provided by the US Department of Veterans Affairs (VA). A recent study outlined ways to centralize that impact, ensuring the caring message reaches those who need it most.

The study examined the impact of the VA Veterans Crisis Line (VCL) caring letters intervention among veterans at increased psychiatric risk. It focused on veterans with ≥ 2 Veterans Health Administration (VHA) health service encounters within 24 months prior to VCL contact. The primary outcome was suicide-related events (SRE), including suicide attempts, intentional self-harm, and suicidal self-directed violence. Secondary outcomes included VHA health care use (all-cause inpatient and outpatient, mental health outpatient, mental health inpatient, and emergency department). 

Of 186,514 VCL callers, 8.3% had a psychiatric hospitalization, 4.8% were flagged as high-risk by the REACH VET program, 6.2% had an SRE, and 12.9% met any of these criteria in the year prior to initial VCL contact. There was no association between caring letters and all-cause mortality or SRE, even though caring letters is one of the only interventions to demonstrate a reduction in suicide mortality as a randomized controlled trial.

While reducing suicide has not been the expected result, caring letters have consistently been associated with increased use of outpatient mental health services. The analysis found that veterans with and without indicators of elevated psychiatric risk were using services more. That, the researchers suggest, is more evidence that caring letters might prompt engagement with VHA care, even among veterans not identified as high risk.

Psychiatrist Jerome A. Motto, MD believed long-term supportive but nondemanding contact could reduce a suicidal person’s sense of isolation and enhance feelings of connectedness. His 1976 intervention established a plan to “exert a suicide prevention influence on high-risk persons who decline to enter the health care system.” In Motto’s 5-year follow-up study of 3,006 psychiatric inpatients, half of those who were not following their postdischarge treatment plan received calls or letters expressing interest in their well-being. Suicidal deaths were found to “diverge progressively,” leading Motto to claim the study showed “tentative evidence” that a high-risk population for suicide can be identified and that risk might be reduced through a systematic approach.

Despite those findings, the results of studies on repeated follow-up contact have been mixed. One review outlined how 5 studies showed a statistically significant reduction in suicidal behavior, 4 showed mixed results with trends toward a preventive effect, and 2 studies did not show a preventive effect.

In 2020, the VA launched an intervention for veterans who contacted the VCL. In the first 12 months, CLs were sent to > 100,000 veterans. In feedback interviews, participants described feeling appreciated, cared for, encouraged, and connected. They also said that the CLs helped them engage with community resources and made them more likely to seek VA care. Even veterans who were skeptical of the utility of the caring letters sometimes admitted keeping them.

Finding effective ways to prevent suicide among veterans has been a top priority for the VA. In 2021, then-US Surgeon General Jerome Adams issued a Call to Action that recommended using caring letters when gaps in care may exist, including following crisis line calls.

Caring messages to veterans at risk for suicide come in many forms: cards, letters, phone calls, email, and text messages. Each message can have a major impact on the veteran’s mental health and their decision to use health care provided by the US Department of Veterans Affairs (VA). A recent study outlined ways to centralize that impact, ensuring the caring message reaches those who need it most.

The study examined the impact of the VA Veterans Crisis Line (VCL) caring letters intervention among veterans at increased psychiatric risk. It focused on veterans with ≥ 2 Veterans Health Administration (VHA) health service encounters within 24 months prior to VCL contact. The primary outcome was suicide-related events (SRE), including suicide attempts, intentional self-harm, and suicidal self-directed violence. Secondary outcomes included VHA health care use (all-cause inpatient and outpatient, mental health outpatient, mental health inpatient, and emergency department). 

Of 186,514 VCL callers, 8.3% had a psychiatric hospitalization, 4.8% were flagged as high-risk by the REACH VET program, 6.2% had an SRE, and 12.9% met any of these criteria in the year prior to initial VCL contact. There was no association between caring letters and all-cause mortality or SRE, even though caring letters is one of the only interventions to demonstrate a reduction in suicide mortality as a randomized controlled trial.

While reducing suicide has not been the expected result, caring letters have consistently been associated with increased use of outpatient mental health services. The analysis found that veterans with and without indicators of elevated psychiatric risk were using services more. That, the researchers suggest, is more evidence that caring letters might prompt engagement with VHA care, even among veterans not identified as high risk.

Psychiatrist Jerome A. Motto, MD believed long-term supportive but nondemanding contact could reduce a suicidal person’s sense of isolation and enhance feelings of connectedness. His 1976 intervention established a plan to “exert a suicide prevention influence on high-risk persons who decline to enter the health care system.” In Motto’s 5-year follow-up study of 3,006 psychiatric inpatients, half of those who were not following their postdischarge treatment plan received calls or letters expressing interest in their well-being. Suicidal deaths were found to “diverge progressively,” leading Motto to claim the study showed “tentative evidence” that a high-risk population for suicide can be identified and that risk might be reduced through a systematic approach.

Despite those findings, the results of studies on repeated follow-up contact have been mixed. One review outlined how 5 studies showed a statistically significant reduction in suicidal behavior, 4 showed mixed results with trends toward a preventive effect, and 2 studies did not show a preventive effect.

In 2020, the VA launched an intervention for veterans who contacted the VCL. In the first 12 months, CLs were sent to > 100,000 veterans. In feedback interviews, participants described feeling appreciated, cared for, encouraged, and connected. They also said that the CLs helped them engage with community resources and made them more likely to seek VA care. Even veterans who were skeptical of the utility of the caring letters sometimes admitted keeping them.

Finding effective ways to prevent suicide among veterans has been a top priority for the VA. In 2021, then-US Surgeon General Jerome Adams issued a Call to Action that recommended using caring letters when gaps in care may exist, including following crisis line calls.

Traumatic and environmental exposures during military service may put women veterans at risk for early menopause, a recent longitudinal analysis of data from 668 women in the Gulf War Era Cohort Study found.

The study examined associations between possible early menopause (aged < 45 years) and participants’ Gulf War deployment, military environmental exposures (MEEs), Gulf War Illness, military sexual trauma (MST) and posttraumatic stress disorder (PTSD). 

Of 384 Gulf War–deployed veterans, 63% reported MEEs and 26% reported MST during deployment. More than half (57%) of study participants (both Gulf War veterans and nondeployed veterans) met criteria for Gulf War Illness, and 23% met criteria for probable PTSD. 

At follow-up, 15% of the women had possible early menopause—higher than population estimates for early menopause in the US, which range from 5% to 10%.

Gulf War deployment, Gulf War–related environmental exposures, and MST during deployment were not significantly associated with early menopause. However, both Gulf War Illness (odds ratio [OR], 1.83; 95% CI, 1.14 to 2.95) and probable PTSD (OR, 2.45; 95% CI, 1.54 to 3.90) were strongly associated with early menopause. Women with probable PTSD at baseline had more than double the odds of possible early menopause.

Previous research suggests that deployment, MEEs, and Gulf War Illness are broadly associated with adverse reproductive health conditions in women veterans. Exposure to persistent organic pollutants and combustion byproducts (eg, from industrial processes and burn pits) have been linked to ovarian dysfunction and oocyte destruction presumed to contribute to accelerated ovarian aging.

The average age for menopause in the US is 52 years. About 5% of women go through early menopause naturally. Early and premature (< 40 years) menopause may also result from a medical or surgical cause, such as a hysterectomy. Regardless the cause, early menopause can have a profound impact on a woman’s physical, emotional, and mental health. It is associated with premature mortality, poor bone health, sexual dysfunction, a 50% increased risk of cardiovascular disease, and 2-fold increased odds of depression.

“Sometimes we talk about menopause symptoms thinking that they're just sort of 1 brief point in time, but we're also talking about things that may affect women's health and functioning for a third or half of a lifespan,” Carolyn Gibson, PhD, MPH, said at the 2024 Spotlight on Women's Health Cyberseminar Series.

Gibson, a staff psychologist at the San Francisco Veterans Affairs (VA) Women’s Mental Health Program and lead author on the recent early-menopause study, pointed to some of the chronic physical health issues that might develop, such as cardiovascular disease, but also the psychological effects.

“It's just important,” she said during the Cyberseminar Series. “To think about the number of things that women in midlife tend to be juggling and managing, all of which may turn up the volume on symptom experience, effect of vulnerability to health and mental health challenges during this period.”

The findings of the study have clinical implications. Midlife women veterans (aged 45 to 64 years) are the largest group of women veterans enrolled in VA health care. Early menopause brings additional age-related care considerations. The authors advise prioritizing support for routine screening for menopause status and symptoms as well as gender-sensitive training, resources, and staffing to provide comprehensive, trauma-informed, evidence-based menopause care for women at any age.

Traumatic and environmental exposures during military service may put women veterans at risk for early menopause, a recent longitudinal analysis of data from 668 women in the Gulf War Era Cohort Study found.

The study examined associations between possible early menopause (aged < 45 years) and participants’ Gulf War deployment, military environmental exposures (MEEs), Gulf War Illness, military sexual trauma (MST) and posttraumatic stress disorder (PTSD). 

Of 384 Gulf War–deployed veterans, 63% reported MEEs and 26% reported MST during deployment. More than half (57%) of study participants (both Gulf War veterans and nondeployed veterans) met criteria for Gulf War Illness, and 23% met criteria for probable PTSD. 

At follow-up, 15% of the women had possible early menopause—higher than population estimates for early menopause in the US, which range from 5% to 10%.

Gulf War deployment, Gulf War–related environmental exposures, and MST during deployment were not significantly associated with early menopause. However, both Gulf War Illness (odds ratio [OR], 1.83; 95% CI, 1.14 to 2.95) and probable PTSD (OR, 2.45; 95% CI, 1.54 to 3.90) were strongly associated with early menopause. Women with probable PTSD at baseline had more than double the odds of possible early menopause.

Previous research suggests that deployment, MEEs, and Gulf War Illness are broadly associated with adverse reproductive health conditions in women veterans. Exposure to persistent organic pollutants and combustion byproducts (eg, from industrial processes and burn pits) have been linked to ovarian dysfunction and oocyte destruction presumed to contribute to accelerated ovarian aging.

The average age for menopause in the US is 52 years. About 5% of women go through early menopause naturally. Early and premature (< 40 years) menopause may also result from a medical or surgical cause, such as a hysterectomy. Regardless the cause, early menopause can have a profound impact on a woman’s physical, emotional, and mental health. It is associated with premature mortality, poor bone health, sexual dysfunction, a 50% increased risk of cardiovascular disease, and 2-fold increased odds of depression.

“Sometimes we talk about menopause symptoms thinking that they're just sort of 1 brief point in time, but we're also talking about things that may affect women's health and functioning for a third or half of a lifespan,” Carolyn Gibson, PhD, MPH, said at the 2024 Spotlight on Women's Health Cyberseminar Series.

Gibson, a staff psychologist at the San Francisco Veterans Affairs (VA) Women’s Mental Health Program and lead author on the recent early-menopause study, pointed to some of the chronic physical health issues that might develop, such as cardiovascular disease, but also the psychological effects.

“It's just important,” she said during the Cyberseminar Series. “To think about the number of things that women in midlife tend to be juggling and managing, all of which may turn up the volume on symptom experience, effect of vulnerability to health and mental health challenges during this period.”

The findings of the study have clinical implications. Midlife women veterans (aged 45 to 64 years) are the largest group of women veterans enrolled in VA health care. Early menopause brings additional age-related care considerations. The authors advise prioritizing support for routine screening for menopause status and symptoms as well as gender-sensitive training, resources, and staffing to provide comprehensive, trauma-informed, evidence-based menopause care for women at any age.

Traumatic and environmental exposures during military service may put women veterans at risk for early menopause, a recent longitudinal analysis of data from 668 women in the Gulf War Era Cohort Study found.

The study examined associations between possible early menopause (aged < 45 years) and participants’ Gulf War deployment, military environmental exposures (MEEs), Gulf War Illness, military sexual trauma (MST) and posttraumatic stress disorder (PTSD). 

Of 384 Gulf War–deployed veterans, 63% reported MEEs and 26% reported MST during deployment. More than half (57%) of study participants (both Gulf War veterans and nondeployed veterans) met criteria for Gulf War Illness, and 23% met criteria for probable PTSD. 

At follow-up, 15% of the women had possible early menopause—higher than population estimates for early menopause in the US, which range from 5% to 10%.

Gulf War deployment, Gulf War–related environmental exposures, and MST during deployment were not significantly associated with early menopause. However, both Gulf War Illness (odds ratio [OR], 1.83; 95% CI, 1.14 to 2.95) and probable PTSD (OR, 2.45; 95% CI, 1.54 to 3.90) were strongly associated with early menopause. Women with probable PTSD at baseline had more than double the odds of possible early menopause.

Previous research suggests that deployment, MEEs, and Gulf War Illness are broadly associated with adverse reproductive health conditions in women veterans. Exposure to persistent organic pollutants and combustion byproducts (eg, from industrial processes and burn pits) have been linked to ovarian dysfunction and oocyte destruction presumed to contribute to accelerated ovarian aging.

The average age for menopause in the US is 52 years. About 5% of women go through early menopause naturally. Early and premature (< 40 years) menopause may also result from a medical or surgical cause, such as a hysterectomy. Regardless the cause, early menopause can have a profound impact on a woman’s physical, emotional, and mental health. It is associated with premature mortality, poor bone health, sexual dysfunction, a 50% increased risk of cardiovascular disease, and 2-fold increased odds of depression.

“Sometimes we talk about menopause symptoms thinking that they're just sort of 1 brief point in time, but we're also talking about things that may affect women's health and functioning for a third or half of a lifespan,” Carolyn Gibson, PhD, MPH, said at the 2024 Spotlight on Women's Health Cyberseminar Series.

Gibson, a staff psychologist at the San Francisco Veterans Affairs (VA) Women’s Mental Health Program and lead author on the recent early-menopause study, pointed to some of the chronic physical health issues that might develop, such as cardiovascular disease, but also the psychological effects.

“It's just important,” she said during the Cyberseminar Series. “To think about the number of things that women in midlife tend to be juggling and managing, all of which may turn up the volume on symptom experience, effect of vulnerability to health and mental health challenges during this period.”

The findings of the study have clinical implications. Midlife women veterans (aged 45 to 64 years) are the largest group of women veterans enrolled in VA health care. Early menopause brings additional age-related care considerations. The authors advise prioritizing support for routine screening for menopause status and symptoms as well as gender-sensitive training, resources, and staffing to provide comprehensive, trauma-informed, evidence-based menopause care for women at any age.

To the Editor:

Drug-induced hyperpigmentation is a common cause of an acquired increase in pigmentation. Belumosudil is an oral selective inhibitor of Rho-associated coiled-coil containing protein kinase (ROCK2) that is approved for the treatment of chronic graft-vs-host disease (GVHD). We describe a patient who developed diffuse skin bronzing 3 weeks after initiation of belumosudil treatment.

A 64-year-old fair-skinned woman presented to the dermatology clinic with bronzing of the skin and dystrophic nails 3 weeks after starting belumosudil for treatment of chronic GVHD. Six months prior to presentation, the patient had received a bone marrow transplant for chronic lymphoid leukemia. She presented to dermatology 6 months after the transplant with a new-onset rash that was suspicious for GVHD. Physical examination revealed pruritic pink papules diffusely scattered on the legs and forearms (Figure 1). The patient declined biopsy at that time and later followed up with oncology. The patient’s oncologist supported a diagnosis of GVHD, and the patient began treatment with belumosudil 200 mg/d which was intended to be taken until treatment failure due to progression of chronic GVHD.

Three weeks after starting belumosudil, the patient developed diffuse bronzing of the skin and brown, evenly colored patches scattered on the trunk, back, and upper and lower extremities on a background of the presumed GVHD rash (Figure 2). The hyperpigmentation was abrupt, starting on the chest and spreading to the abdomen, extremities, and back (Figure 3).

Again, the patient was offered biopsy for the new-onset pigmentation but declined. During this time, she had no notable sun exposure and primarily stayed indoors despite living in a region with a sunny semi-arid climate. Her medication and supplement list were reviewed and included acalabrutinib, a multivitamin, lutein, biotin, and a fish oil supplement. A compete blood cell count as well as ferritin, transferrin, cortisol, and adrenocorticotropic hormone levels were unremarkable.

The patient continued to take belumosudil for treatment of GVHD. The hyperpigmentation faded slightly by a 2-month follow-up visit but persisted and was stable. She has not tried other treatments for GVHD to manage the hyperpigmentation.

Conditions known to cause diffuse bronzing of the skin include Addison disease, hemochromatosis, Cushing disease, and medication adverse events. Our patient presented with an absence of systemic symptoms, normal laboratory results, and no clinical indicators suggesting alternate causes. Given that the onset of the hyperpigmentation was 3 weeks after she started a new medication, we hypothesized that the bronzing was an adverse effect of the belumosudil—though this correlation cannot be definitively proven by this case.

The most common offending agents for drug-induced skin hyperpigmentation are nonsteroidal anti- inflammatory drugs, antimalarials, amiodarone, cytotoxic drugs, and tetracyclines.^1,2 Our patient’s medication list included the cytotoxic agent acalabrutinib, a Bruton tyrosine kinase inhibitor used for the treatment of non-Hodgkin lymphoma. It has been associated with dermatologic findings of ecchymosis, bruising, panniculitis, and cellulitis, but there are no known reports of hyperpigmentation.³ Our patient had been taking acalabrutinib for 6 months when the GVHD rash developed. At the time, she also was taking a multivitamin and lutein, biotin, and fish oil supplements, none of which have been associated with hyperpigmentation.

Polypharmacy adds a layer of difficulty in identifying the inciting cause of pigmentary change. In our case, symptoms began 3 weeks after the initiation of belumosudil. There were no cutaneous reactions observed in the ROCKstar study of belumosudil; the most common adverse events were upper respiratory tract infection, diarrhea, fatigue, nausea, increased liver enzymes, and dyspnea.^4,5 Patients on belumosudil have developed aggressive cutaneous squamous cell carcinoma.⁶ However, a search of PubMed articles indexed for MEDLINE using the search terms acalabrutinib or belumosudil with hyperpigmentation or cutaneous reaction returned no reports of these medications causing hyperpigmentation or cutaneous deposits.

Treatment of drug-induced hyperpigmentation is difficult because discontinuation of the offending agent typically confirms diagnosis, but interruption of treatment is not always possible, as in our patient. The skin changes can fade over time, but effects typically are long lasting.

Dermatologists play a key role in the identification of drug-induced skin hyperpigmentation. After endocrine or metabolic causes of skin hyperpigmentation have been ruled out, a thorough review of the patient’s medication list should be done to assess for a drug-induced cause. Treatment is limited to sun avoidance, as interruption of treatment may not be possible, and lesions typically do fade over time. These chronic skin changes can have a psychosocial effect on patients and regular follow-up is recommended.

To the Editor:

Drug-induced hyperpigmentation is a common cause of an acquired increase in pigmentation. Belumosudil is an oral selective inhibitor of Rho-associated coiled-coil containing protein kinase (ROCK2) that is approved for the treatment of chronic graft-vs-host disease (GVHD). We describe a patient who developed diffuse skin bronzing 3 weeks after initiation of belumosudil treatment.

A 64-year-old fair-skinned woman presented to the dermatology clinic with bronzing of the skin and dystrophic nails 3 weeks after starting belumosudil for treatment of chronic GVHD. Six months prior to presentation, the patient had received a bone marrow transplant for chronic lymphoid leukemia. She presented to dermatology 6 months after the transplant with a new-onset rash that was suspicious for GVHD. Physical examination revealed pruritic pink papules diffusely scattered on the legs and forearms (Figure 1). The patient declined biopsy at that time and later followed up with oncology. The patient’s oncologist supported a diagnosis of GVHD, and the patient began treatment with belumosudil 200 mg/d which was intended to be taken until treatment failure due to progression of chronic GVHD.

Three weeks after starting belumosudil, the patient developed diffuse bronzing of the skin and brown, evenly colored patches scattered on the trunk, back, and upper and lower extremities on a background of the presumed GVHD rash (Figure 2). The hyperpigmentation was abrupt, starting on the chest and spreading to the abdomen, extremities, and back (Figure 3).

Again, the patient was offered biopsy for the new-onset pigmentation but declined. During this time, she had no notable sun exposure and primarily stayed indoors despite living in a region with a sunny semi-arid climate. Her medication and supplement list were reviewed and included acalabrutinib, a multivitamin, lutein, biotin, and a fish oil supplement. A compete blood cell count as well as ferritin, transferrin, cortisol, and adrenocorticotropic hormone levels were unremarkable.

The patient continued to take belumosudil for treatment of GVHD. The hyperpigmentation faded slightly by a 2-month follow-up visit but persisted and was stable. She has not tried other treatments for GVHD to manage the hyperpigmentation.

Conditions known to cause diffuse bronzing of the skin include Addison disease, hemochromatosis, Cushing disease, and medication adverse events. Our patient presented with an absence of systemic symptoms, normal laboratory results, and no clinical indicators suggesting alternate causes. Given that the onset of the hyperpigmentation was 3 weeks after she started a new medication, we hypothesized that the bronzing was an adverse effect of the belumosudil—though this correlation cannot be definitively proven by this case.

The most common offending agents for drug-induced skin hyperpigmentation are nonsteroidal anti- inflammatory drugs, antimalarials, amiodarone, cytotoxic drugs, and tetracyclines.^1,2 Our patient’s medication list included the cytotoxic agent acalabrutinib, a Bruton tyrosine kinase inhibitor used for the treatment of non-Hodgkin lymphoma. It has been associated with dermatologic findings of ecchymosis, bruising, panniculitis, and cellulitis, but there are no known reports of hyperpigmentation.³ Our patient had been taking acalabrutinib for 6 months when the GVHD rash developed. At the time, she also was taking a multivitamin and lutein, biotin, and fish oil supplements, none of which have been associated with hyperpigmentation.

Polypharmacy adds a layer of difficulty in identifying the inciting cause of pigmentary change. In our case, symptoms began 3 weeks after the initiation of belumosudil. There were no cutaneous reactions observed in the ROCKstar study of belumosudil; the most common adverse events were upper respiratory tract infection, diarrhea, fatigue, nausea, increased liver enzymes, and dyspnea.^4,5 Patients on belumosudil have developed aggressive cutaneous squamous cell carcinoma.⁶ However, a search of PubMed articles indexed for MEDLINE using the search terms acalabrutinib or belumosudil with hyperpigmentation or cutaneous reaction returned no reports of these medications causing hyperpigmentation or cutaneous deposits.

Treatment of drug-induced hyperpigmentation is difficult because discontinuation of the offending agent typically confirms diagnosis, but interruption of treatment is not always possible, as in our patient. The skin changes can fade over time, but effects typically are long lasting.

Dermatologists play a key role in the identification of drug-induced skin hyperpigmentation. After endocrine or metabolic causes of skin hyperpigmentation have been ruled out, a thorough review of the patient’s medication list should be done to assess for a drug-induced cause. Treatment is limited to sun avoidance, as interruption of treatment may not be possible, and lesions typically do fade over time. These chronic skin changes can have a psychosocial effect on patients and regular follow-up is recommended.

To the Editor:

Drug-induced hyperpigmentation is a common cause of an acquired increase in pigmentation. Belumosudil is an oral selective inhibitor of Rho-associated coiled-coil containing protein kinase (ROCK2) that is approved for the treatment of chronic graft-vs-host disease (GVHD). We describe a patient who developed diffuse skin bronzing 3 weeks after initiation of belumosudil treatment.

A 64-year-old fair-skinned woman presented to the dermatology clinic with bronzing of the skin and dystrophic nails 3 weeks after starting belumosudil for treatment of chronic GVHD. Six months prior to presentation, the patient had received a bone marrow transplant for chronic lymphoid leukemia. She presented to dermatology 6 months after the transplant with a new-onset rash that was suspicious for GVHD. Physical examination revealed pruritic pink papules diffusely scattered on the legs and forearms (Figure 1). The patient declined biopsy at that time and later followed up with oncology. The patient’s oncologist supported a diagnosis of GVHD, and the patient began treatment with belumosudil 200 mg/d which was intended to be taken until treatment failure due to progression of chronic GVHD.

Three weeks after starting belumosudil, the patient developed diffuse bronzing of the skin and brown, evenly colored patches scattered on the trunk, back, and upper and lower extremities on a background of the presumed GVHD rash (Figure 2). The hyperpigmentation was abrupt, starting on the chest and spreading to the abdomen, extremities, and back (Figure 3).

Again, the patient was offered biopsy for the new-onset pigmentation but declined. During this time, she had no notable sun exposure and primarily stayed indoors despite living in a region with a sunny semi-arid climate. Her medication and supplement list were reviewed and included acalabrutinib, a multivitamin, lutein, biotin, and a fish oil supplement. A compete blood cell count as well as ferritin, transferrin, cortisol, and adrenocorticotropic hormone levels were unremarkable.

The patient continued to take belumosudil for treatment of GVHD. The hyperpigmentation faded slightly by a 2-month follow-up visit but persisted and was stable. She has not tried other treatments for GVHD to manage the hyperpigmentation.

Conditions known to cause diffuse bronzing of the skin include Addison disease, hemochromatosis, Cushing disease, and medication adverse events. Our patient presented with an absence of systemic symptoms, normal laboratory results, and no clinical indicators suggesting alternate causes. Given that the onset of the hyperpigmentation was 3 weeks after she started a new medication, we hypothesized that the bronzing was an adverse effect of the belumosudil—though this correlation cannot be definitively proven by this case.

The most common offending agents for drug-induced skin hyperpigmentation are nonsteroidal anti- inflammatory drugs, antimalarials, amiodarone, cytotoxic drugs, and tetracyclines.^1,2 Our patient’s medication list included the cytotoxic agent acalabrutinib, a Bruton tyrosine kinase inhibitor used for the treatment of non-Hodgkin lymphoma. It has been associated with dermatologic findings of ecchymosis, bruising, panniculitis, and cellulitis, but there are no known reports of hyperpigmentation.³ Our patient had been taking acalabrutinib for 6 months when the GVHD rash developed. At the time, she also was taking a multivitamin and lutein, biotin, and fish oil supplements, none of which have been associated with hyperpigmentation.

Polypharmacy adds a layer of difficulty in identifying the inciting cause of pigmentary change. In our case, symptoms began 3 weeks after the initiation of belumosudil. There were no cutaneous reactions observed in the ROCKstar study of belumosudil; the most common adverse events were upper respiratory tract infection, diarrhea, fatigue, nausea, increased liver enzymes, and dyspnea.^4,5 Patients on belumosudil have developed aggressive cutaneous squamous cell carcinoma.⁶ However, a search of PubMed articles indexed for MEDLINE using the search terms acalabrutinib or belumosudil with hyperpigmentation or cutaneous reaction returned no reports of these medications causing hyperpigmentation or cutaneous deposits.

Treatment of drug-induced hyperpigmentation is difficult because discontinuation of the offending agent typically confirms diagnosis, but interruption of treatment is not always possible, as in our patient. The skin changes can fade over time, but effects typically are long lasting.

Dermatologists play a key role in the identification of drug-induced skin hyperpigmentation. After endocrine or metabolic causes of skin hyperpigmentation have been ruled out, a thorough review of the patient’s medication list should be done to assess for a drug-induced cause. Treatment is limited to sun avoidance, as interruption of treatment may not be possible, and lesions typically do fade over time. These chronic skin changes can have a psychosocial effect on patients and regular follow-up is recommended.

In our June issue, I highlighted the potentially seismic clinical implications of the U.S. Supreme Court’s then-pending decision in the Kennedy vs. Braidwood Management, Inc., case. That ruling, recently released at the conclusion of the Court’s term, ultimately affirmed the Affordable Care Act’s mandate requiring insurers to cover certain preventive services, including colorectal cancer screening tests, without cost-sharing.

In doing so, however, the court determined that members of the U.S. Preventive Services Task Force (USPSTF), which recommends these services, are “inferior officers” appropriately appointed by the Secretary of Health and Human Services (HHS), rather than needing Senate confirmation. Thus, the decision reinforced the HHS Secretary’s authority to oversee and potentially influence USPSTF recommendations in the future. While the decision represented a victory in upholding a key provision of the ACA, it also signaled a potential threat to the scientific independence of the body charged with making those preventive care recommendations in a scientifically rigorous, unbiased manner. 

As anticipated, the HHS Secretary responded to the Supreme Court’s ruling by abruptly canceling the USPSTF’s scheduled July meeting. This decision, coupled with his recent disbanding of the entire 17-member Advisory Committee on Immunization Practices — the group responsible for shaping evidence-based vaccine policy — has raised serious concerns across the healthcare field. On July 9th, AGA joined a coalition of 104 health organizations in submitting a letter to the Chair and Ranking Members of the Senate Committee on Health, Education, Labor and Pensions and the House Committee on Energy and Commerce, urging them to protect the integrity of the USPSTF.

The fight to protect science-based health policy is far from over — effective advocacy necessitates that clinicians use their professional platforms to push back against the politicization of science – not only for the integrity of the medical profession, but for the health and future of the patients we serve. At a time when medical misinformation runs rampant, undermining the independence of scientific bodies risks sowing confusion, eroding public trust, and compromising patient care for years to come.

Megan A. Adams, MD, JD, MSc 

Editor in Chief

In our June issue, I highlighted the potentially seismic clinical implications of the U.S. Supreme Court’s then-pending decision in the Kennedy vs. Braidwood Management, Inc., case. That ruling, recently released at the conclusion of the Court’s term, ultimately affirmed the Affordable Care Act’s mandate requiring insurers to cover certain preventive services, including colorectal cancer screening tests, without cost-sharing.

In doing so, however, the court determined that members of the U.S. Preventive Services Task Force (USPSTF), which recommends these services, are “inferior officers” appropriately appointed by the Secretary of Health and Human Services (HHS), rather than needing Senate confirmation. Thus, the decision reinforced the HHS Secretary’s authority to oversee and potentially influence USPSTF recommendations in the future. While the decision represented a victory in upholding a key provision of the ACA, it also signaled a potential threat to the scientific independence of the body charged with making those preventive care recommendations in a scientifically rigorous, unbiased manner. 

As anticipated, the HHS Secretary responded to the Supreme Court’s ruling by abruptly canceling the USPSTF’s scheduled July meeting. This decision, coupled with his recent disbanding of the entire 17-member Advisory Committee on Immunization Practices — the group responsible for shaping evidence-based vaccine policy — has raised serious concerns across the healthcare field. On July 9th, AGA joined a coalition of 104 health organizations in submitting a letter to the Chair and Ranking Members of the Senate Committee on Health, Education, Labor and Pensions and the House Committee on Energy and Commerce, urging them to protect the integrity of the USPSTF.

The fight to protect science-based health policy is far from over — effective advocacy necessitates that clinicians use their professional platforms to push back against the politicization of science – not only for the integrity of the medical profession, but for the health and future of the patients we serve. At a time when medical misinformation runs rampant, undermining the independence of scientific bodies risks sowing confusion, eroding public trust, and compromising patient care for years to come.

Megan A. Adams, MD, JD, MSc 

Editor in Chief

In our June issue, I highlighted the potentially seismic clinical implications of the U.S. Supreme Court’s then-pending decision in the Kennedy vs. Braidwood Management, Inc., case. That ruling, recently released at the conclusion of the Court’s term, ultimately affirmed the Affordable Care Act’s mandate requiring insurers to cover certain preventive services, including colorectal cancer screening tests, without cost-sharing.

In doing so, however, the court determined that members of the U.S. Preventive Services Task Force (USPSTF), which recommends these services, are “inferior officers” appropriately appointed by the Secretary of Health and Human Services (HHS), rather than needing Senate confirmation. Thus, the decision reinforced the HHS Secretary’s authority to oversee and potentially influence USPSTF recommendations in the future. While the decision represented a victory in upholding a key provision of the ACA, it also signaled a potential threat to the scientific independence of the body charged with making those preventive care recommendations in a scientifically rigorous, unbiased manner. 

As anticipated, the HHS Secretary responded to the Supreme Court’s ruling by abruptly canceling the USPSTF’s scheduled July meeting. This decision, coupled with his recent disbanding of the entire 17-member Advisory Committee on Immunization Practices — the group responsible for shaping evidence-based vaccine policy — has raised serious concerns across the healthcare field. On July 9th, AGA joined a coalition of 104 health organizations in submitting a letter to the Chair and Ranking Members of the Senate Committee on Health, Education, Labor and Pensions and the House Committee on Energy and Commerce, urging them to protect the integrity of the USPSTF.

The fight to protect science-based health policy is far from over — effective advocacy necessitates that clinicians use their professional platforms to push back against the politicization of science – not only for the integrity of the medical profession, but for the health and future of the patients we serve. At a time when medical misinformation runs rampant, undermining the independence of scientific bodies risks sowing confusion, eroding public trust, and compromising patient care for years to come.

Megan A. Adams, MD, JD, MSc 

Editor in Chief