Contrary to previous analyses, women without a history of psychiatric illness who take combined hormonal contraceptives do not have an increased risk for attempted suicide but may have a reduced risk with extended use, new research suggests.

In a study of more than 800 women younger than age 50 who attempted suicide and more than 3,000 age-matched peers, results showed those who took hormonal contraceptives had a 27% reduced risk for attempted suicide.

areeya_ann/Thinkstock

Further analysis showed this was confined to women without a history of psychiatric illness and the reduction in risk rose to 43% among those who took combined hormonal contraceptives rather than progestin-only versions.

The protective effect against attempted suicide increased further to 46% if ethinyl estradiol (EE)–containing preparations were used. Moreover, the beneficial effect of contraceptive use increased over time.

The main message is the “current use of hormonal contraceptives is not associated with an increased risk of attempted suicide in our population,” study presenter Elena Toffol, MD, PhD, department of public health, University of Helsinki, told meeting attendees at the European Psychiatric Association 2022 Congress.
 

Age range differences

Dr. Toffol said there could be “several reasons” why the results are different from those in previous studies, including that the researchers included a “larger age range.” She noted it is known that “older women have a lower rate of attempted suicide and use different types of contraceptives.”

Dr. Toffol said in an interview that, although it’s “hard to estimate any causality” because this is an observational study, it is “tempting to speculate, and it is plausible, that hormones partly play a role with some, but not all, women being more sensitive to hormonal influences.”

However, the results “may also reflect life choices or a protective life status; for example, more stable relationships or more conscious and health-focused behaviors,” she said.

“It may also be that the underlying characteristics of women who are prescribed or opt for certain types of contraceptives are somehow related to their suicidal risk,” she added.

In 2019, the global age-standardized suicide rate was 9.0 per 100,000, which translates into more than 700,000 deaths every year, Dr. Toffol noted.

However, she emphasized the World Health Organization has calculated that, for every adult who dies by suicide, more than 20 people attempt suicide. In addition, data from the U.S. Centers for Disease Control and Prevention indicate that attempted suicides are three times more common among young women than in men.

“What are the reasons for this gender gap?” Dr. Toffol asked during her presentation.

“It is known that the major risk factor for suicidal behavior is a psychiatric disorder, and in particular depression and mood disorders. And depression and mood disorders are more common in women than in men,” she said.

However, there is also “growing interest into the role of biological factors” in the risk for suicide, including hormones and hormonal contraception. Some studies have also suggested that there is an increased risk for depression and “both completed and attempted suicide” after starting hormonal contraception.

Dr. Toffol added that about 70% of European women use some form of contraception and, among Finnish women, 40% choose a hormonal contraceptive.
 

Nested analysis

The researchers conducted a nested case-control analysis combining 2017 national prescription data on 587,823 women aged 15-49 years with information from general and primary healthcare registers for the years 2018 to 2019.

They were able to identify 818 cases of attempted suicide among the women. These were matched 4:1 with 3,272 age-matched healthy women who acted as the control group. Use of hormonal contraceptives in the previous 180 days was determined for the whole cohort.

Among users of hormonal contraceptives, there were 344 attempted suicides in 2017, at an incidence rate of 0.59 per 1,000 person-years. This compared with 474 attempted suicides among nonusers, at an incidence rate of 0.81 per 1000 person-years.

Kaplan-Meier analysis showed there was a significant difference in rates for attempted suicide among hormonal contraceptive users versus nonusers, at an incidence rate ratio of 0.73 (P < .0001) – and the difference increased over time.

In addition, the incidence of attempted suicide decreased with increasing age, with the highest incidence rate in women aged 15-19 years (1.62 per 1,000 person-years).

Conditional logistic regression analysis that controlled for education, marital status, chronic disease, recent psychiatric hospitalization, and current use of psychotropic medication showed hormonal contraceptive use was not linked to an increased risk of attempted suicide overall, at an odds ratio of 0.79 (95% confidence interval, 0.56-1.11).

However, when they looked specifically at women without a history of psychiatric illness, the association became significant, at an OR of 0.73 for attempted suicide among hormonal contraceptive users (95% CI, 0.58-0.91), while the relationship remained nonsignificant in women with a history of psychiatric disorders.

Further analysis suggested the significant association was confined to women taking combined hormonal contraceptives, at an OR of 0.57 for suicide attempt versus nonusers (95% CI, 0.44-0.75), and those use EE-containing preparations (OR, 0.54; 95% CI, 0.40-0.73).

There was a suggestion in the data that hormonal contraceptives containing desogestrel or drospirenone alongside EE may offer the greatest reduction in attempted suicide risk, but that did not survive multivariate analysis.

Dr. Toffol also noted that they were not able to capture data on use of intrauterine devices in their analysis.

“There is a growing number of municipalities in Finland that are providing free-of-charge contraception to young women” that is often an intrauterine device, she said. The researchers hope to include these women in a future analysis.
 

‘Age matters’

Commenting on the findings, Alexis C. Edwards, PhD, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, said the current study’s findings “made a lot of sense.” Dr. Edwards wasn’t involved with this study but conducted a previous study of 216,702 Swedish women aged 15-22 years that showed use of combination or progestin-only oral contraceptives was associated with an increased risk for suicidal behavior.

She agreed with Dr. Toffol that the “much larger age range” in the new study may have played a role in showing the opposite result.

“The trajectory that we saw if we had been able to continue following the women for longer – which we couldn’t, due to limitations of the registries – [was that] using hormonal contraceptives was going to end up being protective, so I do think that it matters what age you’re looking at,” she said.

Dr. Edwards noted the takeaway from both studies “is that, even if there is a slight increase in risk from using hormonal contraceptives, it’s short lived and it’s probably specific to young women, which is important.”

She suggested the hormonal benefit from extended contraceptive use could come from the regulation of mood, as it offers a “more stable hormonal course than what their body might be putting them through in the absence of using the pill.”

Overall, it is “really lovely to see very well-executed studies on this, providing more empirical evidence on this question, because it is something that’s relevant to anyone who’s potentially going to be using hormonal contraception,” Dr. Edwards said.
 

Clinical implications?

Andrea Fiorillo, MD, PhD, department of psychiatry, University of Campania “Luigi Vanvitelli,” Naples, Italy, said in a press release that the “striking” findings of the current study need “careful evaluation.”

They also need to be replicated in “different cohorts of women and controlled for the impact of several psychosocial stressors, such as economic upheavals, social insecurity, and uncertainty due to the COVID pandemic,” said Dr. Fiorillo, who was not involved with the research.

Nevertheless, she believes the “clinical implications of the study are obvious and may help to destigmatize the use of hormonal contraceptives.”

The study was funded by the Jane and Aatos Erkko Foundation, the Avohoidon Tsukimis äätiö (Foundation for Primary Care Research), the Yrj ö Jahnsson Foundation, and the Finnish Cultural Foundation. No relevant financial relationships were reported.

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

Contrary to previous analyses, women without a history of psychiatric illness who take combined hormonal contraceptives do not have an increased risk for attempted suicide but may have a reduced risk with extended use, new research suggests.

In a study of more than 800 women younger than age 50 who attempted suicide and more than 3,000 age-matched peers, results showed those who took hormonal contraceptives had a 27% reduced risk for attempted suicide.

areeya_ann/Thinkstock

Further analysis showed this was confined to women without a history of psychiatric illness and the reduction in risk rose to 43% among those who took combined hormonal contraceptives rather than progestin-only versions.

The protective effect against attempted suicide increased further to 46% if ethinyl estradiol (EE)–containing preparations were used. Moreover, the beneficial effect of contraceptive use increased over time.

The main message is the “current use of hormonal contraceptives is not associated with an increased risk of attempted suicide in our population,” study presenter Elena Toffol, MD, PhD, department of public health, University of Helsinki, told meeting attendees at the European Psychiatric Association 2022 Congress.
 

Age range differences

Dr. Toffol said there could be “several reasons” why the results are different from those in previous studies, including that the researchers included a “larger age range.” She noted it is known that “older women have a lower rate of attempted suicide and use different types of contraceptives.”

Dr. Toffol said in an interview that, although it’s “hard to estimate any causality” because this is an observational study, it is “tempting to speculate, and it is plausible, that hormones partly play a role with some, but not all, women being more sensitive to hormonal influences.”

However, the results “may also reflect life choices or a protective life status; for example, more stable relationships or more conscious and health-focused behaviors,” she said.

“It may also be that the underlying characteristics of women who are prescribed or opt for certain types of contraceptives are somehow related to their suicidal risk,” she added.

In 2019, the global age-standardized suicide rate was 9.0 per 100,000, which translates into more than 700,000 deaths every year, Dr. Toffol noted.

However, she emphasized the World Health Organization has calculated that, for every adult who dies by suicide, more than 20 people attempt suicide. In addition, data from the U.S. Centers for Disease Control and Prevention indicate that attempted suicides are three times more common among young women than in men.

“What are the reasons for this gender gap?” Dr. Toffol asked during her presentation.

“It is known that the major risk factor for suicidal behavior is a psychiatric disorder, and in particular depression and mood disorders. And depression and mood disorders are more common in women than in men,” she said.

However, there is also “growing interest into the role of biological factors” in the risk for suicide, including hormones and hormonal contraception. Some studies have also suggested that there is an increased risk for depression and “both completed and attempted suicide” after starting hormonal contraception.

Dr. Toffol added that about 70% of European women use some form of contraception and, among Finnish women, 40% choose a hormonal contraceptive.
 

Nested analysis

The researchers conducted a nested case-control analysis combining 2017 national prescription data on 587,823 women aged 15-49 years with information from general and primary healthcare registers for the years 2018 to 2019.

They were able to identify 818 cases of attempted suicide among the women. These were matched 4:1 with 3,272 age-matched healthy women who acted as the control group. Use of hormonal contraceptives in the previous 180 days was determined for the whole cohort.

Among users of hormonal contraceptives, there were 344 attempted suicides in 2017, at an incidence rate of 0.59 per 1,000 person-years. This compared with 474 attempted suicides among nonusers, at an incidence rate of 0.81 per 1000 person-years.

Kaplan-Meier analysis showed there was a significant difference in rates for attempted suicide among hormonal contraceptive users versus nonusers, at an incidence rate ratio of 0.73 (P < .0001) – and the difference increased over time.

In addition, the incidence of attempted suicide decreased with increasing age, with the highest incidence rate in women aged 15-19 years (1.62 per 1,000 person-years).

Conditional logistic regression analysis that controlled for education, marital status, chronic disease, recent psychiatric hospitalization, and current use of psychotropic medication showed hormonal contraceptive use was not linked to an increased risk of attempted suicide overall, at an odds ratio of 0.79 (95% confidence interval, 0.56-1.11).

However, when they looked specifically at women without a history of psychiatric illness, the association became significant, at an OR of 0.73 for attempted suicide among hormonal contraceptive users (95% CI, 0.58-0.91), while the relationship remained nonsignificant in women with a history of psychiatric disorders.

Further analysis suggested the significant association was confined to women taking combined hormonal contraceptives, at an OR of 0.57 for suicide attempt versus nonusers (95% CI, 0.44-0.75), and those use EE-containing preparations (OR, 0.54; 95% CI, 0.40-0.73).

There was a suggestion in the data that hormonal contraceptives containing desogestrel or drospirenone alongside EE may offer the greatest reduction in attempted suicide risk, but that did not survive multivariate analysis.

Dr. Toffol also noted that they were not able to capture data on use of intrauterine devices in their analysis.

“There is a growing number of municipalities in Finland that are providing free-of-charge contraception to young women” that is often an intrauterine device, she said. The researchers hope to include these women in a future analysis.
 

‘Age matters’

Commenting on the findings, Alexis C. Edwards, PhD, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, said the current study’s findings “made a lot of sense.” Dr. Edwards wasn’t involved with this study but conducted a previous study of 216,702 Swedish women aged 15-22 years that showed use of combination or progestin-only oral contraceptives was associated with an increased risk for suicidal behavior.

She agreed with Dr. Toffol that the “much larger age range” in the new study may have played a role in showing the opposite result.

“The trajectory that we saw if we had been able to continue following the women for longer – which we couldn’t, due to limitations of the registries – [was that] using hormonal contraceptives was going to end up being protective, so I do think that it matters what age you’re looking at,” she said.

Dr. Edwards noted the takeaway from both studies “is that, even if there is a slight increase in risk from using hormonal contraceptives, it’s short lived and it’s probably specific to young women, which is important.”

She suggested the hormonal benefit from extended contraceptive use could come from the regulation of mood, as it offers a “more stable hormonal course than what their body might be putting them through in the absence of using the pill.”

Overall, it is “really lovely to see very well-executed studies on this, providing more empirical evidence on this question, because it is something that’s relevant to anyone who’s potentially going to be using hormonal contraception,” Dr. Edwards said.
 

Clinical implications?

Andrea Fiorillo, MD, PhD, department of psychiatry, University of Campania “Luigi Vanvitelli,” Naples, Italy, said in a press release that the “striking” findings of the current study need “careful evaluation.”

They also need to be replicated in “different cohorts of women and controlled for the impact of several psychosocial stressors, such as economic upheavals, social insecurity, and uncertainty due to the COVID pandemic,” said Dr. Fiorillo, who was not involved with the research.

Nevertheless, she believes the “clinical implications of the study are obvious and may help to destigmatize the use of hormonal contraceptives.”

The study was funded by the Jane and Aatos Erkko Foundation, the Avohoidon Tsukimis äätiö (Foundation for Primary Care Research), the Yrj ö Jahnsson Foundation, and the Finnish Cultural Foundation. No relevant financial relationships were reported.

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

Contrary to previous analyses, women without a history of psychiatric illness who take combined hormonal contraceptives do not have an increased risk for attempted suicide but may have a reduced risk with extended use, new research suggests.

In a study of more than 800 women younger than age 50 who attempted suicide and more than 3,000 age-matched peers, results showed those who took hormonal contraceptives had a 27% reduced risk for attempted suicide.

areeya_ann/Thinkstock

Further analysis showed this was confined to women without a history of psychiatric illness and the reduction in risk rose to 43% among those who took combined hormonal contraceptives rather than progestin-only versions.

The protective effect against attempted suicide increased further to 46% if ethinyl estradiol (EE)–containing preparations were used. Moreover, the beneficial effect of contraceptive use increased over time.

The main message is the “current use of hormonal contraceptives is not associated with an increased risk of attempted suicide in our population,” study presenter Elena Toffol, MD, PhD, department of public health, University of Helsinki, told meeting attendees at the European Psychiatric Association 2022 Congress.
 

Age range differences

Dr. Toffol said there could be “several reasons” why the results are different from those in previous studies, including that the researchers included a “larger age range.” She noted it is known that “older women have a lower rate of attempted suicide and use different types of contraceptives.”

Dr. Toffol said in an interview that, although it’s “hard to estimate any causality” because this is an observational study, it is “tempting to speculate, and it is plausible, that hormones partly play a role with some, but not all, women being more sensitive to hormonal influences.”

However, the results “may also reflect life choices or a protective life status; for example, more stable relationships or more conscious and health-focused behaviors,” she said.

“It may also be that the underlying characteristics of women who are prescribed or opt for certain types of contraceptives are somehow related to their suicidal risk,” she added.

In 2019, the global age-standardized suicide rate was 9.0 per 100,000, which translates into more than 700,000 deaths every year, Dr. Toffol noted.

However, she emphasized the World Health Organization has calculated that, for every adult who dies by suicide, more than 20 people attempt suicide. In addition, data from the U.S. Centers for Disease Control and Prevention indicate that attempted suicides are three times more common among young women than in men.

“What are the reasons for this gender gap?” Dr. Toffol asked during her presentation.

“It is known that the major risk factor for suicidal behavior is a psychiatric disorder, and in particular depression and mood disorders. And depression and mood disorders are more common in women than in men,” she said.

However, there is also “growing interest into the role of biological factors” in the risk for suicide, including hormones and hormonal contraception. Some studies have also suggested that there is an increased risk for depression and “both completed and attempted suicide” after starting hormonal contraception.

Dr. Toffol added that about 70% of European women use some form of contraception and, among Finnish women, 40% choose a hormonal contraceptive.
 

Nested analysis

The researchers conducted a nested case-control analysis combining 2017 national prescription data on 587,823 women aged 15-49 years with information from general and primary healthcare registers for the years 2018 to 2019.

They were able to identify 818 cases of attempted suicide among the women. These were matched 4:1 with 3,272 age-matched healthy women who acted as the control group. Use of hormonal contraceptives in the previous 180 days was determined for the whole cohort.

Among users of hormonal contraceptives, there were 344 attempted suicides in 2017, at an incidence rate of 0.59 per 1,000 person-years. This compared with 474 attempted suicides among nonusers, at an incidence rate of 0.81 per 1000 person-years.

Kaplan-Meier analysis showed there was a significant difference in rates for attempted suicide among hormonal contraceptive users versus nonusers, at an incidence rate ratio of 0.73 (P < .0001) – and the difference increased over time.

In addition, the incidence of attempted suicide decreased with increasing age, with the highest incidence rate in women aged 15-19 years (1.62 per 1,000 person-years).

Conditional logistic regression analysis that controlled for education, marital status, chronic disease, recent psychiatric hospitalization, and current use of psychotropic medication showed hormonal contraceptive use was not linked to an increased risk of attempted suicide overall, at an odds ratio of 0.79 (95% confidence interval, 0.56-1.11).

However, when they looked specifically at women without a history of psychiatric illness, the association became significant, at an OR of 0.73 for attempted suicide among hormonal contraceptive users (95% CI, 0.58-0.91), while the relationship remained nonsignificant in women with a history of psychiatric disorders.

Further analysis suggested the significant association was confined to women taking combined hormonal contraceptives, at an OR of 0.57 for suicide attempt versus nonusers (95% CI, 0.44-0.75), and those use EE-containing preparations (OR, 0.54; 95% CI, 0.40-0.73).

There was a suggestion in the data that hormonal contraceptives containing desogestrel or drospirenone alongside EE may offer the greatest reduction in attempted suicide risk, but that did not survive multivariate analysis.

Dr. Toffol also noted that they were not able to capture data on use of intrauterine devices in their analysis.

“There is a growing number of municipalities in Finland that are providing free-of-charge contraception to young women” that is often an intrauterine device, she said. The researchers hope to include these women in a future analysis.
 

‘Age matters’

Commenting on the findings, Alexis C. Edwards, PhD, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, said the current study’s findings “made a lot of sense.” Dr. Edwards wasn’t involved with this study but conducted a previous study of 216,702 Swedish women aged 15-22 years that showed use of combination or progestin-only oral contraceptives was associated with an increased risk for suicidal behavior.

She agreed with Dr. Toffol that the “much larger age range” in the new study may have played a role in showing the opposite result.

“The trajectory that we saw if we had been able to continue following the women for longer – which we couldn’t, due to limitations of the registries – [was that] using hormonal contraceptives was going to end up being protective, so I do think that it matters what age you’re looking at,” she said.

Dr. Edwards noted the takeaway from both studies “is that, even if there is a slight increase in risk from using hormonal contraceptives, it’s short lived and it’s probably specific to young women, which is important.”

She suggested the hormonal benefit from extended contraceptive use could come from the regulation of mood, as it offers a “more stable hormonal course than what their body might be putting them through in the absence of using the pill.”

Overall, it is “really lovely to see very well-executed studies on this, providing more empirical evidence on this question, because it is something that’s relevant to anyone who’s potentially going to be using hormonal contraception,” Dr. Edwards said.
 

Clinical implications?

Andrea Fiorillo, MD, PhD, department of psychiatry, University of Campania “Luigi Vanvitelli,” Naples, Italy, said in a press release that the “striking” findings of the current study need “careful evaluation.”

They also need to be replicated in “different cohorts of women and controlled for the impact of several psychosocial stressors, such as economic upheavals, social insecurity, and uncertainty due to the COVID pandemic,” said Dr. Fiorillo, who was not involved with the research.

Nevertheless, she believes the “clinical implications of the study are obvious and may help to destigmatize the use of hormonal contraceptives.”

The study was funded by the Jane and Aatos Erkko Foundation, the Avohoidon Tsukimis äätiö (Foundation for Primary Care Research), the Yrj ö Jahnsson Foundation, and the Finnish Cultural Foundation. No relevant financial relationships were reported.

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

The underlying cause of David Bennett’s death on March 8, two months after he received the heart of a genetically altered pig, remains unknown and is only slightly less mysterious for what can likely be ruled out, suggests a progress report on the case from the director of the cardiac xenotransplantation program where the pioneering surgery took place.

Mr. Bennett died in “diastolic heart failure,” reported Muhammad M. Mohiuddin, MBBS, University of Maryland School of Medicine, Baltimore, “but the mechanism is still under investigation.”

University of Maryland Medical Center

Rocky clinical course

Early characterizations of the patient’s death focused more on his diminished, end-stage clinical condition at the time of the surgery than on immune rejection or other direct effects of the xenograft or on the first-of-its-kind procedure itself.

The 57-year-old Mr. Bennett had presented to the University of Maryland team with nonischemic cardiomyopathy, on multiple inotropes, and requiring an intra-aortic balloon pump, Dr. Mohiuddin said in his ATC presentation. The patient had suffered multiple arrests and resuscitations, and by the time of surgery had been hospitalized for almost 2 months, including 40 days on veno-arterial extracorporeal membrane oxygenation (ECMO).

The transplant procedure itself went as planned until removal of the aortic cross clamp, which triggered a type-A aortic dissection. “We put a graft in the ascending aorta and a stent in the descending aorta. Even after 2 days, we found the dissection extending to the renal artery, so we had to go back and also put a stent in the renal artery,” Dr. Mohiuddin said.

Mr. Bennett also underwent two exploratory laparotomies in the first 10 days after transplantation, after CT imaging revealed signs of possible bowel inflammation and ischemia.

Further, he had to fight back a series of infections that led to major changes to his experimental drug regimen, which included immunosuppressants methylprednisolone and mycophenolate mofetil (MMF), the investigational anti-CD40 antibody KPL-404 (Kiniksa Pharmaceuticals), and the anti-inflammatories etanercept (Enbrel) and tocilizumab (Actemra).

One episode of sepsis, in particular, forced temporary withdrawal of MMF and a reduction in methylprednisolone dosage. It’s unknown whether the 30-day MMF suspension played a role in Mr. Bennett’s ultimate clinical deterioration and death, but it’s “highly possible,” Dr. Mohiuddin said in an interview.

Realistically, Mr. Bennett’s death was likely “multifactorial,” Dr. Mohiuddin said. He was in such poor clinical condition going into the procedure, and afterward confronted so many clinical challenges, that “it’s very difficult to say that one thing caused it.”

That hasn’t lessened speculation that the patient’s heart failed secondary to immunologic rejection or PCMV infection, either in Mr. Bennett or the donor pig.
 

A role for PCMV?

Weeks after Mr. Bennett’s death, as previously reported, his surgeon announced at a public forum that PCMV had been identified in the transplanted heart and in tissues of the donor pig. Mr. Bennett’s circulation showed traces of the viral DNA but not of the virus itself.

The presence of PCMV in transplanted porcine hearts is a well-recognized potential hazard in animal models but is considered avoidable with proper screening. In Mr. Bennett’s case, preoperative screening of the pig donor missed signs of the virus.  

Still, PCMV could potentially have contributed to Mr. Bennett’s death, acknowledged Bartley P. Griffith, MD, University of Maryland School of Medicine, who had announced the PCMV finding in an AST-sponsored April 20 webcast.

Preclinical evidence does suggest that PCMV can harm a xenograft organ, observed David H. Sachs, MD, Columbia University Medical Center, New York, from the audience during the comment period after Dr. Mohiuddin’s presentation.

“Each species has a CMV, and they’re quite species-specific,” observed the renowned surgeon and xenotransplantation immunologist. “We showed almost 10 years ago that if PCMV was in a pig kidney, it led to a much shortened survival of the pig kidney in a baboon. There was never any evidence, however, that the CMV infected the baboon or any baboon cells.”

Dr. Sachs asked Dr. Mohiuddin for confirmation that Mr. Bennett displayed no more than DNAemia, circulating cell-free PCMV DNA presumably shed from the porcine heart, but no sign of the virus itself outside of the heart’s porcine cells.

Cell-free DNA had shown up in Mr. Bennett’s circulation about 20 days after the surgery, with concentrations rising until at least day 50. Post-hoc polymerase chain reaction (PCR) testing disclosed PCMV only in the pig’s spleen and porcine cells of the transplanted heart, Dr. Mohiuddin noted.

“We have not found any evidence that the patient was infected by PCMV,” nor was there evidence of any disease related to PCMV, Dr. Mohiuddin replied.

Nor of ongoing rejection

Mr. Bennett’s new heart passed a critical test in the first post-implantation hours by avoiding acute rejection, a potentially disastrous outcome that three of the pig’s 10 gene edits had been designed to prevent.

Although chronic immune rejection was always a concern despite Mr. Bennett’s novel immunosuppressant regimen, myocardial biopsy on postoperative days 34, 50, and 56 and necropsy showed “no signs of typical xenograft rejection,” Dr. Mohiuddin said at the ATC presentation. But “there’s a chance of atypical rejection which we were not accustomed to.”

By day 50, his diastolic function showed echocardiographic signs of deterioration, and “we started seeing interstitial edema with some extravasation of red blood cells, which we thought would resolve over a period of time,” he said. Eventually, however, “we saw that turn into fibroblasts and scar tissue.”

Mr. Bennett once again went on veno-arterial ECMO but died 10 days later. Once they had seen histologic evidence of fibrosis, Dr. Mohiuddin told this news organization, the team believed the myocardial injury was irreversible. “That was the reason we gave up on recovery.”

Mr. Bennett’s xenotransplantation journey has taught the field a lot, he said. “By no means was this a failure; we consider this a huge success. You can do all the experiments in animal models, but you won’t find out the true mechanism of rejection unless you do these kinds of human experiments.”
 

Looking ahead to clinical trials

Research involving humans is always subject to vagaries of human nature, including degree of adherence to prescribed therapy and – in xenotransplantation – precautions in place to mitigate any risks to public health. Such risks theoretically include transfer of porcine viruses or other pathogens to the patient and subsequent release into the general population.

Looking ahead to the possibility of clinical trials after this successful xenotransplantation experience, transplant nephrologist and epidemiologist Peter P. Reese, MD, PhD, University of Pennsylvania, Philadelphia, raised the potentially controversial issue in discussion following Dr. Mohiuddin’s presentation.

It’s known that Mr. Bennett had been repeatedly turned down for a conventional allograft transplant primarily because of his history of treatment noncompliance. Should such a record, Dr. Reese asked, be a relative contraindication to enrollment in any future xenotransplantation trials? Or does the field need a standardized gauge of a patient’s readiness, once discharged, to adhere not only to all medications – including those that fight infection – but also with rules established for public safety, such as routine contact reporting?

“It makes me wonder about choosing a noncompliant patient for these trials,” Dr. Reese said. “If we discharge a patient from the hospital who is at risk for a zoonotic infection that could spread if they basically refuse to cooperate with us or with public health authorities, it really could have negative consequences for the reputation of the field.”

Dr. Mohiuddin agreed such concerns are valid. Mr. Bennett “and all his immediate contacts” signed consent forms acknowledging their willingness to be followed should he be discharged. Mr. Bennett himself “signed a consent to inform us if he has any other intimate contact with someone,” he said in an interview.

“But those are only on paper.” Had Mr. Bennett survived to be discharged, Dr. Mohuiddin said, “no one knows how he would have behaved.”

Dr. Mohiuddin said the research staff had prepared to monitor Mr. Bennett at his home if that’s what it took. “We were ready to follow him as long as we could. There was a surveillance plan in place.”

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

The underlying cause of David Bennett’s death on March 8, two months after he received the heart of a genetically altered pig, remains unknown and is only slightly less mysterious for what can likely be ruled out, suggests a progress report on the case from the director of the cardiac xenotransplantation program where the pioneering surgery took place.

Mr. Bennett died in “diastolic heart failure,” reported Muhammad M. Mohiuddin, MBBS, University of Maryland School of Medicine, Baltimore, “but the mechanism is still under investigation.”

University of Maryland Medical Center

Rocky clinical course

Early characterizations of the patient’s death focused more on his diminished, end-stage clinical condition at the time of the surgery than on immune rejection or other direct effects of the xenograft or on the first-of-its-kind procedure itself.

The 57-year-old Mr. Bennett had presented to the University of Maryland team with nonischemic cardiomyopathy, on multiple inotropes, and requiring an intra-aortic balloon pump, Dr. Mohiuddin said in his ATC presentation. The patient had suffered multiple arrests and resuscitations, and by the time of surgery had been hospitalized for almost 2 months, including 40 days on veno-arterial extracorporeal membrane oxygenation (ECMO).

The transplant procedure itself went as planned until removal of the aortic cross clamp, which triggered a type-A aortic dissection. “We put a graft in the ascending aorta and a stent in the descending aorta. Even after 2 days, we found the dissection extending to the renal artery, so we had to go back and also put a stent in the renal artery,” Dr. Mohiuddin said.

Mr. Bennett also underwent two exploratory laparotomies in the first 10 days after transplantation, after CT imaging revealed signs of possible bowel inflammation and ischemia.

Further, he had to fight back a series of infections that led to major changes to his experimental drug regimen, which included immunosuppressants methylprednisolone and mycophenolate mofetil (MMF), the investigational anti-CD40 antibody KPL-404 (Kiniksa Pharmaceuticals), and the anti-inflammatories etanercept (Enbrel) and tocilizumab (Actemra).

One episode of sepsis, in particular, forced temporary withdrawal of MMF and a reduction in methylprednisolone dosage. It’s unknown whether the 30-day MMF suspension played a role in Mr. Bennett’s ultimate clinical deterioration and death, but it’s “highly possible,” Dr. Mohiuddin said in an interview.

Realistically, Mr. Bennett’s death was likely “multifactorial,” Dr. Mohiuddin said. He was in such poor clinical condition going into the procedure, and afterward confronted so many clinical challenges, that “it’s very difficult to say that one thing caused it.”

That hasn’t lessened speculation that the patient’s heart failed secondary to immunologic rejection or PCMV infection, either in Mr. Bennett or the donor pig.
 

A role for PCMV?

Weeks after Mr. Bennett’s death, as previously reported, his surgeon announced at a public forum that PCMV had been identified in the transplanted heart and in tissues of the donor pig. Mr. Bennett’s circulation showed traces of the viral DNA but not of the virus itself.

The presence of PCMV in transplanted porcine hearts is a well-recognized potential hazard in animal models but is considered avoidable with proper screening. In Mr. Bennett’s case, preoperative screening of the pig donor missed signs of the virus.  

Still, PCMV could potentially have contributed to Mr. Bennett’s death, acknowledged Bartley P. Griffith, MD, University of Maryland School of Medicine, who had announced the PCMV finding in an AST-sponsored April 20 webcast.

Preclinical evidence does suggest that PCMV can harm a xenograft organ, observed David H. Sachs, MD, Columbia University Medical Center, New York, from the audience during the comment period after Dr. Mohiuddin’s presentation.

“Each species has a CMV, and they’re quite species-specific,” observed the renowned surgeon and xenotransplantation immunologist. “We showed almost 10 years ago that if PCMV was in a pig kidney, it led to a much shortened survival of the pig kidney in a baboon. There was never any evidence, however, that the CMV infected the baboon or any baboon cells.”

Dr. Sachs asked Dr. Mohiuddin for confirmation that Mr. Bennett displayed no more than DNAemia, circulating cell-free PCMV DNA presumably shed from the porcine heart, but no sign of the virus itself outside of the heart’s porcine cells.

Cell-free DNA had shown up in Mr. Bennett’s circulation about 20 days after the surgery, with concentrations rising until at least day 50. Post-hoc polymerase chain reaction (PCR) testing disclosed PCMV only in the pig’s spleen and porcine cells of the transplanted heart, Dr. Mohiuddin noted.

“We have not found any evidence that the patient was infected by PCMV,” nor was there evidence of any disease related to PCMV, Dr. Mohiuddin replied.

Nor of ongoing rejection

Mr. Bennett’s new heart passed a critical test in the first post-implantation hours by avoiding acute rejection, a potentially disastrous outcome that three of the pig’s 10 gene edits had been designed to prevent.

Although chronic immune rejection was always a concern despite Mr. Bennett’s novel immunosuppressant regimen, myocardial biopsy on postoperative days 34, 50, and 56 and necropsy showed “no signs of typical xenograft rejection,” Dr. Mohiuddin said at the ATC presentation. But “there’s a chance of atypical rejection which we were not accustomed to.”

By day 50, his diastolic function showed echocardiographic signs of deterioration, and “we started seeing interstitial edema with some extravasation of red blood cells, which we thought would resolve over a period of time,” he said. Eventually, however, “we saw that turn into fibroblasts and scar tissue.”

Mr. Bennett once again went on veno-arterial ECMO but died 10 days later. Once they had seen histologic evidence of fibrosis, Dr. Mohiuddin told this news organization, the team believed the myocardial injury was irreversible. “That was the reason we gave up on recovery.”

Mr. Bennett’s xenotransplantation journey has taught the field a lot, he said. “By no means was this a failure; we consider this a huge success. You can do all the experiments in animal models, but you won’t find out the true mechanism of rejection unless you do these kinds of human experiments.”
 

Looking ahead to clinical trials

Research involving humans is always subject to vagaries of human nature, including degree of adherence to prescribed therapy and – in xenotransplantation – precautions in place to mitigate any risks to public health. Such risks theoretically include transfer of porcine viruses or other pathogens to the patient and subsequent release into the general population.

Looking ahead to the possibility of clinical trials after this successful xenotransplantation experience, transplant nephrologist and epidemiologist Peter P. Reese, MD, PhD, University of Pennsylvania, Philadelphia, raised the potentially controversial issue in discussion following Dr. Mohiuddin’s presentation.

It’s known that Mr. Bennett had been repeatedly turned down for a conventional allograft transplant primarily because of his history of treatment noncompliance. Should such a record, Dr. Reese asked, be a relative contraindication to enrollment in any future xenotransplantation trials? Or does the field need a standardized gauge of a patient’s readiness, once discharged, to adhere not only to all medications – including those that fight infection – but also with rules established for public safety, such as routine contact reporting?

“It makes me wonder about choosing a noncompliant patient for these trials,” Dr. Reese said. “If we discharge a patient from the hospital who is at risk for a zoonotic infection that could spread if they basically refuse to cooperate with us or with public health authorities, it really could have negative consequences for the reputation of the field.”

Dr. Mohiuddin agreed such concerns are valid. Mr. Bennett “and all his immediate contacts” signed consent forms acknowledging their willingness to be followed should he be discharged. Mr. Bennett himself “signed a consent to inform us if he has any other intimate contact with someone,” he said in an interview.

“But those are only on paper.” Had Mr. Bennett survived to be discharged, Dr. Mohuiddin said, “no one knows how he would have behaved.”

Dr. Mohiuddin said the research staff had prepared to monitor Mr. Bennett at his home if that’s what it took. “We were ready to follow him as long as we could. There was a surveillance plan in place.”

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

The underlying cause of David Bennett’s death on March 8, two months after he received the heart of a genetically altered pig, remains unknown and is only slightly less mysterious for what can likely be ruled out, suggests a progress report on the case from the director of the cardiac xenotransplantation program where the pioneering surgery took place.

Mr. Bennett died in “diastolic heart failure,” reported Muhammad M. Mohiuddin, MBBS, University of Maryland School of Medicine, Baltimore, “but the mechanism is still under investigation.”

University of Maryland Medical Center

Rocky clinical course

Early characterizations of the patient’s death focused more on his diminished, end-stage clinical condition at the time of the surgery than on immune rejection or other direct effects of the xenograft or on the first-of-its-kind procedure itself.

The 57-year-old Mr. Bennett had presented to the University of Maryland team with nonischemic cardiomyopathy, on multiple inotropes, and requiring an intra-aortic balloon pump, Dr. Mohiuddin said in his ATC presentation. The patient had suffered multiple arrests and resuscitations, and by the time of surgery had been hospitalized for almost 2 months, including 40 days on veno-arterial extracorporeal membrane oxygenation (ECMO).

The transplant procedure itself went as planned until removal of the aortic cross clamp, which triggered a type-A aortic dissection. “We put a graft in the ascending aorta and a stent in the descending aorta. Even after 2 days, we found the dissection extending to the renal artery, so we had to go back and also put a stent in the renal artery,” Dr. Mohiuddin said.

Mr. Bennett also underwent two exploratory laparotomies in the first 10 days after transplantation, after CT imaging revealed signs of possible bowel inflammation and ischemia.

Further, he had to fight back a series of infections that led to major changes to his experimental drug regimen, which included immunosuppressants methylprednisolone and mycophenolate mofetil (MMF), the investigational anti-CD40 antibody KPL-404 (Kiniksa Pharmaceuticals), and the anti-inflammatories etanercept (Enbrel) and tocilizumab (Actemra).

One episode of sepsis, in particular, forced temporary withdrawal of MMF and a reduction in methylprednisolone dosage. It’s unknown whether the 30-day MMF suspension played a role in Mr. Bennett’s ultimate clinical deterioration and death, but it’s “highly possible,” Dr. Mohiuddin said in an interview.

Realistically, Mr. Bennett’s death was likely “multifactorial,” Dr. Mohiuddin said. He was in such poor clinical condition going into the procedure, and afterward confronted so many clinical challenges, that “it’s very difficult to say that one thing caused it.”

That hasn’t lessened speculation that the patient’s heart failed secondary to immunologic rejection or PCMV infection, either in Mr. Bennett or the donor pig.
 

A role for PCMV?

Weeks after Mr. Bennett’s death, as previously reported, his surgeon announced at a public forum that PCMV had been identified in the transplanted heart and in tissues of the donor pig. Mr. Bennett’s circulation showed traces of the viral DNA but not of the virus itself.

The presence of PCMV in transplanted porcine hearts is a well-recognized potential hazard in animal models but is considered avoidable with proper screening. In Mr. Bennett’s case, preoperative screening of the pig donor missed signs of the virus.  

Still, PCMV could potentially have contributed to Mr. Bennett’s death, acknowledged Bartley P. Griffith, MD, University of Maryland School of Medicine, who had announced the PCMV finding in an AST-sponsored April 20 webcast.

Preclinical evidence does suggest that PCMV can harm a xenograft organ, observed David H. Sachs, MD, Columbia University Medical Center, New York, from the audience during the comment period after Dr. Mohiuddin’s presentation.

“Each species has a CMV, and they’re quite species-specific,” observed the renowned surgeon and xenotransplantation immunologist. “We showed almost 10 years ago that if PCMV was in a pig kidney, it led to a much shortened survival of the pig kidney in a baboon. There was never any evidence, however, that the CMV infected the baboon or any baboon cells.”

Dr. Sachs asked Dr. Mohiuddin for confirmation that Mr. Bennett displayed no more than DNAemia, circulating cell-free PCMV DNA presumably shed from the porcine heart, but no sign of the virus itself outside of the heart’s porcine cells.

Cell-free DNA had shown up in Mr. Bennett’s circulation about 20 days after the surgery, with concentrations rising until at least day 50. Post-hoc polymerase chain reaction (PCR) testing disclosed PCMV only in the pig’s spleen and porcine cells of the transplanted heart, Dr. Mohiuddin noted.

“We have not found any evidence that the patient was infected by PCMV,” nor was there evidence of any disease related to PCMV, Dr. Mohiuddin replied.

Nor of ongoing rejection

Mr. Bennett’s new heart passed a critical test in the first post-implantation hours by avoiding acute rejection, a potentially disastrous outcome that three of the pig’s 10 gene edits had been designed to prevent.

Although chronic immune rejection was always a concern despite Mr. Bennett’s novel immunosuppressant regimen, myocardial biopsy on postoperative days 34, 50, and 56 and necropsy showed “no signs of typical xenograft rejection,” Dr. Mohiuddin said at the ATC presentation. But “there’s a chance of atypical rejection which we were not accustomed to.”

By day 50, his diastolic function showed echocardiographic signs of deterioration, and “we started seeing interstitial edema with some extravasation of red blood cells, which we thought would resolve over a period of time,” he said. Eventually, however, “we saw that turn into fibroblasts and scar tissue.”

Mr. Bennett once again went on veno-arterial ECMO but died 10 days later. Once they had seen histologic evidence of fibrosis, Dr. Mohiuddin told this news organization, the team believed the myocardial injury was irreversible. “That was the reason we gave up on recovery.”

Mr. Bennett’s xenotransplantation journey has taught the field a lot, he said. “By no means was this a failure; we consider this a huge success. You can do all the experiments in animal models, but you won’t find out the true mechanism of rejection unless you do these kinds of human experiments.”
 

Looking ahead to clinical trials

Research involving humans is always subject to vagaries of human nature, including degree of adherence to prescribed therapy and – in xenotransplantation – precautions in place to mitigate any risks to public health. Such risks theoretically include transfer of porcine viruses or other pathogens to the patient and subsequent release into the general population.

Looking ahead to the possibility of clinical trials after this successful xenotransplantation experience, transplant nephrologist and epidemiologist Peter P. Reese, MD, PhD, University of Pennsylvania, Philadelphia, raised the potentially controversial issue in discussion following Dr. Mohiuddin’s presentation.

It’s known that Mr. Bennett had been repeatedly turned down for a conventional allograft transplant primarily because of his history of treatment noncompliance. Should such a record, Dr. Reese asked, be a relative contraindication to enrollment in any future xenotransplantation trials? Or does the field need a standardized gauge of a patient’s readiness, once discharged, to adhere not only to all medications – including those that fight infection – but also with rules established for public safety, such as routine contact reporting?

“It makes me wonder about choosing a noncompliant patient for these trials,” Dr. Reese said. “If we discharge a patient from the hospital who is at risk for a zoonotic infection that could spread if they basically refuse to cooperate with us or with public health authorities, it really could have negative consequences for the reputation of the field.”

Dr. Mohiuddin agreed such concerns are valid. Mr. Bennett “and all his immediate contacts” signed consent forms acknowledging their willingness to be followed should he be discharged. Mr. Bennett himself “signed a consent to inform us if he has any other intimate contact with someone,” he said in an interview.

“But those are only on paper.” Had Mr. Bennett survived to be discharged, Dr. Mohuiddin said, “no one knows how he would have behaved.”

Dr. Mohiuddin said the research staff had prepared to monitor Mr. Bennett at his home if that’s what it took. “We were ready to follow him as long as we could. There was a surveillance plan in place.”

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

A recent study linking the consumption of fish to melanoma had sushi eaters looking up the number of the nearest dermatologist. But experts said the findings had several important limitations and that no one should change their diet based on the results.

© oleksajewicz/Thinkstock

“It wouldn’t impact my fish consumption at all,” said Sancy Leachman, MD, PhD, who directs the melanoma program at Oregon Health & Science University’s Knight Cancer Institute in Portland. “Fish are part of a healthy diet,” particularly if it replaces less healthy proteins such as beef.

Even the authors of the study advised caution when interpreting the findings.

“I wouldn’t encourage anyone to change their fish consumption habits just because of this paper,” said study leader Eunyoung Cho, ScD, an epidemiologist at Brown University, Providence, R.I. “Fish is cardioprotective and is related to reduced risk of developing certain cancers too.”
 

Solid findings or fishing expedition?

The study quickly generated headlines and was the most viewed article of the journal Cancer Causes & Control within a day of its publication.

Dr. Cho, who is on the editorial board of the journal, analyzed the results of a study funded by the National Institutes of Health and the Association for the Advancement of Retired Persons that began in the 1990s and explored possible links between fish consumption and developing different forms of cancer.

Previous research from this project had shown eating fish was associated with an increased risk of melanoma – but no other type of cancer.

Dr. Cho speculated that the risk is due to contaminants, such as mercury and arsenic, in fish. But she was curious to see if she could find a connection between the amount of fish consumed and the risk of developing skin cancer.

At the beginning of the study people reported how much fish they had consumed over the previous year, which varied widely by person. Then researchers tracked participants for 15 years, recording who developed cancer and who did not.

Dietary recall can be difficult; people often say they can’t remember what they ate yesterday, much less 1 year ago. Still, dietitian Clare Collins, PhD, of the University of Newcastle (Australia), noted that previous research showed that the dietary recall tool for this study is reliable.

NIH researchers never checked to see how their diet changed over time, as this was a study meant to observe changes in health status starting from a baseline point. The researchers assumed that the level of fish intake recorded at the beginning of the study remained steady.

Of 491,000 people tracked in the study, 5,000 developed malignant melanoma and another 3,300 developed melanoma cells on the skin surface. People who ate the most fish – an average of almost 43 g, or about 1.5 ounces, per day – were 23% more likely to develop melanoma than the lightest fish eaters, who averaged 3 g per day.  

That risk is modest, Dr. Leachman said, especially for people with red hair who, she said, are 400% more likely to get melanoma than others. “A 23% increase, in the whole scheme of things, is not nearly as important as not getting sunburned if you’re a redhead,” Dr. Leachman said.

And what about the sun? Sun exposure is the principal risk factor for developing melanoma, and the researchers didn’t account for that factor. People who developed melanoma during the study may simply have spent more time in tanning beds or on the beach – or perhaps fishing and then eating their catch.

Dr. Cho and colleagues tried to consider the effects of solar radiation by looking at average sun exposure times in the places where the participants in the study were living when the research began. Using that framework, variation in sun exposure made no difference to melanoma risk, but Dr. Leachman said the technique isn’t foolproof.

“They assumed that they were going to get a certain amount of ultraviolet light just based on where they lived. We don’t know how long they lived there or if they really had ultraviolet exposure or not,” Dr. Leachman said. Someone in presumably less sunny Pennsylvania could get more sun than someone in sun-drenched Arizona depending on their lifestyle and habits.

The kind of study Dr. Cho published cannot account for individual behaviors related to sun exposure, a limitation her team readily acknowledges. Nor does it include information about moles or hair color – important considerations for skin cancers. It may be that redheads with moles who barely ate any fish developed melanoma at higher rates than anyone else, but the data don’t allow for that kind of analysis.

Dr. Cho’s group found that canned tuna and any type of fish that wasn’t fried were associated with a higher risk of developing melanoma, as people reported eating more of those products. However, people who said they ate greater quantities of fried fish had a lower risk of melanoma, a counterintuitive finding that she said warrants further research.

Given that the study showed only a modest chance of developing melanoma regardless of fish intake, and left so many questions unanswered, what was the point?

Other journals declined to publish this paper, Dr. Cho acknowledged, but she defended the article as a step toward better understanding the health impact of environmental contaminants in fish.

Dr. Leachman agreed. “These kinds of studies are very important to do. They have large data sets, where you can start to see trends that may be important,” she said. “They can help you identify things that might be related. These experiments are hypothesis generating.”

“I already published an article showing that total mercury level is related to skin cancer, and we know very well that in the U.S. fish consumption is the major source of mercury contamination,” Dr. Cho said. “So, I naturally thought that fish consumption may be associated with increased risk of skin cancer too.” Dr. Cho said she believed the findings confirm that hypothesis.

Dr. Cho said the next step would be to measure blood levels of different contaminants such as mercury and arsenic in people with melanoma, to determine which toxin is the biggest driver of melanoma. She said she plans to seek funding for that research.

Meanwhile, pass the salmon – but go light on the salt.

Dr. Cho and Dr. Leachman reported no relevant financial relationships. Dr. Cho is on the editorial board of Cancer Causes & Control.

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

A recent study linking the consumption of fish to melanoma had sushi eaters looking up the number of the nearest dermatologist. But experts said the findings had several important limitations and that no one should change their diet based on the results.

© oleksajewicz/Thinkstock

“It wouldn’t impact my fish consumption at all,” said Sancy Leachman, MD, PhD, who directs the melanoma program at Oregon Health & Science University’s Knight Cancer Institute in Portland. “Fish are part of a healthy diet,” particularly if it replaces less healthy proteins such as beef.

Even the authors of the study advised caution when interpreting the findings.

“I wouldn’t encourage anyone to change their fish consumption habits just because of this paper,” said study leader Eunyoung Cho, ScD, an epidemiologist at Brown University, Providence, R.I. “Fish is cardioprotective and is related to reduced risk of developing certain cancers too.”
 

Solid findings or fishing expedition?

The study quickly generated headlines and was the most viewed article of the journal Cancer Causes & Control within a day of its publication.

Dr. Cho, who is on the editorial board of the journal, analyzed the results of a study funded by the National Institutes of Health and the Association for the Advancement of Retired Persons that began in the 1990s and explored possible links between fish consumption and developing different forms of cancer.

Previous research from this project had shown eating fish was associated with an increased risk of melanoma – but no other type of cancer.

Dr. Cho speculated that the risk is due to contaminants, such as mercury and arsenic, in fish. But she was curious to see if she could find a connection between the amount of fish consumed and the risk of developing skin cancer.

At the beginning of the study people reported how much fish they had consumed over the previous year, which varied widely by person. Then researchers tracked participants for 15 years, recording who developed cancer and who did not.

Dietary recall can be difficult; people often say they can’t remember what they ate yesterday, much less 1 year ago. Still, dietitian Clare Collins, PhD, of the University of Newcastle (Australia), noted that previous research showed that the dietary recall tool for this study is reliable.

NIH researchers never checked to see how their diet changed over time, as this was a study meant to observe changes in health status starting from a baseline point. The researchers assumed that the level of fish intake recorded at the beginning of the study remained steady.

Of 491,000 people tracked in the study, 5,000 developed malignant melanoma and another 3,300 developed melanoma cells on the skin surface. People who ate the most fish – an average of almost 43 g, or about 1.5 ounces, per day – were 23% more likely to develop melanoma than the lightest fish eaters, who averaged 3 g per day.  

That risk is modest, Dr. Leachman said, especially for people with red hair who, she said, are 400% more likely to get melanoma than others. “A 23% increase, in the whole scheme of things, is not nearly as important as not getting sunburned if you’re a redhead,” Dr. Leachman said.

And what about the sun? Sun exposure is the principal risk factor for developing melanoma, and the researchers didn’t account for that factor. People who developed melanoma during the study may simply have spent more time in tanning beds or on the beach – or perhaps fishing and then eating their catch.

Dr. Cho and colleagues tried to consider the effects of solar radiation by looking at average sun exposure times in the places where the participants in the study were living when the research began. Using that framework, variation in sun exposure made no difference to melanoma risk, but Dr. Leachman said the technique isn’t foolproof.

“They assumed that they were going to get a certain amount of ultraviolet light just based on where they lived. We don’t know how long they lived there or if they really had ultraviolet exposure or not,” Dr. Leachman said. Someone in presumably less sunny Pennsylvania could get more sun than someone in sun-drenched Arizona depending on their lifestyle and habits.

The kind of study Dr. Cho published cannot account for individual behaviors related to sun exposure, a limitation her team readily acknowledges. Nor does it include information about moles or hair color – important considerations for skin cancers. It may be that redheads with moles who barely ate any fish developed melanoma at higher rates than anyone else, but the data don’t allow for that kind of analysis.

Dr. Cho’s group found that canned tuna and any type of fish that wasn’t fried were associated with a higher risk of developing melanoma, as people reported eating more of those products. However, people who said they ate greater quantities of fried fish had a lower risk of melanoma, a counterintuitive finding that she said warrants further research.

Given that the study showed only a modest chance of developing melanoma regardless of fish intake, and left so many questions unanswered, what was the point?

Other journals declined to publish this paper, Dr. Cho acknowledged, but she defended the article as a step toward better understanding the health impact of environmental contaminants in fish.

Dr. Leachman agreed. “These kinds of studies are very important to do. They have large data sets, where you can start to see trends that may be important,” she said. “They can help you identify things that might be related. These experiments are hypothesis generating.”

“I already published an article showing that total mercury level is related to skin cancer, and we know very well that in the U.S. fish consumption is the major source of mercury contamination,” Dr. Cho said. “So, I naturally thought that fish consumption may be associated with increased risk of skin cancer too.” Dr. Cho said she believed the findings confirm that hypothesis.

Dr. Cho said the next step would be to measure blood levels of different contaminants such as mercury and arsenic in people with melanoma, to determine which toxin is the biggest driver of melanoma. She said she plans to seek funding for that research.

Meanwhile, pass the salmon – but go light on the salt.

Dr. Cho and Dr. Leachman reported no relevant financial relationships. Dr. Cho is on the editorial board of Cancer Causes & Control.

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

A recent study linking the consumption of fish to melanoma had sushi eaters looking up the number of the nearest dermatologist. But experts said the findings had several important limitations and that no one should change their diet based on the results.

© oleksajewicz/Thinkstock

“It wouldn’t impact my fish consumption at all,” said Sancy Leachman, MD, PhD, who directs the melanoma program at Oregon Health & Science University’s Knight Cancer Institute in Portland. “Fish are part of a healthy diet,” particularly if it replaces less healthy proteins such as beef.

Even the authors of the study advised caution when interpreting the findings.

“I wouldn’t encourage anyone to change their fish consumption habits just because of this paper,” said study leader Eunyoung Cho, ScD, an epidemiologist at Brown University, Providence, R.I. “Fish is cardioprotective and is related to reduced risk of developing certain cancers too.”
 

Solid findings or fishing expedition?

The study quickly generated headlines and was the most viewed article of the journal Cancer Causes & Control within a day of its publication.

Dr. Cho, who is on the editorial board of the journal, analyzed the results of a study funded by the National Institutes of Health and the Association for the Advancement of Retired Persons that began in the 1990s and explored possible links between fish consumption and developing different forms of cancer.

Previous research from this project had shown eating fish was associated with an increased risk of melanoma – but no other type of cancer.

Dr. Cho speculated that the risk is due to contaminants, such as mercury and arsenic, in fish. But she was curious to see if she could find a connection between the amount of fish consumed and the risk of developing skin cancer.

At the beginning of the study people reported how much fish they had consumed over the previous year, which varied widely by person. Then researchers tracked participants for 15 years, recording who developed cancer and who did not.

Dietary recall can be difficult; people often say they can’t remember what they ate yesterday, much less 1 year ago. Still, dietitian Clare Collins, PhD, of the University of Newcastle (Australia), noted that previous research showed that the dietary recall tool for this study is reliable.

NIH researchers never checked to see how their diet changed over time, as this was a study meant to observe changes in health status starting from a baseline point. The researchers assumed that the level of fish intake recorded at the beginning of the study remained steady.

Of 491,000 people tracked in the study, 5,000 developed malignant melanoma and another 3,300 developed melanoma cells on the skin surface. People who ate the most fish – an average of almost 43 g, or about 1.5 ounces, per day – were 23% more likely to develop melanoma than the lightest fish eaters, who averaged 3 g per day.  

That risk is modest, Dr. Leachman said, especially for people with red hair who, she said, are 400% more likely to get melanoma than others. “A 23% increase, in the whole scheme of things, is not nearly as important as not getting sunburned if you’re a redhead,” Dr. Leachman said.

And what about the sun? Sun exposure is the principal risk factor for developing melanoma, and the researchers didn’t account for that factor. People who developed melanoma during the study may simply have spent more time in tanning beds or on the beach – or perhaps fishing and then eating their catch.

Dr. Cho and colleagues tried to consider the effects of solar radiation by looking at average sun exposure times in the places where the participants in the study were living when the research began. Using that framework, variation in sun exposure made no difference to melanoma risk, but Dr. Leachman said the technique isn’t foolproof.

“They assumed that they were going to get a certain amount of ultraviolet light just based on where they lived. We don’t know how long they lived there or if they really had ultraviolet exposure or not,” Dr. Leachman said. Someone in presumably less sunny Pennsylvania could get more sun than someone in sun-drenched Arizona depending on their lifestyle and habits.

The kind of study Dr. Cho published cannot account for individual behaviors related to sun exposure, a limitation her team readily acknowledges. Nor does it include information about moles or hair color – important considerations for skin cancers. It may be that redheads with moles who barely ate any fish developed melanoma at higher rates than anyone else, but the data don’t allow for that kind of analysis.

Dr. Cho’s group found that canned tuna and any type of fish that wasn’t fried were associated with a higher risk of developing melanoma, as people reported eating more of those products. However, people who said they ate greater quantities of fried fish had a lower risk of melanoma, a counterintuitive finding that she said warrants further research.

Given that the study showed only a modest chance of developing melanoma regardless of fish intake, and left so many questions unanswered, what was the point?

Other journals declined to publish this paper, Dr. Cho acknowledged, but she defended the article as a step toward better understanding the health impact of environmental contaminants in fish.

Dr. Leachman agreed. “These kinds of studies are very important to do. They have large data sets, where you can start to see trends that may be important,” she said. “They can help you identify things that might be related. These experiments are hypothesis generating.”

“I already published an article showing that total mercury level is related to skin cancer, and we know very well that in the U.S. fish consumption is the major source of mercury contamination,” Dr. Cho said. “So, I naturally thought that fish consumption may be associated with increased risk of skin cancer too.” Dr. Cho said she believed the findings confirm that hypothesis.

Dr. Cho said the next step would be to measure blood levels of different contaminants such as mercury and arsenic in people with melanoma, to determine which toxin is the biggest driver of melanoma. She said she plans to seek funding for that research.

Meanwhile, pass the salmon – but go light on the salt.

Dr. Cho and Dr. Leachman reported no relevant financial relationships. Dr. Cho is on the editorial board of Cancer Causes & Control.

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

Photographs courtesy of Richard P. Usatine, MD (Figure A), and Tizita Yosef Kidane, MD (Figure B).

THE COMPARISON

A Nodular basal cell carcinoma (BCC) with a pearly rolled border, central pigmentation, and telangiectasia on the forehead of an 80-year-old Hispanic woman (light skin tone).

B Nodular BCC on the cheek of a 64-year-old Black man. The dark nonhealing ulcer had a subtle, pearly, rolled border and no visible telangiectasia.

Basal cell carcinoma is most prevalent in individuals with lighter skin tones and rarely affects those with darker skin tones. Unfortunately, the lower incidence and lack of surveillance frequently result in a delayed diagnosis and increased morbidity for the skin of color population.¹

Epidemiology

Basal cell carcinoma is the most common skin cancer in White, Asian, and Hispanic individuals and the second most common in Black individuals. Squamous cell carcinoma is the most common skin cancer in Black individuals.²

Although BCCs are rare in individuals with darker skin tones, they most often develop in sun-exposed areas of the head and neck region.¹ In one study in an academic urban medical center, BCCs were more likely to occur in lightly pigmented vs darkly pigmented Black individuals.³

Key clinical features in people with darker skin tones

The classic BCC manifestation of a pearly papule with rolled borders and telangiectasia may not be seen in the skin of color population, especially among those with darker skin tones.⁴ In patient A, a Hispanic woman, these features are present along with hyperpigmentation. More than 50% of BCCs are pigmented in patients with skin of color vs only 5% in White individuals.^5-7 The incidence of a pigmented BCC is twice as frequent in Hispanic individuals (Figure, A) as in non-Hispanic White individuals.⁷ Any skin cancer can present with ulcerations, so while this is not specific to BCC, it is a reason to consider biopsy.

Worth noting

Pigmented BCC can mimic melanoma clinically and even when viewed with a dermatoscope, but such a suspicious lesion should prompt the clinician to perform a biopsy regardless of the type of suspected cancer. With experience and training, however, physicians can use dermoscopy to help make this distinction.

Note that skin of color is found in a heterogeneous population with a spectrum of skin tones and genetic/ ethnic variability. In my practice in San Antonio (R.P.U.), BCC is uncommon in Black patients and relatively common in Hispanic patients with lighter skin tones (Figure, A). There is speculation that a lower incidence of BCC in the skin of color population leads to a low index of suspicion, which contributes to delayed diagnoses with poorer outcomes. ¹ There are no firm data to support this because the rare occurrence of BCC in darker skin tones makes this a challenge to study.

Health disparity highlight

In general, barriers to health care include poverty, lack of education, lack of health insurance, and systemic racism. One study on keratinocyte skin cancers including BCC and SCC found that these cancers were more costly to treat and required more health care resources, such as ambulatory visits and medication costs, in non-Hispanic Black and Hispanic White patients compared to non- Hispanic White patients.⁸

Final thoughts

Efforts are needed to achieve health equity through education of patients and health care providers about the appearance of BCC in skin of color with the goal of earlier diagnosis. Any nonhealing ulcer on the skin (Figure, B) should prompt consideration of skin cancer regardless of skin color.

Photographs courtesy of Richard P. Usatine, MD (Figure A), and Tizita Yosef Kidane, MD (Figure B).

THE COMPARISON

A Nodular basal cell carcinoma (BCC) with a pearly rolled border, central pigmentation, and telangiectasia on the forehead of an 80-year-old Hispanic woman (light skin tone).

B Nodular BCC on the cheek of a 64-year-old Black man. The dark nonhealing ulcer had a subtle, pearly, rolled border and no visible telangiectasia.

Basal cell carcinoma is most prevalent in individuals with lighter skin tones and rarely affects those with darker skin tones. Unfortunately, the lower incidence and lack of surveillance frequently result in a delayed diagnosis and increased morbidity for the skin of color population.¹

Epidemiology

Basal cell carcinoma is the most common skin cancer in White, Asian, and Hispanic individuals and the second most common in Black individuals. Squamous cell carcinoma is the most common skin cancer in Black individuals.²

Although BCCs are rare in individuals with darker skin tones, they most often develop in sun-exposed areas of the head and neck region.¹ In one study in an academic urban medical center, BCCs were more likely to occur in lightly pigmented vs darkly pigmented Black individuals.³

Key clinical features in people with darker skin tones

The classic BCC manifestation of a pearly papule with rolled borders and telangiectasia may not be seen in the skin of color population, especially among those with darker skin tones.⁴ In patient A, a Hispanic woman, these features are present along with hyperpigmentation. More than 50% of BCCs are pigmented in patients with skin of color vs only 5% in White individuals.^5-7 The incidence of a pigmented BCC is twice as frequent in Hispanic individuals (Figure, A) as in non-Hispanic White individuals.⁷ Any skin cancer can present with ulcerations, so while this is not specific to BCC, it is a reason to consider biopsy.

Worth noting

Pigmented BCC can mimic melanoma clinically and even when viewed with a dermatoscope, but such a suspicious lesion should prompt the clinician to perform a biopsy regardless of the type of suspected cancer. With experience and training, however, physicians can use dermoscopy to help make this distinction.

Note that skin of color is found in a heterogeneous population with a spectrum of skin tones and genetic/ ethnic variability. In my practice in San Antonio (R.P.U.), BCC is uncommon in Black patients and relatively common in Hispanic patients with lighter skin tones (Figure, A). There is speculation that a lower incidence of BCC in the skin of color population leads to a low index of suspicion, which contributes to delayed diagnoses with poorer outcomes. ¹ There are no firm data to support this because the rare occurrence of BCC in darker skin tones makes this a challenge to study.

Health disparity highlight

In general, barriers to health care include poverty, lack of education, lack of health insurance, and systemic racism. One study on keratinocyte skin cancers including BCC and SCC found that these cancers were more costly to treat and required more health care resources, such as ambulatory visits and medication costs, in non-Hispanic Black and Hispanic White patients compared to non- Hispanic White patients.⁸

Final thoughts

Efforts are needed to achieve health equity through education of patients and health care providers about the appearance of BCC in skin of color with the goal of earlier diagnosis. Any nonhealing ulcer on the skin (Figure, B) should prompt consideration of skin cancer regardless of skin color.

Photographs courtesy of Richard P. Usatine, MD (Figure A), and Tizita Yosef Kidane, MD (Figure B).

THE COMPARISON

A Nodular basal cell carcinoma (BCC) with a pearly rolled border, central pigmentation, and telangiectasia on the forehead of an 80-year-old Hispanic woman (light skin tone).

B Nodular BCC on the cheek of a 64-year-old Black man. The dark nonhealing ulcer had a subtle, pearly, rolled border and no visible telangiectasia.

Basal cell carcinoma is most prevalent in individuals with lighter skin tones and rarely affects those with darker skin tones. Unfortunately, the lower incidence and lack of surveillance frequently result in a delayed diagnosis and increased morbidity for the skin of color population.¹

Epidemiology

Basal cell carcinoma is the most common skin cancer in White, Asian, and Hispanic individuals and the second most common in Black individuals. Squamous cell carcinoma is the most common skin cancer in Black individuals.²

Although BCCs are rare in individuals with darker skin tones, they most often develop in sun-exposed areas of the head and neck region.¹ In one study in an academic urban medical center, BCCs were more likely to occur in lightly pigmented vs darkly pigmented Black individuals.³

Key clinical features in people with darker skin tones

The classic BCC manifestation of a pearly papule with rolled borders and telangiectasia may not be seen in the skin of color population, especially among those with darker skin tones.⁴ In patient A, a Hispanic woman, these features are present along with hyperpigmentation. More than 50% of BCCs are pigmented in patients with skin of color vs only 5% in White individuals.^5-7 The incidence of a pigmented BCC is twice as frequent in Hispanic individuals (Figure, A) as in non-Hispanic White individuals.⁷ Any skin cancer can present with ulcerations, so while this is not specific to BCC, it is a reason to consider biopsy.

Worth noting

Pigmented BCC can mimic melanoma clinically and even when viewed with a dermatoscope, but such a suspicious lesion should prompt the clinician to perform a biopsy regardless of the type of suspected cancer. With experience and training, however, physicians can use dermoscopy to help make this distinction.

Note that skin of color is found in a heterogeneous population with a spectrum of skin tones and genetic/ ethnic variability. In my practice in San Antonio (R.P.U.), BCC is uncommon in Black patients and relatively common in Hispanic patients with lighter skin tones (Figure, A). There is speculation that a lower incidence of BCC in the skin of color population leads to a low index of suspicion, which contributes to delayed diagnoses with poorer outcomes. ¹ There are no firm data to support this because the rare occurrence of BCC in darker skin tones makes this a challenge to study.

Health disparity highlight

In general, barriers to health care include poverty, lack of education, lack of health insurance, and systemic racism. One study on keratinocyte skin cancers including BCC and SCC found that these cancers were more costly to treat and required more health care resources, such as ambulatory visits and medication costs, in non-Hispanic Black and Hispanic White patients compared to non- Hispanic White patients.⁸

Final thoughts

Efforts are needed to achieve health equity through education of patients and health care providers about the appearance of BCC in skin of color with the goal of earlier diagnosis. Any nonhealing ulcer on the skin (Figure, B) should prompt consideration of skin cancer regardless of skin color.

Prediabetes is not only a predictor of diabetes and the cardiovascular complications that ensue, but it is also a risk factor by itself for myocardial infarction, according to data drawn from almost 1.8 million patients hospitalized for MI.

“Our study serves as a wakeup call for clinicians and patients to shift the focus to preventing prediabetes, and not just diabetes, said Geethika Thota, MD, at the annual meeting of the Endocrine Society.

There are plenty of data suggesting that prediabetes places patients on a trajectory toward cardiovascular disease. In a meta-analysis of 129 studies published 2 years ago, prediabetes was not only associated with a statistically significant 16% increase in coronary heart disease, but also a 13% increased risk of all-cause mortality relative to those with normoglycemia.
 

Data drawn from 1.8 million patients

In this study, 1,794,149 weighted patient hospitalizations for MI were drawn from the National Inpatient Sample database. Excluding patients who eventually developed diabetes, roughly 1% of these patients had a history of prediabetes in the past, according to a search of ICD-10 codes.

Before adjustment for other risk factors, prediabetes was linked to a greater than 40% increased odds of MI (odds ratio, 1.41; P < .01). After adjustment for a large array of known MI risk factors – including prior history of MI, dyslipidemia, hypertension, nicotine dependence, and obesity – prediabetes remained an independent risk factor, corresponding with a 25% increased risk of MI (OR, 1.25; P < .01).

A history of prediabetes was also an independent risk factor for percutaneous intervention and coronary artery bypass grafting, with increased risk of 45% and 95%, respectively.

As a retrospective study looking at prediabetes as a risk factor in those who already had a MI, it is possible that not all patients with prediabetes were properly coded, but Dr. Thota said that was unlikely to have been an issue of sufficient magnitude to have affected the major conclusions.
 

Relevance seen for community care

Although the study was drawn from hospitalized patients, its relevance is for the community setting, where screening and intervention for prediabetes has the potential to alter the risk, according to Dr. Thota.

Most clinicians are likely aware of the value of screening for prediabetes, which was defined in this study as a hemoglobin A1c of 5.7%-6.4%, but Dr. Thota suggested that many might not fully grasp the full scope of goals. Early detection and prevention will prevent diabetes and, by extension, cardiovascular disease, but her data suggest that control of prediabetes with lower cardiovascular risk by a more direct route.

“Despite mounting evidence, many clinicians are unaware that prediabetes is also a major risk factor for atherosclerotic cardiovascular disease,” said Dr. Thota, an internal medicine resident at Saint Peter’s University Hospital, New Brunswick, N.J.

Like diabetes, the prevalence of prediabetes is growing rapidly, according to data from the Centers for Disease Control that Dr. Thota cited. In 2020, the Centers for Disease Control and Prevention estimated that 38% of the adult population have prediabetes. By 2030, one model predicts a further 25% growth.

Screening for hyperglycemia is part of routine patient evaluations at Dr. Thota’s center. In an interview, she said that once a diagnosis of prediabetes is entered in the electronic medical record, the history is carried forward so that changes in status are continually monitored.
 

Worsening prediabetes should be addressed

“Prediabetes is not treated with medication, at least initially,” Dr. Thota explained. Rather, patients are educated about important lifestyle changes, such as diet and physical activity, that can reverse the diagnosis. However, patients who remain on a path of worsening hyperglycemia are candidates for more intensive lifestyle intervention and might be considered selectively for metformin.

“Early recognition of prediabetes through screening is important,” Dr. Thota emphasized. The benefit for preventing patients from progressing to diabetes is well recognized, but these data provide the basis for incentivizing lifestyle changes in patients with prediabetes by telling them that it can reduce their risk for MI.

These data have an important message, but they are not surprising, according to Deepak L. Bhatt, MD, executive director, interventional cardiovascular programs, Brigham and Women’s Hospital Heart & Vascular Center, Boston.

“In fact, in daily practice we see a substantial percentage of patients with MI who have prediabetes that had not been previously recognized or formally diagnosed,” Dr. Bhatt said in an interview.

“Identifying these patients – preferably prior to coming in with cardiovascular complications – is important both to reduce cardiovascular risk but also to try and prevent progression at diabetes,” he added.

Dr. Bhatt went on to say that this large analysis, confirming that prediabetes is independently associated with MI, should prompt clinicians to screen patients rigorously for this condition.

“At a minimum, such patients would be candidates for intensive lifestyle modification aimed at weight loss and treatment of frequent coexistent conditions, such as hypertension and dyslipidemia,” Dr. Bhatt said.

Dr. Thota reports no potential conflicts of interest. Dr. Bhatt has financial relationships with more than 30 pharmaceutical companies, many of which make products relevant to the management of diabetes and cardiovascular disease.

Prediabetes is not only a predictor of diabetes and the cardiovascular complications that ensue, but it is also a risk factor by itself for myocardial infarction, according to data drawn from almost 1.8 million patients hospitalized for MI.

“Our study serves as a wakeup call for clinicians and patients to shift the focus to preventing prediabetes, and not just diabetes, said Geethika Thota, MD, at the annual meeting of the Endocrine Society.

There are plenty of data suggesting that prediabetes places patients on a trajectory toward cardiovascular disease. In a meta-analysis of 129 studies published 2 years ago, prediabetes was not only associated with a statistically significant 16% increase in coronary heart disease, but also a 13% increased risk of all-cause mortality relative to those with normoglycemia.
 

Data drawn from 1.8 million patients

In this study, 1,794,149 weighted patient hospitalizations for MI were drawn from the National Inpatient Sample database. Excluding patients who eventually developed diabetes, roughly 1% of these patients had a history of prediabetes in the past, according to a search of ICD-10 codes.

Before adjustment for other risk factors, prediabetes was linked to a greater than 40% increased odds of MI (odds ratio, 1.41; P < .01). After adjustment for a large array of known MI risk factors – including prior history of MI, dyslipidemia, hypertension, nicotine dependence, and obesity – prediabetes remained an independent risk factor, corresponding with a 25% increased risk of MI (OR, 1.25; P < .01).

A history of prediabetes was also an independent risk factor for percutaneous intervention and coronary artery bypass grafting, with increased risk of 45% and 95%, respectively.

As a retrospective study looking at prediabetes as a risk factor in those who already had a MI, it is possible that not all patients with prediabetes were properly coded, but Dr. Thota said that was unlikely to have been an issue of sufficient magnitude to have affected the major conclusions.
 

Relevance seen for community care

Although the study was drawn from hospitalized patients, its relevance is for the community setting, where screening and intervention for prediabetes has the potential to alter the risk, according to Dr. Thota.

Most clinicians are likely aware of the value of screening for prediabetes, which was defined in this study as a hemoglobin A1c of 5.7%-6.4%, but Dr. Thota suggested that many might not fully grasp the full scope of goals. Early detection and prevention will prevent diabetes and, by extension, cardiovascular disease, but her data suggest that control of prediabetes with lower cardiovascular risk by a more direct route.

“Despite mounting evidence, many clinicians are unaware that prediabetes is also a major risk factor for atherosclerotic cardiovascular disease,” said Dr. Thota, an internal medicine resident at Saint Peter’s University Hospital, New Brunswick, N.J.

Like diabetes, the prevalence of prediabetes is growing rapidly, according to data from the Centers for Disease Control that Dr. Thota cited. In 2020, the Centers for Disease Control and Prevention estimated that 38% of the adult population have prediabetes. By 2030, one model predicts a further 25% growth.

Screening for hyperglycemia is part of routine patient evaluations at Dr. Thota’s center. In an interview, she said that once a diagnosis of prediabetes is entered in the electronic medical record, the history is carried forward so that changes in status are continually monitored.
 

Worsening prediabetes should be addressed

“Prediabetes is not treated with medication, at least initially,” Dr. Thota explained. Rather, patients are educated about important lifestyle changes, such as diet and physical activity, that can reverse the diagnosis. However, patients who remain on a path of worsening hyperglycemia are candidates for more intensive lifestyle intervention and might be considered selectively for metformin.

“Early recognition of prediabetes through screening is important,” Dr. Thota emphasized. The benefit for preventing patients from progressing to diabetes is well recognized, but these data provide the basis for incentivizing lifestyle changes in patients with prediabetes by telling them that it can reduce their risk for MI.

These data have an important message, but they are not surprising, according to Deepak L. Bhatt, MD, executive director, interventional cardiovascular programs, Brigham and Women’s Hospital Heart & Vascular Center, Boston.

“In fact, in daily practice we see a substantial percentage of patients with MI who have prediabetes that had not been previously recognized or formally diagnosed,” Dr. Bhatt said in an interview.

“Identifying these patients – preferably prior to coming in with cardiovascular complications – is important both to reduce cardiovascular risk but also to try and prevent progression at diabetes,” he added.

Dr. Bhatt went on to say that this large analysis, confirming that prediabetes is independently associated with MI, should prompt clinicians to screen patients rigorously for this condition.

“At a minimum, such patients would be candidates for intensive lifestyle modification aimed at weight loss and treatment of frequent coexistent conditions, such as hypertension and dyslipidemia,” Dr. Bhatt said.

Dr. Thota reports no potential conflicts of interest. Dr. Bhatt has financial relationships with more than 30 pharmaceutical companies, many of which make products relevant to the management of diabetes and cardiovascular disease.

Prediabetes is not only a predictor of diabetes and the cardiovascular complications that ensue, but it is also a risk factor by itself for myocardial infarction, according to data drawn from almost 1.8 million patients hospitalized for MI.

“Our study serves as a wakeup call for clinicians and patients to shift the focus to preventing prediabetes, and not just diabetes, said Geethika Thota, MD, at the annual meeting of the Endocrine Society.

There are plenty of data suggesting that prediabetes places patients on a trajectory toward cardiovascular disease. In a meta-analysis of 129 studies published 2 years ago, prediabetes was not only associated with a statistically significant 16% increase in coronary heart disease, but also a 13% increased risk of all-cause mortality relative to those with normoglycemia.
 

Data drawn from 1.8 million patients

In this study, 1,794,149 weighted patient hospitalizations for MI were drawn from the National Inpatient Sample database. Excluding patients who eventually developed diabetes, roughly 1% of these patients had a history of prediabetes in the past, according to a search of ICD-10 codes.

Before adjustment for other risk factors, prediabetes was linked to a greater than 40% increased odds of MI (odds ratio, 1.41; P < .01). After adjustment for a large array of known MI risk factors – including prior history of MI, dyslipidemia, hypertension, nicotine dependence, and obesity – prediabetes remained an independent risk factor, corresponding with a 25% increased risk of MI (OR, 1.25; P < .01).

A history of prediabetes was also an independent risk factor for percutaneous intervention and coronary artery bypass grafting, with increased risk of 45% and 95%, respectively.

As a retrospective study looking at prediabetes as a risk factor in those who already had a MI, it is possible that not all patients with prediabetes were properly coded, but Dr. Thota said that was unlikely to have been an issue of sufficient magnitude to have affected the major conclusions.
 

Relevance seen for community care

Although the study was drawn from hospitalized patients, its relevance is for the community setting, where screening and intervention for prediabetes has the potential to alter the risk, according to Dr. Thota.

Most clinicians are likely aware of the value of screening for prediabetes, which was defined in this study as a hemoglobin A1c of 5.7%-6.4%, but Dr. Thota suggested that many might not fully grasp the full scope of goals. Early detection and prevention will prevent diabetes and, by extension, cardiovascular disease, but her data suggest that control of prediabetes with lower cardiovascular risk by a more direct route.

“Despite mounting evidence, many clinicians are unaware that prediabetes is also a major risk factor for atherosclerotic cardiovascular disease,” said Dr. Thota, an internal medicine resident at Saint Peter’s University Hospital, New Brunswick, N.J.

Like diabetes, the prevalence of prediabetes is growing rapidly, according to data from the Centers for Disease Control that Dr. Thota cited. In 2020, the Centers for Disease Control and Prevention estimated that 38% of the adult population have prediabetes. By 2030, one model predicts a further 25% growth.

Screening for hyperglycemia is part of routine patient evaluations at Dr. Thota’s center. In an interview, she said that once a diagnosis of prediabetes is entered in the electronic medical record, the history is carried forward so that changes in status are continually monitored.
 

Worsening prediabetes should be addressed

“Prediabetes is not treated with medication, at least initially,” Dr. Thota explained. Rather, patients are educated about important lifestyle changes, such as diet and physical activity, that can reverse the diagnosis. However, patients who remain on a path of worsening hyperglycemia are candidates for more intensive lifestyle intervention and might be considered selectively for metformin.

“Early recognition of prediabetes through screening is important,” Dr. Thota emphasized. The benefit for preventing patients from progressing to diabetes is well recognized, but these data provide the basis for incentivizing lifestyle changes in patients with prediabetes by telling them that it can reduce their risk for MI.

These data have an important message, but they are not surprising, according to Deepak L. Bhatt, MD, executive director, interventional cardiovascular programs, Brigham and Women’s Hospital Heart & Vascular Center, Boston.

“In fact, in daily practice we see a substantial percentage of patients with MI who have prediabetes that had not been previously recognized or formally diagnosed,” Dr. Bhatt said in an interview.

“Identifying these patients – preferably prior to coming in with cardiovascular complications – is important both to reduce cardiovascular risk but also to try and prevent progression at diabetes,” he added.

Dr. Bhatt went on to say that this large analysis, confirming that prediabetes is independently associated with MI, should prompt clinicians to screen patients rigorously for this condition.

“At a minimum, such patients would be candidates for intensive lifestyle modification aimed at weight loss and treatment of frequent coexistent conditions, such as hypertension and dyslipidemia,” Dr. Bhatt said.

Dr. Thota reports no potential conflicts of interest. Dr. Bhatt has financial relationships with more than 30 pharmaceutical companies, many of which make products relevant to the management of diabetes and cardiovascular disease.

The Diagnosis: Proximal-Type Epithelioid Sarcoma

Proximal-type epithelioid sarcoma (PES) is a rare high-grade sarcoma of uncertain histogenesis that may present with a benign clinical appearance. Proximal-type epithelioid sarcoma peaks at 20 to 40 years of age and has a slight male predominance. This tumor exhibits aggressive behavior with both local recurrence and metastasis.¹ The average overall survival is poor; however, tumor size less than 5 cm and complete excision with tumor-free margin status improves the prognosis.² Proximal-type epithelioid sarcoma should not be confused with distal-type epithelioid sarcoma, which has a better prognosis and occurs in younger patients.¹ Treatment of PES is wide excision, and chemotherapy trials with tazemetostat are ongoing.³

The deceptively banal clinical appearance of PES may delay appropriate diagnosis and treatment. Proximal-type epithelioid sarcoma often grows in sheets (quiz image [top] inset) and loose nests1 but also may take on a more corded appearance mimicking myoepithelial carcinoma. The cells themselves are plump dyscohesive epithelioid cells (quiz image [top]) with large nucleoli and eosinophilic cytoplasm or hyaline globules1 (quiz image [bottom]), but cells also may be focally spindled. Myxoid stroma, hemorrhage, and necrosis often are prominent features. Epithelioid sarcomas characteristically demonstrate positive immunostaining for both epithelial and mesenchymal markers (pan-cytokeratin and vimentin),¹ with the majority having loss of expression of integrase interactor 1 (INI-1).² Histology in this case was positive for cytokeratin monoclonal antibodies CAM5.2 and OSCAR, epithelial membrane antigen, and vimentin; it showed loss of INI-1 staining (quiz image [bottom]). Negative stains included S-100, p63, cytokeratins 7 and 20, CD34, CD31, ERG, glial fibrillary acidic protein, transducin-like enhancer of split 1, CD117, myogenin, synaptophysin, chromogranin, CD10, inhibin, CD99, and estrogen receptor.

The differential diagnosis of PES includes poorly differentiated squamous cell carcinoma (Figure 1 [inset]), melanoma, myoepithelial carcinoma, and epithelioid angiosarcoma. Primary squamous cell carcinoma of the vulva presents as an endophytic or exophytic mass with raised borders. Vulvar cancer is uncommon among gynecologic malignancies, with squamous cell carcinoma being the most commonly encountered.⁴ Vulvar intraepithelial neoplasia (VIN) is increasing in incidence, while the occurrence of invasive squamous cell carcinoma remains stable.⁵ Human papillomavirus–related VIN (usual-type VIN) is less likely to progress to squamous cell carcinoma than differentiated VIN (d-VIN), a dysplasia that is unrelated to human papillomavirus that frequently harbors p53 mutations.⁴ The presence of histologic epidermal involvement can help distinguish squamous cell carcinoma from PES (Figure 1). As opposed to PES, metastatic squamous cell carcinoma is characterized by intercellular bridges and often at least focal keratinization (Figure 1). Squamous cell carcinoma demonstrates positivity with p63 and p40 immunohistochemical stains, while PES rarely stains for either.⁶

Melanoma is the second most common vulvar malignancy. Vulvar melanoma tends to occur in women of advanced age but has been reported in girls as young as 10 years old.⁷ There is some evidence that patients with lichen sclerosus may be at an increased risk for the development of vulvar melanoma.⁸ Compared to PES, primary vulvar melanoma usually demonstrates epidermal involvement as well as clinical findings of a pigmented lesion (Figure 2). A notable minority of vulvar melanomas are amelanotic.⁹ Melanoma may be distinguished from PES with a panel of melanocytic markers—human melanoma black 45, Melan-A, SRY-box transcription factor 10, S-100, and microphthalmia transcription factor—that rarely are expressed in the latter. Both PES and rhabdoid melanoma have eosinophilic and tinctorial cytoplasmic inclusions.¹⁰ Melanin pigment and more cohesive nests are helpful clues that may point to melanoma when present.

Myoepithelial carcinoma of the vulva is rare.¹¹ Myoepithelial carcinoma of soft tissue is more aggressive than its benign counterpart, with up to a 50% metastasis rate.¹² The presence of prominent corded or trabecular growth in a myxoid or hyaline background may point to the diagnosis (Figure 3). Similar to PES, myoepithelial carcinoma may lose expression of nuclear INI-1, while myoepithelial carcinoma is more likely to express S-100 and glial fibrillary acidic protein.¹³ Rearrangements of EWS RNA binding protein 1, EWSR1, have been found in half of myoepithelial neoplasms.¹²

Angiosarcomas represent 5% of cutaneous sarcomas and rarely have been reported in the vulva, primarily occurring in the setting of long-standing lymphedema and radiation.¹⁴ Angiosarcoma more often occurs on the head and neck, breasts, or extremities. Additional risk factors for the development of angiosarcoma include toxin exposure (eg, polyvinyl chloride, thorium dioxide, arsenic), anabolic steroids, and filariasis, as well as genetic disorders (eg, neurofibromatosis type 1, BRCA gene mutations, Maffucci syndrome).¹⁵ Epithelioid angiosarcoma is an infiltrative tumor composed of irregular anastomosing vascular channels with extravasated erythrocytes (Figure 4). Solid growth and necrosis may be present in more aggressive tumors. The cells themselves are pleomorphic endothelial cells with vesicular chromatin and prominent nucleoli. Epithelioid angiosarcoma may resemble carcinoma and have focal keratin expression. However, the characteristic eosinophilic cytoplasm seen in PES should not be identified in epithelioid angiosarcoma. Unlike PES, epithelioid angiosarcoma is positive for CD31 and has retained expression for INI-1. Both angiosarcoma and proximal-type epithelioid sarcoma may express vascular markers CD34 and FLI-1¹⁶; thus an expanded panel of immunohistochemical studies may be of utility.

The Diagnosis: Proximal-Type Epithelioid Sarcoma

Proximal-type epithelioid sarcoma (PES) is a rare high-grade sarcoma of uncertain histogenesis that may present with a benign clinical appearance. Proximal-type epithelioid sarcoma peaks at 20 to 40 years of age and has a slight male predominance. This tumor exhibits aggressive behavior with both local recurrence and metastasis.¹ The average overall survival is poor; however, tumor size less than 5 cm and complete excision with tumor-free margin status improves the prognosis.² Proximal-type epithelioid sarcoma should not be confused with distal-type epithelioid sarcoma, which has a better prognosis and occurs in younger patients.¹ Treatment of PES is wide excision, and chemotherapy trials with tazemetostat are ongoing.³

The deceptively banal clinical appearance of PES may delay appropriate diagnosis and treatment. Proximal-type epithelioid sarcoma often grows in sheets (quiz image [top] inset) and loose nests1 but also may take on a more corded appearance mimicking myoepithelial carcinoma. The cells themselves are plump dyscohesive epithelioid cells (quiz image [top]) with large nucleoli and eosinophilic cytoplasm or hyaline globules1 (quiz image [bottom]), but cells also may be focally spindled. Myxoid stroma, hemorrhage, and necrosis often are prominent features. Epithelioid sarcomas characteristically demonstrate positive immunostaining for both epithelial and mesenchymal markers (pan-cytokeratin and vimentin),¹ with the majority having loss of expression of integrase interactor 1 (INI-1).² Histology in this case was positive for cytokeratin monoclonal antibodies CAM5.2 and OSCAR, epithelial membrane antigen, and vimentin; it showed loss of INI-1 staining (quiz image [bottom]). Negative stains included S-100, p63, cytokeratins 7 and 20, CD34, CD31, ERG, glial fibrillary acidic protein, transducin-like enhancer of split 1, CD117, myogenin, synaptophysin, chromogranin, CD10, inhibin, CD99, and estrogen receptor.

The differential diagnosis of PES includes poorly differentiated squamous cell carcinoma (Figure 1 [inset]), melanoma, myoepithelial carcinoma, and epithelioid angiosarcoma. Primary squamous cell carcinoma of the vulva presents as an endophytic or exophytic mass with raised borders. Vulvar cancer is uncommon among gynecologic malignancies, with squamous cell carcinoma being the most commonly encountered.⁴ Vulvar intraepithelial neoplasia (VIN) is increasing in incidence, while the occurrence of invasive squamous cell carcinoma remains stable.⁵ Human papillomavirus–related VIN (usual-type VIN) is less likely to progress to squamous cell carcinoma than differentiated VIN (d-VIN), a dysplasia that is unrelated to human papillomavirus that frequently harbors p53 mutations.⁴ The presence of histologic epidermal involvement can help distinguish squamous cell carcinoma from PES (Figure 1). As opposed to PES, metastatic squamous cell carcinoma is characterized by intercellular bridges and often at least focal keratinization (Figure 1). Squamous cell carcinoma demonstrates positivity with p63 and p40 immunohistochemical stains, while PES rarely stains for either.⁶

Melanoma is the second most common vulvar malignancy. Vulvar melanoma tends to occur in women of advanced age but has been reported in girls as young as 10 years old.⁷ There is some evidence that patients with lichen sclerosus may be at an increased risk for the development of vulvar melanoma.⁸ Compared to PES, primary vulvar melanoma usually demonstrates epidermal involvement as well as clinical findings of a pigmented lesion (Figure 2). A notable minority of vulvar melanomas are amelanotic.⁹ Melanoma may be distinguished from PES with a panel of melanocytic markers—human melanoma black 45, Melan-A, SRY-box transcription factor 10, S-100, and microphthalmia transcription factor—that rarely are expressed in the latter. Both PES and rhabdoid melanoma have eosinophilic and tinctorial cytoplasmic inclusions.¹⁰ Melanin pigment and more cohesive nests are helpful clues that may point to melanoma when present.

Myoepithelial carcinoma of the vulva is rare.¹¹ Myoepithelial carcinoma of soft tissue is more aggressive than its benign counterpart, with up to a 50% metastasis rate.¹² The presence of prominent corded or trabecular growth in a myxoid or hyaline background may point to the diagnosis (Figure 3). Similar to PES, myoepithelial carcinoma may lose expression of nuclear INI-1, while myoepithelial carcinoma is more likely to express S-100 and glial fibrillary acidic protein.¹³ Rearrangements of EWS RNA binding protein 1, EWSR1, have been found in half of myoepithelial neoplasms.¹²

Angiosarcomas represent 5% of cutaneous sarcomas and rarely have been reported in the vulva, primarily occurring in the setting of long-standing lymphedema and radiation.¹⁴ Angiosarcoma more often occurs on the head and neck, breasts, or extremities. Additional risk factors for the development of angiosarcoma include toxin exposure (eg, polyvinyl chloride, thorium dioxide, arsenic), anabolic steroids, and filariasis, as well as genetic disorders (eg, neurofibromatosis type 1, BRCA gene mutations, Maffucci syndrome).¹⁵ Epithelioid angiosarcoma is an infiltrative tumor composed of irregular anastomosing vascular channels with extravasated erythrocytes (Figure 4). Solid growth and necrosis may be present in more aggressive tumors. The cells themselves are pleomorphic endothelial cells with vesicular chromatin and prominent nucleoli. Epithelioid angiosarcoma may resemble carcinoma and have focal keratin expression. However, the characteristic eosinophilic cytoplasm seen in PES should not be identified in epithelioid angiosarcoma. Unlike PES, epithelioid angiosarcoma is positive for CD31 and has retained expression for INI-1. Both angiosarcoma and proximal-type epithelioid sarcoma may express vascular markers CD34 and FLI-1¹⁶; thus an expanded panel of immunohistochemical studies may be of utility.

The Diagnosis: Proximal-Type Epithelioid Sarcoma

Proximal-type epithelioid sarcoma (PES) is a rare high-grade sarcoma of uncertain histogenesis that may present with a benign clinical appearance. Proximal-type epithelioid sarcoma peaks at 20 to 40 years of age and has a slight male predominance. This tumor exhibits aggressive behavior with both local recurrence and metastasis.¹ The average overall survival is poor; however, tumor size less than 5 cm and complete excision with tumor-free margin status improves the prognosis.² Proximal-type epithelioid sarcoma should not be confused with distal-type epithelioid sarcoma, which has a better prognosis and occurs in younger patients.¹ Treatment of PES is wide excision, and chemotherapy trials with tazemetostat are ongoing.³

The deceptively banal clinical appearance of PES may delay appropriate diagnosis and treatment. Proximal-type epithelioid sarcoma often grows in sheets (quiz image [top] inset) and loose nests1 but also may take on a more corded appearance mimicking myoepithelial carcinoma. The cells themselves are plump dyscohesive epithelioid cells (quiz image [top]) with large nucleoli and eosinophilic cytoplasm or hyaline globules1 (quiz image [bottom]), but cells also may be focally spindled. Myxoid stroma, hemorrhage, and necrosis often are prominent features. Epithelioid sarcomas characteristically demonstrate positive immunostaining for both epithelial and mesenchymal markers (pan-cytokeratin and vimentin),¹ with the majority having loss of expression of integrase interactor 1 (INI-1).² Histology in this case was positive for cytokeratin monoclonal antibodies CAM5.2 and OSCAR, epithelial membrane antigen, and vimentin; it showed loss of INI-1 staining (quiz image [bottom]). Negative stains included S-100, p63, cytokeratins 7 and 20, CD34, CD31, ERG, glial fibrillary acidic protein, transducin-like enhancer of split 1, CD117, myogenin, synaptophysin, chromogranin, CD10, inhibin, CD99, and estrogen receptor.

The differential diagnosis of PES includes poorly differentiated squamous cell carcinoma (Figure 1 [inset]), melanoma, myoepithelial carcinoma, and epithelioid angiosarcoma. Primary squamous cell carcinoma of the vulva presents as an endophytic or exophytic mass with raised borders. Vulvar cancer is uncommon among gynecologic malignancies, with squamous cell carcinoma being the most commonly encountered.⁴ Vulvar intraepithelial neoplasia (VIN) is increasing in incidence, while the occurrence of invasive squamous cell carcinoma remains stable.⁵ Human papillomavirus–related VIN (usual-type VIN) is less likely to progress to squamous cell carcinoma than differentiated VIN (d-VIN), a dysplasia that is unrelated to human papillomavirus that frequently harbors p53 mutations.⁴ The presence of histologic epidermal involvement can help distinguish squamous cell carcinoma from PES (Figure 1). As opposed to PES, metastatic squamous cell carcinoma is characterized by intercellular bridges and often at least focal keratinization (Figure 1). Squamous cell carcinoma demonstrates positivity with p63 and p40 immunohistochemical stains, while PES rarely stains for either.⁶

Melanoma is the second most common vulvar malignancy. Vulvar melanoma tends to occur in women of advanced age but has been reported in girls as young as 10 years old.⁷ There is some evidence that patients with lichen sclerosus may be at an increased risk for the development of vulvar melanoma.⁸ Compared to PES, primary vulvar melanoma usually demonstrates epidermal involvement as well as clinical findings of a pigmented lesion (Figure 2). A notable minority of vulvar melanomas are amelanotic.⁹ Melanoma may be distinguished from PES with a panel of melanocytic markers—human melanoma black 45, Melan-A, SRY-box transcription factor 10, S-100, and microphthalmia transcription factor—that rarely are expressed in the latter. Both PES and rhabdoid melanoma have eosinophilic and tinctorial cytoplasmic inclusions.¹⁰ Melanin pigment and more cohesive nests are helpful clues that may point to melanoma when present.

Myoepithelial carcinoma of the vulva is rare.¹¹ Myoepithelial carcinoma of soft tissue is more aggressive than its benign counterpart, with up to a 50% metastasis rate.¹² The presence of prominent corded or trabecular growth in a myxoid or hyaline background may point to the diagnosis (Figure 3). Similar to PES, myoepithelial carcinoma may lose expression of nuclear INI-1, while myoepithelial carcinoma is more likely to express S-100 and glial fibrillary acidic protein.¹³ Rearrangements of EWS RNA binding protein 1, EWSR1, have been found in half of myoepithelial neoplasms.¹²

Angiosarcomas represent 5% of cutaneous sarcomas and rarely have been reported in the vulva, primarily occurring in the setting of long-standing lymphedema and radiation.¹⁴ Angiosarcoma more often occurs on the head and neck, breasts, or extremities. Additional risk factors for the development of angiosarcoma include toxin exposure (eg, polyvinyl chloride, thorium dioxide, arsenic), anabolic steroids, and filariasis, as well as genetic disorders (eg, neurofibromatosis type 1, BRCA gene mutations, Maffucci syndrome).¹⁵ Epithelioid angiosarcoma is an infiltrative tumor composed of irregular anastomosing vascular channels with extravasated erythrocytes (Figure 4). Solid growth and necrosis may be present in more aggressive tumors. The cells themselves are pleomorphic endothelial cells with vesicular chromatin and prominent nucleoli. Epithelioid angiosarcoma may resemble carcinoma and have focal keratin expression. However, the characteristic eosinophilic cytoplasm seen in PES should not be identified in epithelioid angiosarcoma. Unlike PES, epithelioid angiosarcoma is positive for CD31 and has retained expression for INI-1. Both angiosarcoma and proximal-type epithelioid sarcoma may express vascular markers CD34 and FLI-1¹⁶; thus an expanded panel of immunohistochemical studies may be of utility.

To the Editor:

The internet is a popular resource for patients seeking information about dermatologic treatments. Hydroquinone (HQ) cream 4% is approved by the US Food and Drug Administration for skin hyperpigmentation.¹ The agency enforced the CARES (Coronavirus Aid, Relief, and Economic Security) Act and OTC (over-the-counter) Monograph Reform on September 25, 2020, to restrict distribution of OTC HQ.² Exogenous ochronosis is listed as a potential adverse effect in the prescribing information for HQ.¹

We sought to assess online resources on HQ for accuracy of information, including the recent OTC ban, as well as readability. The word hydroquinone was searched on 3 internet search engines—Google, Yahoo, and Bing—on December 12, 2020, each for the first 20 URLs (ie, websites)(total of 60 URLs). Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA)(Figure) reporting guidelines were used to assess a list of relevant websites to include in the final analysis. Website data were reviewed by both authors. Eighteen duplicates and 27 irrelevant and non–English-language URLs were excluded. The remaining 15 websites were analyzed. Based on a previously published and validated tool, a pro forma was designed to evaluate information on HQ for each website based on accountability, quality, readability, display, support, and transparency (Table).^1,3

Scores for all 15 websites are listed in eTable 1. The mean overall (total) score was 25.3 points (of a maximum possible score of 44 points; range, 18–34). The average accountability score was 6.3 (of a possible 10; range, 3–10); average quality score, 10.9 (of a possible 17; range, 5–16); and average readability score, 2.1 (of a possible 5; range, 0–5).

The mean display score was 0.3 (of a possible 4; range, 0–2); 66.7% of websites (10/15) had advertisements or irrelevant material. Only 6.7% and 13.3% of websites included relevant videos or images, respectively, on applying HQ (eTable 2). We identified only 3 photographs—across all 15 websites—that depicted skin, all of which were Fitzpatrick skin types II or III. Therefore, none of the websites included a diversity of images to indicate broad ethnic relatability.

The average support score was 2.5 (of a possible 4; range, 1–3); 20% (3/15) of URLs included chat sites, message boards, or forums, and approximately half (8/15 [53.3%]) included references. Only 7 URLs (46.7%) had been updated in the last 12 months. Only 4 (26.7%) were written by a board-certified dermatologist (eTable 2). Most (60%) websites contained advertising, though none were sponsored by a pharmaceutical company that manufactures HQ.

Only 46.7% (7/15) of websites recommended limiting a course of HQ treatment to 3 months; only 40% (6/15) mentioned shelf life or photochemical degradation when exposed to air. Although 93.3% (14/15) of URLs mentioned ochronosis, a clinical description of the condition was provided in only 33.3% (5/15)—none with images.

Only 2 sites (13.3%; Everyday Health and WebMD) met the accepted 7th-grade reading level for online patient education material; those sites scored lower on quality (9 of 17 and 6 of 17, respectively) than sites with higher overall scores.

None of the 15 websites studied, therefore, demonstrated optimal features on combined measures of accountability, quality, readability, display, support, and transparency regarding HQ. Notably, the American Academy of Dermatology website (www.aad.org) was not among the 15 websites studied; the AAD website mentions HQ in a section on melasma, but only minimal detail is provided.

Limitations of this study include the small number of websites analyzed and possible selection bias because only 3 internet search engines were used to identify websites for study and analysis.

Previously, we analyzed content about HQ on the video-sharing and social media platform YouTube.⁴ The most viewed YouTube videos on HQ had poor-quality information (ie, only 20% mentioned ochronosis and only 28.6% recommended sunscreen [N=70]). However, average reading level of these videos was 7th grade.^4,5 Therefore, YouTube HQ content, though comprehensible, generally is of poor quality.

By conducting a search for website content about HQ, we found that the most popular URLs had either accurate information with poor readability or lower-quality educational material that was more comprehensible. We conclude that there is a need to develop online patient education materials on HQ that are characterized by high-quality, up-to-date medical information; have been written by board-certified dermatologists; are comprehensible (ie, no more than approximately 1200 words and written at a 7th-grade reading level); and contain relevant clinical images and references. We encourage dermatologists to recognize the limitations of online patient education resources on HQ and educate patients on the proper use of the drug as well as its potential adverse effects

To the Editor:

The internet is a popular resource for patients seeking information about dermatologic treatments. Hydroquinone (HQ) cream 4% is approved by the US Food and Drug Administration for skin hyperpigmentation.¹ The agency enforced the CARES (Coronavirus Aid, Relief, and Economic Security) Act and OTC (over-the-counter) Monograph Reform on September 25, 2020, to restrict distribution of OTC HQ.² Exogenous ochronosis is listed as a potential adverse effect in the prescribing information for HQ.¹

We sought to assess online resources on HQ for accuracy of information, including the recent OTC ban, as well as readability. The word hydroquinone was searched on 3 internet search engines—Google, Yahoo, and Bing—on December 12, 2020, each for the first 20 URLs (ie, websites)(total of 60 URLs). Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA)(Figure) reporting guidelines were used to assess a list of relevant websites to include in the final analysis. Website data were reviewed by both authors. Eighteen duplicates and 27 irrelevant and non–English-language URLs were excluded. The remaining 15 websites were analyzed. Based on a previously published and validated tool, a pro forma was designed to evaluate information on HQ for each website based on accountability, quality, readability, display, support, and transparency (Table).^1,3

Scores for all 15 websites are listed in eTable 1. The mean overall (total) score was 25.3 points (of a maximum possible score of 44 points; range, 18–34). The average accountability score was 6.3 (of a possible 10; range, 3–10); average quality score, 10.9 (of a possible 17; range, 5–16); and average readability score, 2.1 (of a possible 5; range, 0–5).

The mean display score was 0.3 (of a possible 4; range, 0–2); 66.7% of websites (10/15) had advertisements or irrelevant material. Only 6.7% and 13.3% of websites included relevant videos or images, respectively, on applying HQ (eTable 2). We identified only 3 photographs—across all 15 websites—that depicted skin, all of which were Fitzpatrick skin types II or III. Therefore, none of the websites included a diversity of images to indicate broad ethnic relatability.

The average support score was 2.5 (of a possible 4; range, 1–3); 20% (3/15) of URLs included chat sites, message boards, or forums, and approximately half (8/15 [53.3%]) included references. Only 7 URLs (46.7%) had been updated in the last 12 months. Only 4 (26.7%) were written by a board-certified dermatologist (eTable 2). Most (60%) websites contained advertising, though none were sponsored by a pharmaceutical company that manufactures HQ.

Only 46.7% (7/15) of websites recommended limiting a course of HQ treatment to 3 months; only 40% (6/15) mentioned shelf life or photochemical degradation when exposed to air. Although 93.3% (14/15) of URLs mentioned ochronosis, a clinical description of the condition was provided in only 33.3% (5/15)—none with images.

Only 2 sites (13.3%; Everyday Health and WebMD) met the accepted 7th-grade reading level for online patient education material; those sites scored lower on quality (9 of 17 and 6 of 17, respectively) than sites with higher overall scores.

None of the 15 websites studied, therefore, demonstrated optimal features on combined measures of accountability, quality, readability, display, support, and transparency regarding HQ. Notably, the American Academy of Dermatology website (www.aad.org) was not among the 15 websites studied; the AAD website mentions HQ in a section on melasma, but only minimal detail is provided.

Limitations of this study include the small number of websites analyzed and possible selection bias because only 3 internet search engines were used to identify websites for study and analysis.

Previously, we analyzed content about HQ on the video-sharing and social media platform YouTube.⁴ The most viewed YouTube videos on HQ had poor-quality information (ie, only 20% mentioned ochronosis and only 28.6% recommended sunscreen [N=70]). However, average reading level of these videos was 7th grade.^4,5 Therefore, YouTube HQ content, though comprehensible, generally is of poor quality.

By conducting a search for website content about HQ, we found that the most popular URLs had either accurate information with poor readability or lower-quality educational material that was more comprehensible. We conclude that there is a need to develop online patient education materials on HQ that are characterized by high-quality, up-to-date medical information; have been written by board-certified dermatologists; are comprehensible (ie, no more than approximately 1200 words and written at a 7th-grade reading level); and contain relevant clinical images and references. We encourage dermatologists to recognize the limitations of online patient education resources on HQ and educate patients on the proper use of the drug as well as its potential adverse effects

To the Editor:

The internet is a popular resource for patients seeking information about dermatologic treatments. Hydroquinone (HQ) cream 4% is approved by the US Food and Drug Administration for skin hyperpigmentation.¹ The agency enforced the CARES (Coronavirus Aid, Relief, and Economic Security) Act and OTC (over-the-counter) Monograph Reform on September 25, 2020, to restrict distribution of OTC HQ.² Exogenous ochronosis is listed as a potential adverse effect in the prescribing information for HQ.¹

We sought to assess online resources on HQ for accuracy of information, including the recent OTC ban, as well as readability. The word hydroquinone was searched on 3 internet search engines—Google, Yahoo, and Bing—on December 12, 2020, each for the first 20 URLs (ie, websites)(total of 60 URLs). Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA)(Figure) reporting guidelines were used to assess a list of relevant websites to include in the final analysis. Website data were reviewed by both authors. Eighteen duplicates and 27 irrelevant and non–English-language URLs were excluded. The remaining 15 websites were analyzed. Based on a previously published and validated tool, a pro forma was designed to evaluate information on HQ for each website based on accountability, quality, readability, display, support, and transparency (Table).^1,3

Scores for all 15 websites are listed in eTable 1. The mean overall (total) score was 25.3 points (of a maximum possible score of 44 points; range, 18–34). The average accountability score was 6.3 (of a possible 10; range, 3–10); average quality score, 10.9 (of a possible 17; range, 5–16); and average readability score, 2.1 (of a possible 5; range, 0–5).

The mean display score was 0.3 (of a possible 4; range, 0–2); 66.7% of websites (10/15) had advertisements or irrelevant material. Only 6.7% and 13.3% of websites included relevant videos or images, respectively, on applying HQ (eTable 2). We identified only 3 photographs—across all 15 websites—that depicted skin, all of which were Fitzpatrick skin types II or III. Therefore, none of the websites included a diversity of images to indicate broad ethnic relatability.

The average support score was 2.5 (of a possible 4; range, 1–3); 20% (3/15) of URLs included chat sites, message boards, or forums, and approximately half (8/15 [53.3%]) included references. Only 7 URLs (46.7%) had been updated in the last 12 months. Only 4 (26.7%) were written by a board-certified dermatologist (eTable 2). Most (60%) websites contained advertising, though none were sponsored by a pharmaceutical company that manufactures HQ.

Only 46.7% (7/15) of websites recommended limiting a course of HQ treatment to 3 months; only 40% (6/15) mentioned shelf life or photochemical degradation when exposed to air. Although 93.3% (14/15) of URLs mentioned ochronosis, a clinical description of the condition was provided in only 33.3% (5/15)—none with images.

Only 2 sites (13.3%; Everyday Health and WebMD) met the accepted 7th-grade reading level for online patient education material; those sites scored lower on quality (9 of 17 and 6 of 17, respectively) than sites with higher overall scores.

None of the 15 websites studied, therefore, demonstrated optimal features on combined measures of accountability, quality, readability, display, support, and transparency regarding HQ. Notably, the American Academy of Dermatology website (www.aad.org) was not among the 15 websites studied; the AAD website mentions HQ in a section on melasma, but only minimal detail is provided.

Limitations of this study include the small number of websites analyzed and possible selection bias because only 3 internet search engines were used to identify websites for study and analysis.

Previously, we analyzed content about HQ on the video-sharing and social media platform YouTube.⁴ The most viewed YouTube videos on HQ had poor-quality information (ie, only 20% mentioned ochronosis and only 28.6% recommended sunscreen [N=70]). However, average reading level of these videos was 7th grade.^4,5 Therefore, YouTube HQ content, though comprehensible, generally is of poor quality.

By conducting a search for website content about HQ, we found that the most popular URLs had either accurate information with poor readability or lower-quality educational material that was more comprehensible. We conclude that there is a need to develop online patient education materials on HQ that are characterized by high-quality, up-to-date medical information; have been written by board-certified dermatologists; are comprehensible (ie, no more than approximately 1200 words and written at a 7th-grade reading level); and contain relevant clinical images and references. We encourage dermatologists to recognize the limitations of online patient education resources on HQ and educate patients on the proper use of the drug as well as its potential adverse effects

A Los Angeles County internist will pay nearly $9.5 million to resolve accusations that he submitted false claims to Medicare and California’s Medicaid program.

Part of the payment was a settlement in a civil case in which Minas Kochumian, MD, an internist who ran a solo practice in Northridge, Calif., was accused of submitting claims to Medicare and Medi-Cal for procedures, services, and tests that were never performed. The procedures he falsely billed for included injecting a medication for treating osteoarthritis and osteoporosis, draining tailbone cysts, and removal of various growths.

As part of the settlement, Dr. Kochumian admitted that he intentionally submitted false claims with the intent to deceive the United States and the State of California. The damages and penalties were possible under the federal False Claims Act and the California False Claims Act.

According to the Medical Board of California, Dr. Kochumian’s license is current and set to expire next July.

The allegations against Dr. Kochumian were first brought to the attention of authorities in a whistleblower lawsuit filed by Elize Oganesyan, Dr. Kochumian’s former medical assistant, and Damon Davies, former information technology consultant for the practice. Among her other duties, Ms. Oganesyan was responsible for verifying insurance eligibility and obtaining authorization for drugs, procedures, services, and tests.

The medical assistant first realized that something was amiss when a patient brought her a Medicare Explanation of Benefits document that included charges for an injection the practice had not administered, according to court records. Ms. Oganesyan then realized the clinic was filing claims for other services that were never provided. She stated in the original complaint that the clinic did not even have the necessary equipment for providing some of these tests — skin allergy tests, for example.  

The False Claims Act permits private parties to sue on behalf of the government for false claims for government funds and to receive a share of any recovery. Ms. Oganesyan and Davies will receive more than $1.75 million as their share of the recovery. The whistleblowers’ claims for attorneys’ fees are not resolved by this settlement, according to a statement from the U.S. Attorney’s Office, Eastern District of California.

The $9.5 million payment includes $5.4 million owed by Dr. Kochumian as criminal restitution following his guilty plea to one count of healthcare fraud in a separate criminal case filed in the Central District of California. In addition to the fine, Dr. Kochumian was sentenced to 41 months in prison, according to a statement by California Attorney General Rob Bonta.

“When doctors misuse the state’s Medi-Cal funds, they violate their Hippocratic Oath by harming a program which exists to help California’s Medi-Cal population, including the elderly, the sick, and the vulnerable,” said Mr. Bonta. “Dr. Kochumian’s alleged misconduct violated the trust of the patients in his care, and he selfishly pocketed funds that would otherwise have gone toward critical publicly funded healthcare services.”

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

A Los Angeles County internist will pay nearly $9.5 million to resolve accusations that he submitted false claims to Medicare and California’s Medicaid program.

Part of the payment was a settlement in a civil case in which Minas Kochumian, MD, an internist who ran a solo practice in Northridge, Calif., was accused of submitting claims to Medicare and Medi-Cal for procedures, services, and tests that were never performed. The procedures he falsely billed for included injecting a medication for treating osteoarthritis and osteoporosis, draining tailbone cysts, and removal of various growths.

As part of the settlement, Dr. Kochumian admitted that he intentionally submitted false claims with the intent to deceive the United States and the State of California. The damages and penalties were possible under the federal False Claims Act and the California False Claims Act.

According to the Medical Board of California, Dr. Kochumian’s license is current and set to expire next July.

The allegations against Dr. Kochumian were first brought to the attention of authorities in a whistleblower lawsuit filed by Elize Oganesyan, Dr. Kochumian’s former medical assistant, and Damon Davies, former information technology consultant for the practice. Among her other duties, Ms. Oganesyan was responsible for verifying insurance eligibility and obtaining authorization for drugs, procedures, services, and tests.

The medical assistant first realized that something was amiss when a patient brought her a Medicare Explanation of Benefits document that included charges for an injection the practice had not administered, according to court records. Ms. Oganesyan then realized the clinic was filing claims for other services that were never provided. She stated in the original complaint that the clinic did not even have the necessary equipment for providing some of these tests — skin allergy tests, for example.  

The False Claims Act permits private parties to sue on behalf of the government for false claims for government funds and to receive a share of any recovery. Ms. Oganesyan and Davies will receive more than $1.75 million as their share of the recovery. The whistleblowers’ claims for attorneys’ fees are not resolved by this settlement, according to a statement from the U.S. Attorney’s Office, Eastern District of California.

The $9.5 million payment includes $5.4 million owed by Dr. Kochumian as criminal restitution following his guilty plea to one count of healthcare fraud in a separate criminal case filed in the Central District of California. In addition to the fine, Dr. Kochumian was sentenced to 41 months in prison, according to a statement by California Attorney General Rob Bonta.

“When doctors misuse the state’s Medi-Cal funds, they violate their Hippocratic Oath by harming a program which exists to help California’s Medi-Cal population, including the elderly, the sick, and the vulnerable,” said Mr. Bonta. “Dr. Kochumian’s alleged misconduct violated the trust of the patients in his care, and he selfishly pocketed funds that would otherwise have gone toward critical publicly funded healthcare services.”

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

A Los Angeles County internist will pay nearly $9.5 million to resolve accusations that he submitted false claims to Medicare and California’s Medicaid program.

Part of the payment was a settlement in a civil case in which Minas Kochumian, MD, an internist who ran a solo practice in Northridge, Calif., was accused of submitting claims to Medicare and Medi-Cal for procedures, services, and tests that were never performed. The procedures he falsely billed for included injecting a medication for treating osteoarthritis and osteoporosis, draining tailbone cysts, and removal of various growths.

As part of the settlement, Dr. Kochumian admitted that he intentionally submitted false claims with the intent to deceive the United States and the State of California. The damages and penalties were possible under the federal False Claims Act and the California False Claims Act.

According to the Medical Board of California, Dr. Kochumian’s license is current and set to expire next July.

The allegations against Dr. Kochumian were first brought to the attention of authorities in a whistleblower lawsuit filed by Elize Oganesyan, Dr. Kochumian’s former medical assistant, and Damon Davies, former information technology consultant for the practice. Among her other duties, Ms. Oganesyan was responsible for verifying insurance eligibility and obtaining authorization for drugs, procedures, services, and tests.

The medical assistant first realized that something was amiss when a patient brought her a Medicare Explanation of Benefits document that included charges for an injection the practice had not administered, according to court records. Ms. Oganesyan then realized the clinic was filing claims for other services that were never provided. She stated in the original complaint that the clinic did not even have the necessary equipment for providing some of these tests — skin allergy tests, for example.  

The False Claims Act permits private parties to sue on behalf of the government for false claims for government funds and to receive a share of any recovery. Ms. Oganesyan and Davies will receive more than $1.75 million as their share of the recovery. The whistleblowers’ claims for attorneys’ fees are not resolved by this settlement, according to a statement from the U.S. Attorney’s Office, Eastern District of California.

The $9.5 million payment includes $5.4 million owed by Dr. Kochumian as criminal restitution following his guilty plea to one count of healthcare fraud in a separate criminal case filed in the Central District of California. In addition to the fine, Dr. Kochumian was sentenced to 41 months in prison, according to a statement by California Attorney General Rob Bonta.

“When doctors misuse the state’s Medi-Cal funds, they violate their Hippocratic Oath by harming a program which exists to help California’s Medi-Cal population, including the elderly, the sick, and the vulnerable,” said Mr. Bonta. “Dr. Kochumian’s alleged misconduct violated the trust of the patients in his care, and he selfishly pocketed funds that would otherwise have gone toward critical publicly funded healthcare services.”

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

On the basis of the patient's presentation, family history, and personal history of headache, she seems to be presenting with hemiplegic migraine, an uncommon migraine subtype characterized by recurrent headaches associated with temporary unilateral hemiparesis or hemiplegia. The hemiparesis may resolve before the headache, as seen in the present case, or it may persist for days to weeks. These episodes are sometimes accompanied by ipsilateral numbness, tingling, or paresthesia, with or without a speech disturbance. Visual defects (ie, scintillating scotoma and hemianopia) and aphasia may occur.

Hemiplegic migraine can be sporadic or familial. Familial hemiplegic migraine is the only migraine subtype for which an autosomal dominant mode of inheritance has been identified. The onset is generally in adolescence between 12 and 17 years of age, with an estimated prevalence of 0.01%. Female patients are more likely to have these types of migraines.

Diagnosis of hemiplegic migraine is centered on exclusion of other possible causes of headache with motor weakness. When a patient presents with motor deficit, these symptoms can also be the result of a secondary headache rather than a primary headache disorder. Because of this neurologic aspect of presentation, the differential diagnosis is broad and should span other migraine subtypes, inflammatory or metabolic disorders, and mitochondrial diseases, as well as any condition that shows neurologic deficits without radiologic alterations. Pediatric patients with hemiplegic migraine are often misdiagnosed with epilepsy. Compared with hemiplegic migraine, seizures are much more brief, and any associated hemiparesis is usually characterized by limb jerking, head turning, and loss of consciousness. Of note, up to 7% of patients with familial hemiplegic migraine do eventually develop epilepsy. Although there are no telltale pathognomonic clinical, laboratory, or radiologic findings of hemiplegic migraine, electroencephalography may show asymmetric slow-wave activity contralateral to the hemiparesis. 

In hemiplegic migraine, acute treatment options include antiemetics, NSAIDs, and nonnarcotic pain relievers; triptans and ergotamine preparations are contraindicated in this setting because of their potential vasoconstrictive effects. Even if episode frequency is low, the American Headache Society advises that prophylactic treatment should also be considered in the management of uncommon migraine subtypes such as this one.

Jasmin Harpe, MD, MPH, Headache Fellow, Department of Neurology, Harvard University, John R. Graham Headache Center, Mass General Brigham, Boston, MA

Jasmin Harpe, MD, MPH, has disclosed no relevant financial relationships.

Image Quizzes are fictional or fictionalized clinical scenarios intended to provide evidence-based educational takeaways.

On the basis of the patient's presentation, family history, and personal history of headache, she seems to be presenting with hemiplegic migraine, an uncommon migraine subtype characterized by recurrent headaches associated with temporary unilateral hemiparesis or hemiplegia. The hemiparesis may resolve before the headache, as seen in the present case, or it may persist for days to weeks. These episodes are sometimes accompanied by ipsilateral numbness, tingling, or paresthesia, with or without a speech disturbance. Visual defects (ie, scintillating scotoma and hemianopia) and aphasia may occur.

Hemiplegic migraine can be sporadic or familial. Familial hemiplegic migraine is the only migraine subtype for which an autosomal dominant mode of inheritance has been identified. The onset is generally in adolescence between 12 and 17 years of age, with an estimated prevalence of 0.01%. Female patients are more likely to have these types of migraines.

Diagnosis of hemiplegic migraine is centered on exclusion of other possible causes of headache with motor weakness. When a patient presents with motor deficit, these symptoms can also be the result of a secondary headache rather than a primary headache disorder. Because of this neurologic aspect of presentation, the differential diagnosis is broad and should span other migraine subtypes, inflammatory or metabolic disorders, and mitochondrial diseases, as well as any condition that shows neurologic deficits without radiologic alterations. Pediatric patients with hemiplegic migraine are often misdiagnosed with epilepsy. Compared with hemiplegic migraine, seizures are much more brief, and any associated hemiparesis is usually characterized by limb jerking, head turning, and loss of consciousness. Of note, up to 7% of patients with familial hemiplegic migraine do eventually develop epilepsy. Although there are no telltale pathognomonic clinical, laboratory, or radiologic findings of hemiplegic migraine, electroencephalography may show asymmetric slow-wave activity contralateral to the hemiparesis. 

In hemiplegic migraine, acute treatment options include antiemetics, NSAIDs, and nonnarcotic pain relievers; triptans and ergotamine preparations are contraindicated in this setting because of their potential vasoconstrictive effects. Even if episode frequency is low, the American Headache Society advises that prophylactic treatment should also be considered in the management of uncommon migraine subtypes such as this one.

Jasmin Harpe, MD, MPH, Headache Fellow, Department of Neurology, Harvard University, John R. Graham Headache Center, Mass General Brigham, Boston, MA

Jasmin Harpe, MD, MPH, has disclosed no relevant financial relationships.

Image Quizzes are fictional or fictionalized clinical scenarios intended to provide evidence-based educational takeaways.

On the basis of the patient's presentation, family history, and personal history of headache, she seems to be presenting with hemiplegic migraine, an uncommon migraine subtype characterized by recurrent headaches associated with temporary unilateral hemiparesis or hemiplegia. The hemiparesis may resolve before the headache, as seen in the present case, or it may persist for days to weeks. These episodes are sometimes accompanied by ipsilateral numbness, tingling, or paresthesia, with or without a speech disturbance. Visual defects (ie, scintillating scotoma and hemianopia) and aphasia may occur.

Hemiplegic migraine can be sporadic or familial. Familial hemiplegic migraine is the only migraine subtype for which an autosomal dominant mode of inheritance has been identified. The onset is generally in adolescence between 12 and 17 years of age, with an estimated prevalence of 0.01%. Female patients are more likely to have these types of migraines.

Diagnosis of hemiplegic migraine is centered on exclusion of other possible causes of headache with motor weakness. When a patient presents with motor deficit, these symptoms can also be the result of a secondary headache rather than a primary headache disorder. Because of this neurologic aspect of presentation, the differential diagnosis is broad and should span other migraine subtypes, inflammatory or metabolic disorders, and mitochondrial diseases, as well as any condition that shows neurologic deficits without radiologic alterations. Pediatric patients with hemiplegic migraine are often misdiagnosed with epilepsy. Compared with hemiplegic migraine, seizures are much more brief, and any associated hemiparesis is usually characterized by limb jerking, head turning, and loss of consciousness. Of note, up to 7% of patients with familial hemiplegic migraine do eventually develop epilepsy. Although there are no telltale pathognomonic clinical, laboratory, or radiologic findings of hemiplegic migraine, electroencephalography may show asymmetric slow-wave activity contralateral to the hemiparesis. 

In hemiplegic migraine, acute treatment options include antiemetics, NSAIDs, and nonnarcotic pain relievers; triptans and ergotamine preparations are contraindicated in this setting because of their potential vasoconstrictive effects. Even if episode frequency is low, the American Headache Society advises that prophylactic treatment should also be considered in the management of uncommon migraine subtypes such as this one.

Jasmin Harpe, MD, MPH, Headache Fellow, Department of Neurology, Harvard University, John R. Graham Headache Center, Mass General Brigham, Boston, MA

Jasmin Harpe, MD, MPH, has disclosed no relevant financial relationships.

Image Quizzes are fictional or fictionalized clinical scenarios intended to provide evidence-based educational takeaways.

According to the US Department of Defense, the term readiness refers to the ability to recruit, train, deploy, and sustain military forces that will be ready to “fight tonight” and succeed in combat. Readiness is a top priority for military medicine, which functions to diagnose, treat, and rehabilitate service members so that they can return to the fight. This central concept drives programs across the military—from operational training events to the establishment of medical and dental standards. Readiness is tracked and scrutinized constantly, and although it is a shared responsibility, efforts to increase and sustain readiness often fall on support staff and military medical providers.

In recent years, there has been a greater awareness of the negative effects of mental illness, low morale, and suicidality on military readiness. In 2013, suicide accounted for 28.1% of all deaths that occurred in the US Armed Forces.¹ Put frankly, suicide was one of the leading causes of death among military members.

The most recent Marine Corps Order regarding the Marine Corps Suicide Prevention Program stated that “suicidal behaviors are a barrier to readiness that have lasting effects on Marines and Service Members attached to Marine Commands. . .Families, and the Marine Corps.” It goes on to say that “[e]ffective suicide prevention requires coordinated efforts within a prevention framework dedicated to promoting mental, physical, spiritual, and social fitness. . .[and] mitigating stressors that interfere with mission readiness.”² This statement supports the notion that preventing suicide is not just about treating mental illness; it also involves maximizing physical, spiritual, and social fitness. Although it is well established that various mental health disorders are associated with an increased risk for suicide, it is worth noting that, in one study, only half of individuals who died by suicide had a mental health disorder diagnosed prior to their death.³ These statistics translate to the military. The 2015 Department of Defense Suicide Event Report noted that only 28% of service members who died by suicide and 22% of members with attempted suicide had been documented as having sought mental health care and disclosed their potential for self-harm prior to the event.^1,4 In 2018, a study published by Ursano et al⁵ showed that 36.3% of US soldiers with a documented suicide attempt (N=9650) had no prior mental health diagnoses.

Expanding the scope to include mental health issues in general, only 29% of service members who reported experiencing a mental health problem actually sought mental health care in that same period. Overall, approximately 40% of service members with a reported perceived need for mental health care actually sought care over their entire course of service time,¹ which raises concern for a large population of undiagnosed and undertreated mental illnesses across the military. In response to these statistics, Reger et al³ posited that it is “essential that suicide prevention efforts move outside the silo of mental health.” The authors went on to challenge health care providers across all specialties and civilians alike to take responsibility in understanding, recognizing, and mitigating risk factors for suicide in the general population.³ Although treating a service member’s acne or offering to stand duty for a service member who has been under a great deal of stress in their personal life may appear to be indirect ways of reducing suicide in the US military, they actually may be the most critical means of prevention in a culture that emphasizes resilience and self-reliance, where seeking help for mental health struggles could be perceived as weakness.¹

In this review article, we discuss the concept of cutaneous body image (CBI) and its associated outcomes on health, satisfaction, and quality of life in military service members. We then examine the intersections between common dermatologic conditions, CBI, and mental health and explore the ability and role of the military dermatologist to serve as a positive influence on military readiness.

What is cutaneous body image?

Cutaneous body image is “the individual’s mental perception of his or her skin and its appendages (ie, hair, nails).”⁶ It is measured objectively using the Cutaneous Body Image Scale, a questionnaire that includes 7 items related to the overall satisfaction with the appearance of skin, color of skin, skin of the face, complexion of the face, hair, fingernails, and toenails. Each question is rated using a 10-point Likert scale (0=not at all; 10=very markedly).⁶

Some degree of CBI dissatisfaction is expected and has been shown in the general population at large; for example, more than 56% of women older than 30 years report some degree of dissatisfaction with their skin. Similarly, data from the American Society of Plastic Surgeons showed that while 10.9 million cosmetic procedures were performed in 2006, 9.1 million of them involved minimally invasive procedures such as botulinum toxin type A injections with the purpose of skin rejuvenation and improvement of facial appearance.⁷ However, lower than average CBI can contribute to considerable psychosocial morbidity. Dissatisfaction with CBI is associated with self-consciousness, feelings of inferiority, and social exclusion. These symptoms can be grouped into a construct called interpersonal sensitivity (IS). A 2013 study by Gupta and Gupta⁶ investigated the relationship between CBI, IS, and suicidal ideation among 312 consenting nonclinical participants in Canada. The study found that greater dissatisfaction with an individual’s CBI correlated to increased IS and increased rates of suicidal ideation and intentional self-injury.⁶

Cutaneous body image is particularly relevant to dermatologists, as many common dermatoses can cause cosmetically disfiguring skin conditions; for example, acne and rosacea have the propensity to cause notable disfigurement to the facial unit. Other common conditions such as atopic dermatitis or psoriasis can flare with stress and thereby throw patients into a vicious cycle of physical and psychosocial stress caused by social stigma, cosmetic disfigurement, and reduced CBI, in turn leading to worsening of the disease at hand. Dermatologists need to be aware that common dermatoses can impact a patient’s mental health via poor CBI.⁸ Similarly, dermatologists may be empowered by the awareness that treating common dermatoses, especially those associated with poor cosmesis, have 2-fold benefits—on the skin condition itself and on the patient’s mental health.

How are common dermatoses associated with mental health?

Acne—Acne is one of the most common skin diseases, so much so that in many cases acne has become an accepted and expected part of adolescence and young adulthood. Studies estimate that 85% of the US population aged 12 to 25 years have acne.⁹ For some adults, acne persists even longer, with 1% to 5% of adults reporting to have active lesions at 40 years of age.¹⁰ Acne is a multifactorial skin disease of the pilosebaceous unit that results in the development of inflammatory papules, pustules, and cysts. These lesions are most common on the face but can extend to other areas of the body, such as the chest and back.¹¹ Although the active lesions can be painful and disfiguring, if left untreated, acne may lead to permanent disfigurement and scarring, which can have long-lasting psychosocial impacts.

Individuals with acne have an increased likelihood of self-consciousness, social isolation, depression, and suicidal ideation. This relationship has been well established for decades. In the 1990s, a small study reported that 7 of 16 (43.8%) cases of completed suicide in dermatology patients were in patients with acne.¹² In a recent meta-analysis including 2,276,798 participants across 5 separate studies, researchers found that suicide was positively associated with acne, carrying an odds ratio of 1.50 (95% CI, 1.09-2.06).¹³

Rosacea—Rosacea is a common chronic inflammatory skin disease characterized by facial erythema, telangiectasia, phymatous changes, papules, pustules, and ocular irritation. The estimated worldwide prevalence is 5.5%.¹⁴ In addition to discomfort and irritation of the skin and eyes, rosacea often carries a higher risk of psychological and psychosocial distress due to its potentially disfiguring nature. Rosacea patients are at greater risk for having anxiety disorders and depression,¹⁵ and a 2018 study by Alinia et al¹⁶ showed that there is a direct relationship between rosacea severity and the actual level of depression.Although disease improvement certainly leads to improvements in quality of life and psychosocial status, Alinia et al¹⁶ noted that depression often is associated with poor treatment adherence due to poor motivation and hopelessness. It is critical that dermatologists are aware of these associations and maintain close follow-up with patients, even when the condition is not life-threatening, such as rosacea.

Hidradenitis Suppurativa—Hidradenitis suppurativa (HS) is a chronic inflammatory disease of the pilosebaceous unit that is characterized by the development of painful, malodorous, draining abscesses, fistulas, sinus tracts, and scars in sensitive areas such as the axillae, breasts, groin, and perineum.¹⁷ In severe cases, surgery may be required to excise affected areas. Compared to other cutaneous disease, HS is considered one of the most life-impacting disorders.¹⁸ The physical symptoms themselves often are debilitating, and patients often report considerable psychosocial and psychological impairment with decreased quality of life. Major depression frequently is noted, with 1 in 4 adults with HS also being depressed. In a large cross-sectional analysis of 38,140 adults and 1162 pediatric patients with HS, Wright et al¹⁷ reported the prevalence of depression among adults with HS as 30.0% compared to 16.9% in healthy controls. In children, the prevalence of depression was 11.7% compared to 4.1% in the general population.¹⁷ Similarly, 1 out of every 5 patients with HS experiences anxiety.¹⁸

In the military population, HS often can be duty limiting. The disease requires constant attention to wound care and frequent medical visits. For many service members operating in field training or combat environments, opportunities for and access to showers and basic hygiene is limited. Uniforms and additional necessary combat gear often are thick and occlusive. Taken as a whole, these factors may contribute to worsening of the disease and in severe cases are simply not conducive to the successful management of the condition. However, given the most commonly involved body areas and the nature of the disease, many service members with HS may feel embarrassed to disclose their condition. In uniform, the disease is not easily visible, and for unaware persons, the frequency of medical visits and limited duty status may seem unnecessary. This perception of a service member’s lack of productivity due to an unseen disease may further add to the psychosocial stress they experience.

What treatment options can be considered for military service members?

The treatments for acne, rosacea, and HS are outlined in the eTable.^11,19 Also noted are specific considerations when managing an active-duty service member due to various operational duty restrictions and constraints.

Final Thoughts

Maintaining readiness in the military is essential to the ability to not only “fight tonight” but also to win tonight in whatever operational or combat mission a service member may be. Although many factors impact readiness, the rates of suicide within the armed forces cannot be ignored. Suicide not only eliminates the readiness of the deceased service member but has lasting ripple effects on the overall readiness of their unit and command at large. Most suicides in the military occur in personnel with no prior documented mental health diagnoses or treatment. Therefore, it is the responsibility of all service members to recognize and mitigate stressors and risk factors that may lead to mental health distress and suicidality. In the medical corps, this translates to a responsibility of all medical specialists to recognize and understand unique risk factors for suicidality and to do as much as they can to reduce these risks. For military dermatologists and for civilian physicians treating military service members, it is imperative to predict and understand the relationship between common dermatoses; reduced satisfaction with CBI; and increased risk for mental health illness, self-harm, and suicide. Military dermatologists, as well as other specialists, may be limited in the care they are able to provide due to manpower, staffing, demand, and institutional guidelines; however, to better serve those who serve in a holistic manner, consideration must be given to rethink what is “medically essential” and “cosmetic” and leverage the available skills, techniques, and equipment to increase the readiness of the force.

According to the US Department of Defense, the term readiness refers to the ability to recruit, train, deploy, and sustain military forces that will be ready to “fight tonight” and succeed in combat. Readiness is a top priority for military medicine, which functions to diagnose, treat, and rehabilitate service members so that they can return to the fight. This central concept drives programs across the military—from operational training events to the establishment of medical and dental standards. Readiness is tracked and scrutinized constantly, and although it is a shared responsibility, efforts to increase and sustain readiness often fall on support staff and military medical providers.

In recent years, there has been a greater awareness of the negative effects of mental illness, low morale, and suicidality on military readiness. In 2013, suicide accounted for 28.1% of all deaths that occurred in the US Armed Forces.¹ Put frankly, suicide was one of the leading causes of death among military members.

The most recent Marine Corps Order regarding the Marine Corps Suicide Prevention Program stated that “suicidal behaviors are a barrier to readiness that have lasting effects on Marines and Service Members attached to Marine Commands. . .Families, and the Marine Corps.” It goes on to say that “[e]ffective suicide prevention requires coordinated efforts within a prevention framework dedicated to promoting mental, physical, spiritual, and social fitness. . .[and] mitigating stressors that interfere with mission readiness.”² This statement supports the notion that preventing suicide is not just about treating mental illness; it also involves maximizing physical, spiritual, and social fitness. Although it is well established that various mental health disorders are associated with an increased risk for suicide, it is worth noting that, in one study, only half of individuals who died by suicide had a mental health disorder diagnosed prior to their death.³ These statistics translate to the military. The 2015 Department of Defense Suicide Event Report noted that only 28% of service members who died by suicide and 22% of members with attempted suicide had been documented as having sought mental health care and disclosed their potential for self-harm prior to the event.^1,4 In 2018, a study published by Ursano et al⁵ showed that 36.3% of US soldiers with a documented suicide attempt (N=9650) had no prior mental health diagnoses.

Expanding the scope to include mental health issues in general, only 29% of service members who reported experiencing a mental health problem actually sought mental health care in that same period. Overall, approximately 40% of service members with a reported perceived need for mental health care actually sought care over their entire course of service time,¹ which raises concern for a large population of undiagnosed and undertreated mental illnesses across the military. In response to these statistics, Reger et al³ posited that it is “essential that suicide prevention efforts move outside the silo of mental health.” The authors went on to challenge health care providers across all specialties and civilians alike to take responsibility in understanding, recognizing, and mitigating risk factors for suicide in the general population.³ Although treating a service member’s acne or offering to stand duty for a service member who has been under a great deal of stress in their personal life may appear to be indirect ways of reducing suicide in the US military, they actually may be the most critical means of prevention in a culture that emphasizes resilience and self-reliance, where seeking help for mental health struggles could be perceived as weakness.¹

In this review article, we discuss the concept of cutaneous body image (CBI) and its associated outcomes on health, satisfaction, and quality of life in military service members. We then examine the intersections between common dermatologic conditions, CBI, and mental health and explore the ability and role of the military dermatologist to serve as a positive influence on military readiness.

What is cutaneous body image?

Cutaneous body image is “the individual’s mental perception of his or her skin and its appendages (ie, hair, nails).”⁶ It is measured objectively using the Cutaneous Body Image Scale, a questionnaire that includes 7 items related to the overall satisfaction with the appearance of skin, color of skin, skin of the face, complexion of the face, hair, fingernails, and toenails. Each question is rated using a 10-point Likert scale (0=not at all; 10=very markedly).⁶

Some degree of CBI dissatisfaction is expected and has been shown in the general population at large; for example, more than 56% of women older than 30 years report some degree of dissatisfaction with their skin. Similarly, data from the American Society of Plastic Surgeons showed that while 10.9 million cosmetic procedures were performed in 2006, 9.1 million of them involved minimally invasive procedures such as botulinum toxin type A injections with the purpose of skin rejuvenation and improvement of facial appearance.⁷ However, lower than average CBI can contribute to considerable psychosocial morbidity. Dissatisfaction with CBI is associated with self-consciousness, feelings of inferiority, and social exclusion. These symptoms can be grouped into a construct called interpersonal sensitivity (IS). A 2013 study by Gupta and Gupta⁶ investigated the relationship between CBI, IS, and suicidal ideation among 312 consenting nonclinical participants in Canada. The study found that greater dissatisfaction with an individual’s CBI correlated to increased IS and increased rates of suicidal ideation and intentional self-injury.⁶

Cutaneous body image is particularly relevant to dermatologists, as many common dermatoses can cause cosmetically disfiguring skin conditions; for example, acne and rosacea have the propensity to cause notable disfigurement to the facial unit. Other common conditions such as atopic dermatitis or psoriasis can flare with stress and thereby throw patients into a vicious cycle of physical and psychosocial stress caused by social stigma, cosmetic disfigurement, and reduced CBI, in turn leading to worsening of the disease at hand. Dermatologists need to be aware that common dermatoses can impact a patient’s mental health via poor CBI.⁸ Similarly, dermatologists may be empowered by the awareness that treating common dermatoses, especially those associated with poor cosmesis, have 2-fold benefits—on the skin condition itself and on the patient’s mental health.

How are common dermatoses associated with mental health?

Acne—Acne is one of the most common skin diseases, so much so that in many cases acne has become an accepted and expected part of adolescence and young adulthood. Studies estimate that 85% of the US population aged 12 to 25 years have acne.⁹ For some adults, acne persists even longer, with 1% to 5% of adults reporting to have active lesions at 40 years of age.¹⁰ Acne is a multifactorial skin disease of the pilosebaceous unit that results in the development of inflammatory papules, pustules, and cysts. These lesions are most common on the face but can extend to other areas of the body, such as the chest and back.¹¹ Although the active lesions can be painful and disfiguring, if left untreated, acne may lead to permanent disfigurement and scarring, which can have long-lasting psychosocial impacts.

Individuals with acne have an increased likelihood of self-consciousness, social isolation, depression, and suicidal ideation. This relationship has been well established for decades. In the 1990s, a small study reported that 7 of 16 (43.8%) cases of completed suicide in dermatology patients were in patients with acne.¹² In a recent meta-analysis including 2,276,798 participants across 5 separate studies, researchers found that suicide was positively associated with acne, carrying an odds ratio of 1.50 (95% CI, 1.09-2.06).¹³

Rosacea—Rosacea is a common chronic inflammatory skin disease characterized by facial erythema, telangiectasia, phymatous changes, papules, pustules, and ocular irritation. The estimated worldwide prevalence is 5.5%.¹⁴ In addition to discomfort and irritation of the skin and eyes, rosacea often carries a higher risk of psychological and psychosocial distress due to its potentially disfiguring nature. Rosacea patients are at greater risk for having anxiety disorders and depression,¹⁵ and a 2018 study by Alinia et al¹⁶ showed that there is a direct relationship between rosacea severity and the actual level of depression.Although disease improvement certainly leads to improvements in quality of life and psychosocial status, Alinia et al¹⁶ noted that depression often is associated with poor treatment adherence due to poor motivation and hopelessness. It is critical that dermatologists are aware of these associations and maintain close follow-up with patients, even when the condition is not life-threatening, such as rosacea.

Hidradenitis Suppurativa—Hidradenitis suppurativa (HS) is a chronic inflammatory disease of the pilosebaceous unit that is characterized by the development of painful, malodorous, draining abscesses, fistulas, sinus tracts, and scars in sensitive areas such as the axillae, breasts, groin, and perineum.¹⁷ In severe cases, surgery may be required to excise affected areas. Compared to other cutaneous disease, HS is considered one of the most life-impacting disorders.¹⁸ The physical symptoms themselves often are debilitating, and patients often report considerable psychosocial and psychological impairment with decreased quality of life. Major depression frequently is noted, with 1 in 4 adults with HS also being depressed. In a large cross-sectional analysis of 38,140 adults and 1162 pediatric patients with HS, Wright et al¹⁷ reported the prevalence of depression among adults with HS as 30.0% compared to 16.9% in healthy controls. In children, the prevalence of depression was 11.7% compared to 4.1% in the general population.¹⁷ Similarly, 1 out of every 5 patients with HS experiences anxiety.¹⁸

In the military population, HS often can be duty limiting. The disease requires constant attention to wound care and frequent medical visits. For many service members operating in field training or combat environments, opportunities for and access to showers and basic hygiene is limited. Uniforms and additional necessary combat gear often are thick and occlusive. Taken as a whole, these factors may contribute to worsening of the disease and in severe cases are simply not conducive to the successful management of the condition. However, given the most commonly involved body areas and the nature of the disease, many service members with HS may feel embarrassed to disclose their condition. In uniform, the disease is not easily visible, and for unaware persons, the frequency of medical visits and limited duty status may seem unnecessary. This perception of a service member’s lack of productivity due to an unseen disease may further add to the psychosocial stress they experience.

What treatment options can be considered for military service members?

The treatments for acne, rosacea, and HS are outlined in the eTable.^11,19 Also noted are specific considerations when managing an active-duty service member due to various operational duty restrictions and constraints.

Final Thoughts

Maintaining readiness in the military is essential to the ability to not only “fight tonight” but also to win tonight in whatever operational or combat mission a service member may be. Although many factors impact readiness, the rates of suicide within the armed forces cannot be ignored. Suicide not only eliminates the readiness of the deceased service member but has lasting ripple effects on the overall readiness of their unit and command at large. Most suicides in the military occur in personnel with no prior documented mental health diagnoses or treatment. Therefore, it is the responsibility of all service members to recognize and mitigate stressors and risk factors that may lead to mental health distress and suicidality. In the medical corps, this translates to a responsibility of all medical specialists to recognize and understand unique risk factors for suicidality and to do as much as they can to reduce these risks. For military dermatologists and for civilian physicians treating military service members, it is imperative to predict and understand the relationship between common dermatoses; reduced satisfaction with CBI; and increased risk for mental health illness, self-harm, and suicide. Military dermatologists, as well as other specialists, may be limited in the care they are able to provide due to manpower, staffing, demand, and institutional guidelines; however, to better serve those who serve in a holistic manner, consideration must be given to rethink what is “medically essential” and “cosmetic” and leverage the available skills, techniques, and equipment to increase the readiness of the force.

According to the US Department of Defense, the term readiness refers to the ability to recruit, train, deploy, and sustain military forces that will be ready to “fight tonight” and succeed in combat. Readiness is a top priority for military medicine, which functions to diagnose, treat, and rehabilitate service members so that they can return to the fight. This central concept drives programs across the military—from operational training events to the establishment of medical and dental standards. Readiness is tracked and scrutinized constantly, and although it is a shared responsibility, efforts to increase and sustain readiness often fall on support staff and military medical providers.

In recent years, there has been a greater awareness of the negative effects of mental illness, low morale, and suicidality on military readiness. In 2013, suicide accounted for 28.1% of all deaths that occurred in the US Armed Forces.¹ Put frankly, suicide was one of the leading causes of death among military members.

The most recent Marine Corps Order regarding the Marine Corps Suicide Prevention Program stated that “suicidal behaviors are a barrier to readiness that have lasting effects on Marines and Service Members attached to Marine Commands. . .Families, and the Marine Corps.” It goes on to say that “[e]ffective suicide prevention requires coordinated efforts within a prevention framework dedicated to promoting mental, physical, spiritual, and social fitness. . .[and] mitigating stressors that interfere with mission readiness.”² This statement supports the notion that preventing suicide is not just about treating mental illness; it also involves maximizing physical, spiritual, and social fitness. Although it is well established that various mental health disorders are associated with an increased risk for suicide, it is worth noting that, in one study, only half of individuals who died by suicide had a mental health disorder diagnosed prior to their death.³ These statistics translate to the military. The 2015 Department of Defense Suicide Event Report noted that only 28% of service members who died by suicide and 22% of members with attempted suicide had been documented as having sought mental health care and disclosed their potential for self-harm prior to the event.^1,4 In 2018, a study published by Ursano et al⁵ showed that 36.3% of US soldiers with a documented suicide attempt (N=9650) had no prior mental health diagnoses.

Expanding the scope to include mental health issues in general, only 29% of service members who reported experiencing a mental health problem actually sought mental health care in that same period. Overall, approximately 40% of service members with a reported perceived need for mental health care actually sought care over their entire course of service time,¹ which raises concern for a large population of undiagnosed and undertreated mental illnesses across the military. In response to these statistics, Reger et al³ posited that it is “essential that suicide prevention efforts move outside the silo of mental health.” The authors went on to challenge health care providers across all specialties and civilians alike to take responsibility in understanding, recognizing, and mitigating risk factors for suicide in the general population.³ Although treating a service member’s acne or offering to stand duty for a service member who has been under a great deal of stress in their personal life may appear to be indirect ways of reducing suicide in the US military, they actually may be the most critical means of prevention in a culture that emphasizes resilience and self-reliance, where seeking help for mental health struggles could be perceived as weakness.¹

In this review article, we discuss the concept of cutaneous body image (CBI) and its associated outcomes on health, satisfaction, and quality of life in military service members. We then examine the intersections between common dermatologic conditions, CBI, and mental health and explore the ability and role of the military dermatologist to serve as a positive influence on military readiness.

What is cutaneous body image?

Cutaneous body image is “the individual’s mental perception of his or her skin and its appendages (ie, hair, nails).”⁶ It is measured objectively using the Cutaneous Body Image Scale, a questionnaire that includes 7 items related to the overall satisfaction with the appearance of skin, color of skin, skin of the face, complexion of the face, hair, fingernails, and toenails. Each question is rated using a 10-point Likert scale (0=not at all; 10=very markedly).⁶

Some degree of CBI dissatisfaction is expected and has been shown in the general population at large; for example, more than 56% of women older than 30 years report some degree of dissatisfaction with their skin. Similarly, data from the American Society of Plastic Surgeons showed that while 10.9 million cosmetic procedures were performed in 2006, 9.1 million of them involved minimally invasive procedures such as botulinum toxin type A injections with the purpose of skin rejuvenation and improvement of facial appearance.⁷ However, lower than average CBI can contribute to considerable psychosocial morbidity. Dissatisfaction with CBI is associated with self-consciousness, feelings of inferiority, and social exclusion. These symptoms can be grouped into a construct called interpersonal sensitivity (IS). A 2013 study by Gupta and Gupta⁶ investigated the relationship between CBI, IS, and suicidal ideation among 312 consenting nonclinical participants in Canada. The study found that greater dissatisfaction with an individual’s CBI correlated to increased IS and increased rates of suicidal ideation and intentional self-injury.⁶

Cutaneous body image is particularly relevant to dermatologists, as many common dermatoses can cause cosmetically disfiguring skin conditions; for example, acne and rosacea have the propensity to cause notable disfigurement to the facial unit. Other common conditions such as atopic dermatitis or psoriasis can flare with stress and thereby throw patients into a vicious cycle of physical and psychosocial stress caused by social stigma, cosmetic disfigurement, and reduced CBI, in turn leading to worsening of the disease at hand. Dermatologists need to be aware that common dermatoses can impact a patient’s mental health via poor CBI.⁸ Similarly, dermatologists may be empowered by the awareness that treating common dermatoses, especially those associated with poor cosmesis, have 2-fold benefits—on the skin condition itself and on the patient’s mental health.

How are common dermatoses associated with mental health?

Acne—Acne is one of the most common skin diseases, so much so that in many cases acne has become an accepted and expected part of adolescence and young adulthood. Studies estimate that 85% of the US population aged 12 to 25 years have acne.⁹ For some adults, acne persists even longer, with 1% to 5% of adults reporting to have active lesions at 40 years of age.¹⁰ Acne is a multifactorial skin disease of the pilosebaceous unit that results in the development of inflammatory papules, pustules, and cysts. These lesions are most common on the face but can extend to other areas of the body, such as the chest and back.¹¹ Although the active lesions can be painful and disfiguring, if left untreated, acne may lead to permanent disfigurement and scarring, which can have long-lasting psychosocial impacts.

Individuals with acne have an increased likelihood of self-consciousness, social isolation, depression, and suicidal ideation. This relationship has been well established for decades. In the 1990s, a small study reported that 7 of 16 (43.8%) cases of completed suicide in dermatology patients were in patients with acne.¹² In a recent meta-analysis including 2,276,798 participants across 5 separate studies, researchers found that suicide was positively associated with acne, carrying an odds ratio of 1.50 (95% CI, 1.09-2.06).¹³

Rosacea—Rosacea is a common chronic inflammatory skin disease characterized by facial erythema, telangiectasia, phymatous changes, papules, pustules, and ocular irritation. The estimated worldwide prevalence is 5.5%.¹⁴ In addition to discomfort and irritation of the skin and eyes, rosacea often carries a higher risk of psychological and psychosocial distress due to its potentially disfiguring nature. Rosacea patients are at greater risk for having anxiety disorders and depression,¹⁵ and a 2018 study by Alinia et al¹⁶ showed that there is a direct relationship between rosacea severity and the actual level of depression.Although disease improvement certainly leads to improvements in quality of life and psychosocial status, Alinia et al¹⁶ noted that depression often is associated with poor treatment adherence due to poor motivation and hopelessness. It is critical that dermatologists are aware of these associations and maintain close follow-up with patients, even when the condition is not life-threatening, such as rosacea.

Hidradenitis Suppurativa—Hidradenitis suppurativa (HS) is a chronic inflammatory disease of the pilosebaceous unit that is characterized by the development of painful, malodorous, draining abscesses, fistulas, sinus tracts, and scars in sensitive areas such as the axillae, breasts, groin, and perineum.¹⁷ In severe cases, surgery may be required to excise affected areas. Compared to other cutaneous disease, HS is considered one of the most life-impacting disorders.¹⁸ The physical symptoms themselves often are debilitating, and patients often report considerable psychosocial and psychological impairment with decreased quality of life. Major depression frequently is noted, with 1 in 4 adults with HS also being depressed. In a large cross-sectional analysis of 38,140 adults and 1162 pediatric patients with HS, Wright et al¹⁷ reported the prevalence of depression among adults with HS as 30.0% compared to 16.9% in healthy controls. In children, the prevalence of depression was 11.7% compared to 4.1% in the general population.¹⁷ Similarly, 1 out of every 5 patients with HS experiences anxiety.¹⁸

In the military population, HS often can be duty limiting. The disease requires constant attention to wound care and frequent medical visits. For many service members operating in field training or combat environments, opportunities for and access to showers and basic hygiene is limited. Uniforms and additional necessary combat gear often are thick and occlusive. Taken as a whole, these factors may contribute to worsening of the disease and in severe cases are simply not conducive to the successful management of the condition. However, given the most commonly involved body areas and the nature of the disease, many service members with HS may feel embarrassed to disclose their condition. In uniform, the disease is not easily visible, and for unaware persons, the frequency of medical visits and limited duty status may seem unnecessary. This perception of a service member’s lack of productivity due to an unseen disease may further add to the psychosocial stress they experience.

What treatment options can be considered for military service members?

The treatments for acne, rosacea, and HS are outlined in the eTable.^11,19 Also noted are specific considerations when managing an active-duty service member due to various operational duty restrictions and constraints.

Final Thoughts

Maintaining readiness in the military is essential to the ability to not only “fight tonight” but also to win tonight in whatever operational or combat mission a service member may be. Although many factors impact readiness, the rates of suicide within the armed forces cannot be ignored. Suicide not only eliminates the readiness of the deceased service member but has lasting ripple effects on the overall readiness of their unit and command at large. Most suicides in the military occur in personnel with no prior documented mental health diagnoses or treatment. Therefore, it is the responsibility of all service members to recognize and mitigate stressors and risk factors that may lead to mental health distress and suicidality. In the medical corps, this translates to a responsibility of all medical specialists to recognize and understand unique risk factors for suicidality and to do as much as they can to reduce these risks. For military dermatologists and for civilian physicians treating military service members, it is imperative to predict and understand the relationship between common dermatoses; reduced satisfaction with CBI; and increased risk for mental health illness, self-harm, and suicide. Military dermatologists, as well as other specialists, may be limited in the care they are able to provide due to manpower, staffing, demand, and institutional guidelines; however, to better serve those who serve in a holistic manner, consideration must be given to rethink what is “medically essential” and “cosmetic” and leverage the available skills, techniques, and equipment to increase the readiness of the force.