When people learn they have enough cardiovascular disease risk to start treatment with a statin or antihypertensive drug, the impact on their healthy-lifestyle choices seems to often be a wash, based on findings from more than 40,000 Finland residents followed for at least 4 years after starting their primary-prevention regimen.

American Heart Association

“Patients’ awareness of their risk factors alone seems not to be effective in improving health behaviors,” wrote Maarit J. Korhonen, PhD, and associates in a report published in the Journal of the American Heart Association.

“Initiation of antihypertensive or statin therapy appears to be associated with lifestyle changes, some positive and others negative,” wrote Dr. Korhonen, a pharmacoepidemiologist at the University of Turku (Finland), and associates. This was the first reported study to assess a large-scale and prospectively followed cohort to look for associations between the use of medicines that prevent cardiovascular disease (CVD) and lifestyle changes. Most previous studies of these associations “have been cross sectional and provide no information on potential lifestyle changes during the time window around the initiation of medication use,” they added.

The new study specifically found that, on average, people who began treatment with at least one CVD-prevention medication for the first time were more likely to gain weight and more likely to become less active during the years following their treatment onset. But at the same time, these patients were also more likely to either quit or cut down on their smoking and alcohol consumption, the researchers found.

Their analysis used data from 41,225 people enrolled in the Finnish Public Sector Study, which prospectively began collecting data on a large number of Finland residents in the 1990s. They specifically focused on 81,772 completed questionnaires – collected at 4-year intervals – from people who completed at least two consecutive rounds of the survey during 2000-2013, and who were also at least 40 years old and free of prevalent CVD at the time of their first survey. The participants averaged nearly 53 years of age at their first survey, and 84% were women.

The researchers subdivided the survey responses into 8,837 (11%) people who began a statin, antihypertensive drug, or both during their participation; 26,914 (33%) already on a statin or antihypertensive drug when they completed their first questionnaire; and 46,021 response sets (56%) from people who never began treatment with either drug class. People who initiated a relevant drug began a median of 1.7 years following completion of their first survey, and a median of 2.4 years before their next survey. During follow-up, about 2% of all participants became newly diagnosed with some form of CVD.

The results showed that, after full adjustment for possible confounders, the mean increase in body mass index was larger among those who initiated a CVD-prevention drug, compared with those who did not. Among participants who were obese at entry, those who started a CVD drug had a statistically significant 37% increased rate of remaining obese, compared with those not starting these drugs. Among those who were not obese at baseline, those who began a CVD prevention drug had a statistically significant 82%% higher rate of becoming obese, compared with those not on a CVD-prevention drug. In addition, average daily energy expenditure, a measure of physical activity, showed a statistically significant decline among those who started a CVD drug, compared with those who did not. In contrast, CVD drug initiators had an average 1.85 gram/week decline in alcohol intake, compared with noninitiators, and those who were current smokers at the first survey and then started a CVD drug had a 26% relative drop in their smoking prevalence, compared with those who did not start a CVD drug, both statistically significant differences.

The findings suggest that “patients’ awareness of their risk factors alone seems not to be effective in improving health behaviors,” the authors concluded. “This means that expansion of pharmacologic interventions toward populations at low CVD risk may not necessarily lead to expected benefits at the population level.”

The study received no commercial funding. Dr. Korhonen had no disclosures.

mzoler@mdedge.com

SOURCE: Korhonen MJ et al. J Am Heart Assoc. 2020 Feb 5. doi: 10.1161/JAHA.119.014.168.

When people learn they have enough cardiovascular disease risk to start treatment with a statin or antihypertensive drug, the impact on their healthy-lifestyle choices seems to often be a wash, based on findings from more than 40,000 Finland residents followed for at least 4 years after starting their primary-prevention regimen.

American Heart Association

“Patients’ awareness of their risk factors alone seems not to be effective in improving health behaviors,” wrote Maarit J. Korhonen, PhD, and associates in a report published in the Journal of the American Heart Association.

“Initiation of antihypertensive or statin therapy appears to be associated with lifestyle changes, some positive and others negative,” wrote Dr. Korhonen, a pharmacoepidemiologist at the University of Turku (Finland), and associates. This was the first reported study to assess a large-scale and prospectively followed cohort to look for associations between the use of medicines that prevent cardiovascular disease (CVD) and lifestyle changes. Most previous studies of these associations “have been cross sectional and provide no information on potential lifestyle changes during the time window around the initiation of medication use,” they added.

The new study specifically found that, on average, people who began treatment with at least one CVD-prevention medication for the first time were more likely to gain weight and more likely to become less active during the years following their treatment onset. But at the same time, these patients were also more likely to either quit or cut down on their smoking and alcohol consumption, the researchers found.

Their analysis used data from 41,225 people enrolled in the Finnish Public Sector Study, which prospectively began collecting data on a large number of Finland residents in the 1990s. They specifically focused on 81,772 completed questionnaires – collected at 4-year intervals – from people who completed at least two consecutive rounds of the survey during 2000-2013, and who were also at least 40 years old and free of prevalent CVD at the time of their first survey. The participants averaged nearly 53 years of age at their first survey, and 84% were women.

The researchers subdivided the survey responses into 8,837 (11%) people who began a statin, antihypertensive drug, or both during their participation; 26,914 (33%) already on a statin or antihypertensive drug when they completed their first questionnaire; and 46,021 response sets (56%) from people who never began treatment with either drug class. People who initiated a relevant drug began a median of 1.7 years following completion of their first survey, and a median of 2.4 years before their next survey. During follow-up, about 2% of all participants became newly diagnosed with some form of CVD.

The results showed that, after full adjustment for possible confounders, the mean increase in body mass index was larger among those who initiated a CVD-prevention drug, compared with those who did not. Among participants who were obese at entry, those who started a CVD drug had a statistically significant 37% increased rate of remaining obese, compared with those not starting these drugs. Among those who were not obese at baseline, those who began a CVD prevention drug had a statistically significant 82%% higher rate of becoming obese, compared with those not on a CVD-prevention drug. In addition, average daily energy expenditure, a measure of physical activity, showed a statistically significant decline among those who started a CVD drug, compared with those who did not. In contrast, CVD drug initiators had an average 1.85 gram/week decline in alcohol intake, compared with noninitiators, and those who were current smokers at the first survey and then started a CVD drug had a 26% relative drop in their smoking prevalence, compared with those who did not start a CVD drug, both statistically significant differences.

The findings suggest that “patients’ awareness of their risk factors alone seems not to be effective in improving health behaviors,” the authors concluded. “This means that expansion of pharmacologic interventions toward populations at low CVD risk may not necessarily lead to expected benefits at the population level.”

The study received no commercial funding. Dr. Korhonen had no disclosures.

mzoler@mdedge.com

SOURCE: Korhonen MJ et al. J Am Heart Assoc. 2020 Feb 5. doi: 10.1161/JAHA.119.014.168.

When people learn they have enough cardiovascular disease risk to start treatment with a statin or antihypertensive drug, the impact on their healthy-lifestyle choices seems to often be a wash, based on findings from more than 40,000 Finland residents followed for at least 4 years after starting their primary-prevention regimen.

American Heart Association

“Patients’ awareness of their risk factors alone seems not to be effective in improving health behaviors,” wrote Maarit J. Korhonen, PhD, and associates in a report published in the Journal of the American Heart Association.

“Initiation of antihypertensive or statin therapy appears to be associated with lifestyle changes, some positive and others negative,” wrote Dr. Korhonen, a pharmacoepidemiologist at the University of Turku (Finland), and associates. This was the first reported study to assess a large-scale and prospectively followed cohort to look for associations between the use of medicines that prevent cardiovascular disease (CVD) and lifestyle changes. Most previous studies of these associations “have been cross sectional and provide no information on potential lifestyle changes during the time window around the initiation of medication use,” they added.

The new study specifically found that, on average, people who began treatment with at least one CVD-prevention medication for the first time were more likely to gain weight and more likely to become less active during the years following their treatment onset. But at the same time, these patients were also more likely to either quit or cut down on their smoking and alcohol consumption, the researchers found.

Their analysis used data from 41,225 people enrolled in the Finnish Public Sector Study, which prospectively began collecting data on a large number of Finland residents in the 1990s. They specifically focused on 81,772 completed questionnaires – collected at 4-year intervals – from people who completed at least two consecutive rounds of the survey during 2000-2013, and who were also at least 40 years old and free of prevalent CVD at the time of their first survey. The participants averaged nearly 53 years of age at their first survey, and 84% were women.

The researchers subdivided the survey responses into 8,837 (11%) people who began a statin, antihypertensive drug, or both during their participation; 26,914 (33%) already on a statin or antihypertensive drug when they completed their first questionnaire; and 46,021 response sets (56%) from people who never began treatment with either drug class. People who initiated a relevant drug began a median of 1.7 years following completion of their first survey, and a median of 2.4 years before their next survey. During follow-up, about 2% of all participants became newly diagnosed with some form of CVD.

The results showed that, after full adjustment for possible confounders, the mean increase in body mass index was larger among those who initiated a CVD-prevention drug, compared with those who did not. Among participants who were obese at entry, those who started a CVD drug had a statistically significant 37% increased rate of remaining obese, compared with those not starting these drugs. Among those who were not obese at baseline, those who began a CVD prevention drug had a statistically significant 82%% higher rate of becoming obese, compared with those not on a CVD-prevention drug. In addition, average daily energy expenditure, a measure of physical activity, showed a statistically significant decline among those who started a CVD drug, compared with those who did not. In contrast, CVD drug initiators had an average 1.85 gram/week decline in alcohol intake, compared with noninitiators, and those who were current smokers at the first survey and then started a CVD drug had a 26% relative drop in their smoking prevalence, compared with those who did not start a CVD drug, both statistically significant differences.

The findings suggest that “patients’ awareness of their risk factors alone seems not to be effective in improving health behaviors,” the authors concluded. “This means that expansion of pharmacologic interventions toward populations at low CVD risk may not necessarily lead to expected benefits at the population level.”

The study received no commercial funding. Dr. Korhonen had no disclosures.

mzoler@mdedge.com

SOURCE: Korhonen MJ et al. J Am Heart Assoc. 2020 Feb 5. doi: 10.1161/JAHA.119.014.168.

AUSTIN, TEX. – A customized diet developed to relieve inflammatory bowel disease (IBD) symptoms without compromising nutrition has uncovered a novel molecular mechanism of the diet-microbiome immune interaction that may allow gastroenterologists to tailor patient diets to enhance the gut microbiome, according to a poster presented at the annual congress of the Crohn’s & Colitis Foundation and the American Gastroenterological Association.

The study found that P-glycoprotein (P-gp) expression, associated with healthy gut, increased after adoption of the IBD-Anti-Inflammatory Diet (IBD-AID), said poster presenter and study leader Ana Luisa Maldonado-Contreras, PhD, of the University of Massachusetts Medical School, Worcester. The study involved 19 IBD patients placed on the IBD-AID. This is reportedly the first evidence of a whole-dietary recommendation that may help patients with IBD to reduce their symptoms.

“The IBD-AID has been rationally designed to feed a health-promoting, anti-inflammatory microbiome aiming at reducing chronic inflammation” Dr. Maldonado-Contreras said in an interview. The UMass researchers, led by Barbara Olendzki, RD, MPH, director of the Center for Applied Nutrition, derived the IBD-AID diet from a specific carbohydrate diet and modified it based on their research to increase the diversity of bacteria that produce short-chain fatty acids (SCFAs) and modulate the local immune response.

“SCFAs, such as acetate, propionate, and butyrate, are crucial in maintaining intestinal homeostasis by fueling colonocytes, strengthening the gut barrier function, and controlling local mucosal inflammation,” Dr. Maldonado-Contreras said. SCFAs regulate the production of proinflammatory mediators such as cytokines (tumor necrosis factor–alpha and interleukin 2, 6, and 10), eicosanoids, and chemokines, such as MCP-1 and CINC-2, by acting on macrophages and endothelial cells. High levels of SCFAs down-regulate those proinflammatory mediators.

The study found IBD-AID favored a beneficial gut microbiota. Prebiotic foods such as oats, barley, beans, and tempeh correlated with beneficial counts of Bacteroides and Parabacteroides, both capable of producing SCFAs. Probiotic foods like yogurt, fermented cabbage, and kefir correlated with high levels of Clostridium bolteae, a bacterium that plays a critical role in regulatory T-cell induction. Vegetables and nuts correlated with an abundance of Roseburia hominis, Eubacterium rectale, and Faecalibacterium prausnitzii, which tend to be reduced in IBD patients and are potent butyrate-producing Clostridia with known anti-inflammatory activity. Declines in putative pathogenic strains, such as Escherichia, Alistipes, and Eggerthella accompanied the increase of SCFA-producing bacteria.

Among the study patients treated for at least 8 weeks, the 61.3% who achieved at least 50% dietary compliance reported a dramatic decrease of symptoms and disease severity.

Dr. Maldonado-Contreras explained the role P-gp has as a biomarker of gut microbiota. “P-gp is an ABC-transporter located in the apical side of intestinal epithelial cells and is responsible for suppressing neutrophil migration in healthy individuals,” she said. “Loss of P-gp expression, or a reduction in its function, correlates with inflammation in the gastrointestinal tract in both mice and humans.” The study compared P-gp expression before and after patients went on the IBD-AID diet.

Dr. Maldonado-Contreras credited the study’s reported diet compliance of 76% to adoption of the patient-centered counseling model (J Am Diet Assoc. 2001;101:332-41). “With the patient-centered counseling model, we aimed to build self-efficacy, self-management strategies and to provide cooking-skill abilities to promote long-term behavioral habits related to the IBD-AID,” she said. The IBD-AID recipes, menus, and tips are available online (https://www.umassmed.edu/nutrition/).

The Dr. Maldonado-Contreras along with researchers at Icahn School of Medicine at Mount Sinai in New York are further evaluating an adapted version of the IBD-AID diet in pregnancy in the MELODY trial. “We are evaluating whether adherence to the modified IBD-AID during pregnancy in women with Crohn’s disease could beneficially shift the microbiome of mom and their babies, thereby promoting a healthier immune system during a critical time of the baby’s immune system development,” Dr. Maldonado-Contreras said. The trial has recruited 50 patients with Crohn’s disease and healthy controls so far.

Dr. Maldonado-Contreras has no financial relationships to disclose.
 

AUSTIN, TEX. – A customized diet developed to relieve inflammatory bowel disease (IBD) symptoms without compromising nutrition has uncovered a novel molecular mechanism of the diet-microbiome immune interaction that may allow gastroenterologists to tailor patient diets to enhance the gut microbiome, according to a poster presented at the annual congress of the Crohn’s & Colitis Foundation and the American Gastroenterological Association.

The study found that P-glycoprotein (P-gp) expression, associated with healthy gut, increased after adoption of the IBD-Anti-Inflammatory Diet (IBD-AID), said poster presenter and study leader Ana Luisa Maldonado-Contreras, PhD, of the University of Massachusetts Medical School, Worcester. The study involved 19 IBD patients placed on the IBD-AID. This is reportedly the first evidence of a whole-dietary recommendation that may help patients with IBD to reduce their symptoms.

“The IBD-AID has been rationally designed to feed a health-promoting, anti-inflammatory microbiome aiming at reducing chronic inflammation” Dr. Maldonado-Contreras said in an interview. The UMass researchers, led by Barbara Olendzki, RD, MPH, director of the Center for Applied Nutrition, derived the IBD-AID diet from a specific carbohydrate diet and modified it based on their research to increase the diversity of bacteria that produce short-chain fatty acids (SCFAs) and modulate the local immune response.

“SCFAs, such as acetate, propionate, and butyrate, are crucial in maintaining intestinal homeostasis by fueling colonocytes, strengthening the gut barrier function, and controlling local mucosal inflammation,” Dr. Maldonado-Contreras said. SCFAs regulate the production of proinflammatory mediators such as cytokines (tumor necrosis factor–alpha and interleukin 2, 6, and 10), eicosanoids, and chemokines, such as MCP-1 and CINC-2, by acting on macrophages and endothelial cells. High levels of SCFAs down-regulate those proinflammatory mediators.

The study found IBD-AID favored a beneficial gut microbiota. Prebiotic foods such as oats, barley, beans, and tempeh correlated with beneficial counts of Bacteroides and Parabacteroides, both capable of producing SCFAs. Probiotic foods like yogurt, fermented cabbage, and kefir correlated with high levels of Clostridium bolteae, a bacterium that plays a critical role in regulatory T-cell induction. Vegetables and nuts correlated with an abundance of Roseburia hominis, Eubacterium rectale, and Faecalibacterium prausnitzii, which tend to be reduced in IBD patients and are potent butyrate-producing Clostridia with known anti-inflammatory activity. Declines in putative pathogenic strains, such as Escherichia, Alistipes, and Eggerthella accompanied the increase of SCFA-producing bacteria.

Among the study patients treated for at least 8 weeks, the 61.3% who achieved at least 50% dietary compliance reported a dramatic decrease of symptoms and disease severity.

Dr. Maldonado-Contreras explained the role P-gp has as a biomarker of gut microbiota. “P-gp is an ABC-transporter located in the apical side of intestinal epithelial cells and is responsible for suppressing neutrophil migration in healthy individuals,” she said. “Loss of P-gp expression, or a reduction in its function, correlates with inflammation in the gastrointestinal tract in both mice and humans.” The study compared P-gp expression before and after patients went on the IBD-AID diet.

Dr. Maldonado-Contreras credited the study’s reported diet compliance of 76% to adoption of the patient-centered counseling model (J Am Diet Assoc. 2001;101:332-41). “With the patient-centered counseling model, we aimed to build self-efficacy, self-management strategies and to provide cooking-skill abilities to promote long-term behavioral habits related to the IBD-AID,” she said. The IBD-AID recipes, menus, and tips are available online (https://www.umassmed.edu/nutrition/).

The Dr. Maldonado-Contreras along with researchers at Icahn School of Medicine at Mount Sinai in New York are further evaluating an adapted version of the IBD-AID diet in pregnancy in the MELODY trial. “We are evaluating whether adherence to the modified IBD-AID during pregnancy in women with Crohn’s disease could beneficially shift the microbiome of mom and their babies, thereby promoting a healthier immune system during a critical time of the baby’s immune system development,” Dr. Maldonado-Contreras said. The trial has recruited 50 patients with Crohn’s disease and healthy controls so far.

Dr. Maldonado-Contreras has no financial relationships to disclose.
 

AUSTIN, TEX. – A customized diet developed to relieve inflammatory bowel disease (IBD) symptoms without compromising nutrition has uncovered a novel molecular mechanism of the diet-microbiome immune interaction that may allow gastroenterologists to tailor patient diets to enhance the gut microbiome, according to a poster presented at the annual congress of the Crohn’s & Colitis Foundation and the American Gastroenterological Association.

The study found that P-glycoprotein (P-gp) expression, associated with healthy gut, increased after adoption of the IBD-Anti-Inflammatory Diet (IBD-AID), said poster presenter and study leader Ana Luisa Maldonado-Contreras, PhD, of the University of Massachusetts Medical School, Worcester. The study involved 19 IBD patients placed on the IBD-AID. This is reportedly the first evidence of a whole-dietary recommendation that may help patients with IBD to reduce their symptoms.

“The IBD-AID has been rationally designed to feed a health-promoting, anti-inflammatory microbiome aiming at reducing chronic inflammation” Dr. Maldonado-Contreras said in an interview. The UMass researchers, led by Barbara Olendzki, RD, MPH, director of the Center for Applied Nutrition, derived the IBD-AID diet from a specific carbohydrate diet and modified it based on their research to increase the diversity of bacteria that produce short-chain fatty acids (SCFAs) and modulate the local immune response.

“SCFAs, such as acetate, propionate, and butyrate, are crucial in maintaining intestinal homeostasis by fueling colonocytes, strengthening the gut barrier function, and controlling local mucosal inflammation,” Dr. Maldonado-Contreras said. SCFAs regulate the production of proinflammatory mediators such as cytokines (tumor necrosis factor–alpha and interleukin 2, 6, and 10), eicosanoids, and chemokines, such as MCP-1 and CINC-2, by acting on macrophages and endothelial cells. High levels of SCFAs down-regulate those proinflammatory mediators.

The study found IBD-AID favored a beneficial gut microbiota. Prebiotic foods such as oats, barley, beans, and tempeh correlated with beneficial counts of Bacteroides and Parabacteroides, both capable of producing SCFAs. Probiotic foods like yogurt, fermented cabbage, and kefir correlated with high levels of Clostridium bolteae, a bacterium that plays a critical role in regulatory T-cell induction. Vegetables and nuts correlated with an abundance of Roseburia hominis, Eubacterium rectale, and Faecalibacterium prausnitzii, which tend to be reduced in IBD patients and are potent butyrate-producing Clostridia with known anti-inflammatory activity. Declines in putative pathogenic strains, such as Escherichia, Alistipes, and Eggerthella accompanied the increase of SCFA-producing bacteria.

Among the study patients treated for at least 8 weeks, the 61.3% who achieved at least 50% dietary compliance reported a dramatic decrease of symptoms and disease severity.

Dr. Maldonado-Contreras explained the role P-gp has as a biomarker of gut microbiota. “P-gp is an ABC-transporter located in the apical side of intestinal epithelial cells and is responsible for suppressing neutrophil migration in healthy individuals,” she said. “Loss of P-gp expression, or a reduction in its function, correlates with inflammation in the gastrointestinal tract in both mice and humans.” The study compared P-gp expression before and after patients went on the IBD-AID diet.

Dr. Maldonado-Contreras credited the study’s reported diet compliance of 76% to adoption of the patient-centered counseling model (J Am Diet Assoc. 2001;101:332-41). “With the patient-centered counseling model, we aimed to build self-efficacy, self-management strategies and to provide cooking-skill abilities to promote long-term behavioral habits related to the IBD-AID,” she said. The IBD-AID recipes, menus, and tips are available online (https://www.umassmed.edu/nutrition/).

The Dr. Maldonado-Contreras along with researchers at Icahn School of Medicine at Mount Sinai in New York are further evaluating an adapted version of the IBD-AID diet in pregnancy in the MELODY trial. “We are evaluating whether adherence to the modified IBD-AID during pregnancy in women with Crohn’s disease could beneficially shift the microbiome of mom and their babies, thereby promoting a healthier immune system during a critical time of the baby’s immune system development,” Dr. Maldonado-Contreras said. The trial has recruited 50 patients with Crohn’s disease and healthy controls so far.

Dr. Maldonado-Contreras has no financial relationships to disclose.
 

Academic cancer centers around the United States continue to get caught up in an ever-evolving investigation into researchers – American and Chinese – who did not disclose payments from or the work they did for Chinese institutions while simultaneously accepting taxpayer money through U.S. government grants.

The U.S. Federal Bureau of Investigation has been ferreting out researchers it says have acted illegally.

On Jan. 28, the agency arrested Charles Lieber, a chemist from Harvard University, Cambridge, Mass., and also unveiled charges against Zheng Zaosong, a cancer researcher who is in the United States on a Harvard-sponsored visa.

The FBI said Mr. Zheng, who worked at the Harvard-affiliated Beth Israel Deaconess Medical Center, Boston, tried to smuggle 21 vials of biological material and research to China. Mr. Zheng was arrested in December at Boston’s Logan Airport. He admitted he planned to conduct and publish research in China using the stolen samples, said the FBI.

“All of the individuals charged today were either directly or indirectly working for the Chinese government, at our country’s expense,” said the agent in charge of the FBI’s Boston office, Joseph R. Bonavolonta.

Sen. Charles Grassley (R-IA), who has been pushing for more government action against foreign theft of U.S. research, said in a statement, “I’m glad the FBI appears to be taking foreign threats to taxpayer-funded research seriously, but I fear that this case is only the tip of the iceberg.”

The FBI said it is investigating China-related cases in all 50 states.

Ross McKinney, MD, the chief scientific officer at the Association of American Medical Colleges (AAMC), said he is aware of some 200 investigations, not all of which are cancer related, at 70-75 institutions.

“It’s a very ubiquitous problem,” Dr. McKinney said in an interview.

He also pointed out that some 6,000 National Institutes of Health–funded principal investigators are of Asian background. “So that 200 is a pretty small proportion,” said Dr. McKinney.

The NIH warned some 10,000 institutions in August 2018 that it had uncovered Chinese manipulation of peer review and a lack of disclosure of work for Chinese institutions. It urged the institutions to report irregularities.

For universities, “the trouble is sorting out who is the violator from who is not,” said Dr. McKinney. He noted that they are not set up to investigate whether someone has a laboratory in China.

“The fact that the Chinese government exploited the fact that universities are typically fairly trusting is extremely disappointing,” he said.
 

Moffitt story still unfolding

The most serious allegations have been leveled against six former employees of the Moffitt Cancer Center and Research Institute in Tampa, Florida.

In December 2019, Moffitt announced that the six – including President and CEO Alan List, MD, and the center director, Thomas Sellers, PhD – had left Moffitt as a result of “violations of conflict of interest rules through their work in China.”

New details have emerged, thanks to a new investigative report from a committee of the Florida House of Representatives.

The report said that Sheng Wei, a naturalized U.S. citizen who had worked at Moffitt since 2008 – when Moffitt began its affiliation with the Tianjin Medical University Cancer Institute and Hospital – was instrumental in recruiting top executives into the Thousand Talents program, which Wei had joined in 2010, according to the report. These executives included Dr. List, Dr. Sellers, and also Daniel Sullivan, head of Moffitt’s clinical science program, and cancer biologist Pearlie Epling-Burnette, it noted.

Begun in 2008, China’s Thousand Talents Plan gave salaries, funding, laboratory space, and other incentives to researchers who promised to bring U.S.-gained knowledge and research to China.

All information about this program has been removed from the Internet, but the program may still be active, Dr. McKinney commented.

According to the report, Dr. List pledged to work for the Tianjin cancer center 9 months a year for $71,000 annually. He was appointed head of the hematology department ($85,300 a year) in 2016. He opened a bank account in China to receive that salary and other Thousand Talents payments, the report found. The report notes that the exact amount Dr. List was paid is still not known.

Initially, Dr. Sellers, who was the principal investigator for Moffitt’s National Cancer Institute core grant, said he had not been involved in the Thousand Talents program. He later admitted that he had pledged to work in China 2 months a year for the program and that he’d opened a Chinese bank account and had deposited at least $35,000 into the account, the report notes.

The others pledged to work for the Thousand Talents program and also opened bank accounts in China and received money in those accounts.

Another Moffitt employee, Howard McLeod, MD, had worked for Thousand Talents before he joined Moffitt but did not disclose his China work. Dr. McLeod also supervised and had a close relationship with another researcher, Yijing (Bob) He, MD, who was employed by Moffitt but who lived in China, unbeknownst to Moffitt. “Dr. He appears to have functioned as an agent of Dr. McLeod in China,” said the report.

The report concluded that “none of the Moffitt faculty who were Talents program participants properly or timely disclosed their Talents program involvement to Moffitt, and none disclosed the full extent of their Talents program activities prior to Moffitt’s internal investigation.”

No charges have been filed against any of the former Moffitt employees.

However, the Cancer Letter has reported that Dr. Sellers is claiming he was not involved in the program and that he is preparing to sue Moffitt.

AAMC’s Dr. McKinney notes that it is illegal for researchers to take U.S. government grant money and pledge a certain amount of time but not deliver on that commitment because they are working for someone else – in this case, China. They also lied about not having any other research support, which is also illegal, he said.

The researchers received Chinese money and deposited it in Chinese accounts, which was never reported to the U.S. Internal Revenue Service.

“One of the hallmarks of the Chinese recruitment program was that people were instructed to not tell their normal U.S. host institution and not tell any U.S. government agency about their relationship with China,” Dr. McKinney said. “It was creating a culture where dishonesty in this situation was norm,” he added.

The lack of honesty brings up bigger questions for the field, he said. “Once you start lying about one thing, do you lie about your science, too?”
 

Lack of oversight?

Dr. McKinney said the NIH, as well as universities and hospitals, had a long and trusting relationship with China and should not be blamed for falling prey to the Chinese government’s concerted effort to steal intellectual property.

But some government watchdog groups have chided the NIH for lax oversight. In February 2019, the federal Health & Human Services’ Office of Inspector General found that “NIH has not assessed the risks to national security when permitting data access to foreign [principal investigators].”

Federal investigators have said that Thousand Talents has been one of the biggest threats.

The U.S. Senate Permanent Subcommittee on Investigations reported in November 2019 that “the federal government’s grant-making agencies did little to prevent this from happening, nor did the FBI and other federal agencies develop a coordinated response to mitigate the threat.”

The NIH invests $31 billion a year in medical research through 50,000 competitive grants to more than 300,000 researchers, according to that report. Even after uncovering grant fraud and peer-review manipulation that benefited China, “significant gaps in NIH’s grant integrity process remain,” the report states. Site visits by the NIH’s Division of Grants Compliance and Oversight dropped from 28 in 2012 to just 3 in 2018, the report noted.
 

Widening dragnet

In April 2019, Science reported that the NIH identified five researchers at MD Anderson Cancer Center in Houston who had failed to disclose their ties to Chinese enterprises and who had failed to keep peer review confidential.

Two resigned before they could be fired, one was fired, another eventually left the institution, and the fifth was found to have not willfully engaged in subterfuge.

Just a month later, Emory University in Atlanta announced that it had fired a husband and wife research team. The neuroscientists were known for their studies of Huntington disease. Both were U.S. citizens and had worked at Emory for more than 2 decades, according to the Science report.

The Moffitt situation led to the Florida legislature’s investigation, and also prompted some soul searching. The Tampa Bay Times reported that U.S. Senator Rick Scott (R-FL) asked state universities to provide information on what they are doing to stop foreign influence. The University of Florida then acknowledged that four faculty members resigned or were terminated because of ties to a foreign recruitment program.
 

This article first appeared on Medscape.com.

Academic cancer centers around the United States continue to get caught up in an ever-evolving investigation into researchers – American and Chinese – who did not disclose payments from or the work they did for Chinese institutions while simultaneously accepting taxpayer money through U.S. government grants.

The U.S. Federal Bureau of Investigation has been ferreting out researchers it says have acted illegally.

On Jan. 28, the agency arrested Charles Lieber, a chemist from Harvard University, Cambridge, Mass., and also unveiled charges against Zheng Zaosong, a cancer researcher who is in the United States on a Harvard-sponsored visa.

The FBI said Mr. Zheng, who worked at the Harvard-affiliated Beth Israel Deaconess Medical Center, Boston, tried to smuggle 21 vials of biological material and research to China. Mr. Zheng was arrested in December at Boston’s Logan Airport. He admitted he planned to conduct and publish research in China using the stolen samples, said the FBI.

“All of the individuals charged today were either directly or indirectly working for the Chinese government, at our country’s expense,” said the agent in charge of the FBI’s Boston office, Joseph R. Bonavolonta.

Sen. Charles Grassley (R-IA), who has been pushing for more government action against foreign theft of U.S. research, said in a statement, “I’m glad the FBI appears to be taking foreign threats to taxpayer-funded research seriously, but I fear that this case is only the tip of the iceberg.”

The FBI said it is investigating China-related cases in all 50 states.

Ross McKinney, MD, the chief scientific officer at the Association of American Medical Colleges (AAMC), said he is aware of some 200 investigations, not all of which are cancer related, at 70-75 institutions.

“It’s a very ubiquitous problem,” Dr. McKinney said in an interview.

He also pointed out that some 6,000 National Institutes of Health–funded principal investigators are of Asian background. “So that 200 is a pretty small proportion,” said Dr. McKinney.

The NIH warned some 10,000 institutions in August 2018 that it had uncovered Chinese manipulation of peer review and a lack of disclosure of work for Chinese institutions. It urged the institutions to report irregularities.

For universities, “the trouble is sorting out who is the violator from who is not,” said Dr. McKinney. He noted that they are not set up to investigate whether someone has a laboratory in China.

“The fact that the Chinese government exploited the fact that universities are typically fairly trusting is extremely disappointing,” he said.
 

Moffitt story still unfolding

The most serious allegations have been leveled against six former employees of the Moffitt Cancer Center and Research Institute in Tampa, Florida.

In December 2019, Moffitt announced that the six – including President and CEO Alan List, MD, and the center director, Thomas Sellers, PhD – had left Moffitt as a result of “violations of conflict of interest rules through their work in China.”

New details have emerged, thanks to a new investigative report from a committee of the Florida House of Representatives.

The report said that Sheng Wei, a naturalized U.S. citizen who had worked at Moffitt since 2008 – when Moffitt began its affiliation with the Tianjin Medical University Cancer Institute and Hospital – was instrumental in recruiting top executives into the Thousand Talents program, which Wei had joined in 2010, according to the report. These executives included Dr. List, Dr. Sellers, and also Daniel Sullivan, head of Moffitt’s clinical science program, and cancer biologist Pearlie Epling-Burnette, it noted.

Begun in 2008, China’s Thousand Talents Plan gave salaries, funding, laboratory space, and other incentives to researchers who promised to bring U.S.-gained knowledge and research to China.

All information about this program has been removed from the Internet, but the program may still be active, Dr. McKinney commented.

According to the report, Dr. List pledged to work for the Tianjin cancer center 9 months a year for $71,000 annually. He was appointed head of the hematology department ($85,300 a year) in 2016. He opened a bank account in China to receive that salary and other Thousand Talents payments, the report found. The report notes that the exact amount Dr. List was paid is still not known.

Initially, Dr. Sellers, who was the principal investigator for Moffitt’s National Cancer Institute core grant, said he had not been involved in the Thousand Talents program. He later admitted that he had pledged to work in China 2 months a year for the program and that he’d opened a Chinese bank account and had deposited at least $35,000 into the account, the report notes.

The others pledged to work for the Thousand Talents program and also opened bank accounts in China and received money in those accounts.

Another Moffitt employee, Howard McLeod, MD, had worked for Thousand Talents before he joined Moffitt but did not disclose his China work. Dr. McLeod also supervised and had a close relationship with another researcher, Yijing (Bob) He, MD, who was employed by Moffitt but who lived in China, unbeknownst to Moffitt. “Dr. He appears to have functioned as an agent of Dr. McLeod in China,” said the report.

The report concluded that “none of the Moffitt faculty who were Talents program participants properly or timely disclosed their Talents program involvement to Moffitt, and none disclosed the full extent of their Talents program activities prior to Moffitt’s internal investigation.”

No charges have been filed against any of the former Moffitt employees.

However, the Cancer Letter has reported that Dr. Sellers is claiming he was not involved in the program and that he is preparing to sue Moffitt.

AAMC’s Dr. McKinney notes that it is illegal for researchers to take U.S. government grant money and pledge a certain amount of time but not deliver on that commitment because they are working for someone else – in this case, China. They also lied about not having any other research support, which is also illegal, he said.

The researchers received Chinese money and deposited it in Chinese accounts, which was never reported to the U.S. Internal Revenue Service.

“One of the hallmarks of the Chinese recruitment program was that people were instructed to not tell their normal U.S. host institution and not tell any U.S. government agency about their relationship with China,” Dr. McKinney said. “It was creating a culture where dishonesty in this situation was norm,” he added.

The lack of honesty brings up bigger questions for the field, he said. “Once you start lying about one thing, do you lie about your science, too?”
 

Lack of oversight?

Dr. McKinney said the NIH, as well as universities and hospitals, had a long and trusting relationship with China and should not be blamed for falling prey to the Chinese government’s concerted effort to steal intellectual property.

But some government watchdog groups have chided the NIH for lax oversight. In February 2019, the federal Health & Human Services’ Office of Inspector General found that “NIH has not assessed the risks to national security when permitting data access to foreign [principal investigators].”

Federal investigators have said that Thousand Talents has been one of the biggest threats.

The U.S. Senate Permanent Subcommittee on Investigations reported in November 2019 that “the federal government’s grant-making agencies did little to prevent this from happening, nor did the FBI and other federal agencies develop a coordinated response to mitigate the threat.”

The NIH invests $31 billion a year in medical research through 50,000 competitive grants to more than 300,000 researchers, according to that report. Even after uncovering grant fraud and peer-review manipulation that benefited China, “significant gaps in NIH’s grant integrity process remain,” the report states. Site visits by the NIH’s Division of Grants Compliance and Oversight dropped from 28 in 2012 to just 3 in 2018, the report noted.
 

Widening dragnet

In April 2019, Science reported that the NIH identified five researchers at MD Anderson Cancer Center in Houston who had failed to disclose their ties to Chinese enterprises and who had failed to keep peer review confidential.

Two resigned before they could be fired, one was fired, another eventually left the institution, and the fifth was found to have not willfully engaged in subterfuge.

Just a month later, Emory University in Atlanta announced that it had fired a husband and wife research team. The neuroscientists were known for their studies of Huntington disease. Both were U.S. citizens and had worked at Emory for more than 2 decades, according to the Science report.

The Moffitt situation led to the Florida legislature’s investigation, and also prompted some soul searching. The Tampa Bay Times reported that U.S. Senator Rick Scott (R-FL) asked state universities to provide information on what they are doing to stop foreign influence. The University of Florida then acknowledged that four faculty members resigned or were terminated because of ties to a foreign recruitment program.
 

This article first appeared on Medscape.com.

Academic cancer centers around the United States continue to get caught up in an ever-evolving investigation into researchers – American and Chinese – who did not disclose payments from or the work they did for Chinese institutions while simultaneously accepting taxpayer money through U.S. government grants.

The U.S. Federal Bureau of Investigation has been ferreting out researchers it says have acted illegally.

On Jan. 28, the agency arrested Charles Lieber, a chemist from Harvard University, Cambridge, Mass., and also unveiled charges against Zheng Zaosong, a cancer researcher who is in the United States on a Harvard-sponsored visa.

The FBI said Mr. Zheng, who worked at the Harvard-affiliated Beth Israel Deaconess Medical Center, Boston, tried to smuggle 21 vials of biological material and research to China. Mr. Zheng was arrested in December at Boston’s Logan Airport. He admitted he planned to conduct and publish research in China using the stolen samples, said the FBI.

“All of the individuals charged today were either directly or indirectly working for the Chinese government, at our country’s expense,” said the agent in charge of the FBI’s Boston office, Joseph R. Bonavolonta.

Sen. Charles Grassley (R-IA), who has been pushing for more government action against foreign theft of U.S. research, said in a statement, “I’m glad the FBI appears to be taking foreign threats to taxpayer-funded research seriously, but I fear that this case is only the tip of the iceberg.”

The FBI said it is investigating China-related cases in all 50 states.

Ross McKinney, MD, the chief scientific officer at the Association of American Medical Colleges (AAMC), said he is aware of some 200 investigations, not all of which are cancer related, at 70-75 institutions.

“It’s a very ubiquitous problem,” Dr. McKinney said in an interview.

He also pointed out that some 6,000 National Institutes of Health–funded principal investigators are of Asian background. “So that 200 is a pretty small proportion,” said Dr. McKinney.

The NIH warned some 10,000 institutions in August 2018 that it had uncovered Chinese manipulation of peer review and a lack of disclosure of work for Chinese institutions. It urged the institutions to report irregularities.

For universities, “the trouble is sorting out who is the violator from who is not,” said Dr. McKinney. He noted that they are not set up to investigate whether someone has a laboratory in China.

“The fact that the Chinese government exploited the fact that universities are typically fairly trusting is extremely disappointing,” he said.
 

Moffitt story still unfolding

The most serious allegations have been leveled against six former employees of the Moffitt Cancer Center and Research Institute in Tampa, Florida.

In December 2019, Moffitt announced that the six – including President and CEO Alan List, MD, and the center director, Thomas Sellers, PhD – had left Moffitt as a result of “violations of conflict of interest rules through their work in China.”

New details have emerged, thanks to a new investigative report from a committee of the Florida House of Representatives.

The report said that Sheng Wei, a naturalized U.S. citizen who had worked at Moffitt since 2008 – when Moffitt began its affiliation with the Tianjin Medical University Cancer Institute and Hospital – was instrumental in recruiting top executives into the Thousand Talents program, which Wei had joined in 2010, according to the report. These executives included Dr. List, Dr. Sellers, and also Daniel Sullivan, head of Moffitt’s clinical science program, and cancer biologist Pearlie Epling-Burnette, it noted.

Begun in 2008, China’s Thousand Talents Plan gave salaries, funding, laboratory space, and other incentives to researchers who promised to bring U.S.-gained knowledge and research to China.

All information about this program has been removed from the Internet, but the program may still be active, Dr. McKinney commented.

According to the report, Dr. List pledged to work for the Tianjin cancer center 9 months a year for $71,000 annually. He was appointed head of the hematology department ($85,300 a year) in 2016. He opened a bank account in China to receive that salary and other Thousand Talents payments, the report found. The report notes that the exact amount Dr. List was paid is still not known.

Initially, Dr. Sellers, who was the principal investigator for Moffitt’s National Cancer Institute core grant, said he had not been involved in the Thousand Talents program. He later admitted that he had pledged to work in China 2 months a year for the program and that he’d opened a Chinese bank account and had deposited at least $35,000 into the account, the report notes.

The others pledged to work for the Thousand Talents program and also opened bank accounts in China and received money in those accounts.

Another Moffitt employee, Howard McLeod, MD, had worked for Thousand Talents before he joined Moffitt but did not disclose his China work. Dr. McLeod also supervised and had a close relationship with another researcher, Yijing (Bob) He, MD, who was employed by Moffitt but who lived in China, unbeknownst to Moffitt. “Dr. He appears to have functioned as an agent of Dr. McLeod in China,” said the report.

The report concluded that “none of the Moffitt faculty who were Talents program participants properly or timely disclosed their Talents program involvement to Moffitt, and none disclosed the full extent of their Talents program activities prior to Moffitt’s internal investigation.”

No charges have been filed against any of the former Moffitt employees.

However, the Cancer Letter has reported that Dr. Sellers is claiming he was not involved in the program and that he is preparing to sue Moffitt.

AAMC’s Dr. McKinney notes that it is illegal for researchers to take U.S. government grant money and pledge a certain amount of time but not deliver on that commitment because they are working for someone else – in this case, China. They also lied about not having any other research support, which is also illegal, he said.

The researchers received Chinese money and deposited it in Chinese accounts, which was never reported to the U.S. Internal Revenue Service.

“One of the hallmarks of the Chinese recruitment program was that people were instructed to not tell their normal U.S. host institution and not tell any U.S. government agency about their relationship with China,” Dr. McKinney said. “It was creating a culture where dishonesty in this situation was norm,” he added.

The lack of honesty brings up bigger questions for the field, he said. “Once you start lying about one thing, do you lie about your science, too?”
 

Lack of oversight?

Dr. McKinney said the NIH, as well as universities and hospitals, had a long and trusting relationship with China and should not be blamed for falling prey to the Chinese government’s concerted effort to steal intellectual property.

But some government watchdog groups have chided the NIH for lax oversight. In February 2019, the federal Health & Human Services’ Office of Inspector General found that “NIH has not assessed the risks to national security when permitting data access to foreign [principal investigators].”

Federal investigators have said that Thousand Talents has been one of the biggest threats.

The U.S. Senate Permanent Subcommittee on Investigations reported in November 2019 that “the federal government’s grant-making agencies did little to prevent this from happening, nor did the FBI and other federal agencies develop a coordinated response to mitigate the threat.”

The NIH invests $31 billion a year in medical research through 50,000 competitive grants to more than 300,000 researchers, according to that report. Even after uncovering grant fraud and peer-review manipulation that benefited China, “significant gaps in NIH’s grant integrity process remain,” the report states. Site visits by the NIH’s Division of Grants Compliance and Oversight dropped from 28 in 2012 to just 3 in 2018, the report noted.
 

Widening dragnet

In April 2019, Science reported that the NIH identified five researchers at MD Anderson Cancer Center in Houston who had failed to disclose their ties to Chinese enterprises and who had failed to keep peer review confidential.

Two resigned before they could be fired, one was fired, another eventually left the institution, and the fifth was found to have not willfully engaged in subterfuge.

Just a month later, Emory University in Atlanta announced that it had fired a husband and wife research team. The neuroscientists were known for their studies of Huntington disease. Both were U.S. citizens and had worked at Emory for more than 2 decades, according to the Science report.

The Moffitt situation led to the Florida legislature’s investigation, and also prompted some soul searching. The Tampa Bay Times reported that U.S. Senator Rick Scott (R-FL) asked state universities to provide information on what they are doing to stop foreign influence. The University of Florida then acknowledged that four faculty members resigned or were terminated because of ties to a foreign recruitment program.
 

This article first appeared on Medscape.com.

In clinical practice, for the majority of patients with psoriasis superpotent topical corticosteroids (TCSs) are used as initial therapy as well as ongoing breakthrough therapy to achieve quick resolution of target lesions. However, safe and effective long-term treatment and maintenance options are required for managing the chronic nature of psoriasis to improve patient satisfaction, adherence, and quality of life, especially given that package inserts advise no more than 2 to 4 weeks of continuous use to limit side effects. The long-term use of superpotent TCSs can have a multitude of unwanted cutaneous side effects, such as skin atrophy, telangiectases, striae, and allergic vehicle responses.^1,2 Tachyphylaxis, a decreased response to treatment over time, has been more controversial and may not occur with halobetasol propionate (HP) ointment 0.05%.³ In addition, TCSs are associated with relapse or rebound on withdrawal, which can be problematic but are poorly characterized.

We review the clinical data on HP, a superpotent TCS, in the treatment of psoriasis. We also explore both recent formulation developments and fixed-combination approaches to providing optimal treatment.

Clinical Experience With HP 0.05% in Various Formulations

Halobetasol propionate is a superpotent TCS with extensive clinical experience in treating psoriasis spanning nearly 30 years.^1,2,3-7 Most recently, a twice-daily HP lotion 0.05% formulation was evaluated in patients with moderate to severe disease.⁸ Halobetasol propionate lotion 0.05% applied morning and night was shown to be significantly more effective than vehicle after 2 weeks of treatment (P<.001) in 2 parallel-group studies of 443 patients.⁹ Treatment success (ie, at least a 2-grade improvement in investigator global assessment [IGA] and IGA score of clear or almost clear) was achieved in 44.5% of patients treated with HP lotion 0.05% compared to 6.3% and 7.1% in the 2 vehicle arms. Treatment-related adverse events (AEs) were uncommon, with application-site pain reported in 2 patients treated with HP lotion 0.05% compared to 5 patients treated with vehicle.⁹

Several earlier studies have evaluated the short-term efficacy of twice-daily HP cream 0.05% and HP ointment 0.05% in the treatment of plaque psoriasis, but only 2 placebo-controlled trials have been reported, and data are limited.

Two 2-week studies of twice-daily HP ointment 0.05% (paired-comparison and parallel-group designs) in 204 patients with moderate plaque psoriasis reported improvement in plaque elevation, erythema, and scaling compared to vehicle. Patient global responses and physician global evaluation favored HP ointment 0.05%, and reports of stinging and burning were similar with active treatment and vehicle.⁴

Similarly, HP cream 0.05% applied twice daily was shown to be significantly superior to vehicle in reducing overall disease severity, erythema, plaque elevation, and scaling after 1 and 2 weeks of treatment in a paired-comparison study of 110 patients (P=.0001).⁵ A clinically significant reduction (at least a 1-grade improvement) in erythema, plaque elevation, pruritus, and scaling was noted in 81% to 92% of patients (P=.0001). Patients’ self-assessment of effectiveness rated HP cream 0.05% as excellent, very good, or good in 69% of patients compared to 20% for vehicle. Treatment-related AEs were reported by 4 patients.⁵

A small, noncontrolled, 2-week pediatric study (N=11) demonstrated the efficacy of combined therapy with HP cream 0.05% every morning and HP ointment 0.05% every night due to the then-perceived preference for creams as being more pleasant to apply during the day and ointments being more efficacious. Reported side effects were relatively mild, with application-site burning being the most common.¹⁰

Potential local AEs associated with HP are similar to those seen with other superpotent TCSs. Overall, they were reported in 0% to 13% of patients. The most common AEs were burning, pruritus, erythema, hypopigmentation, dryness, and folliculitis.^5-8,10-14 Isolated cases of moderate telangiectasia and mild atrophy also have been reported.^8,10

Comparative Studies With Other TCSs

In comparative studies of patients with severe localized plaque psoriasis, HP ointment 0.05% applied twice daily for up to 4 weeks was significantly superior compared to clobetasol propionate ointment 0.05% for the number of patients with none or mild disease (P=.023⁷) or comparisons of global evaluation scores (P=.013¹⁵) at week 2, or compared to betamethasone valerate ointment 0.1% (P=.02).⁶ It also was more effective than betamethasone dipropionate ointment 0.05% with healing seen in 40% of patients treated with HP ointment 0.05% within 24 days compared to 25% of patients treated with betamethasone dipropionate ointment 0.05%.⁸ Patient acceptance of HP ointment 0.05% based on cosmetic acceptability and ease of application was better (very good in 90% vs 80% of patients⁷) or significantly better compared to clobetasol propionate ointment 0.05% (P=.042 and P=.019¹⁵) and betamethasone dipropionate ointment 0.05% (P=.02).⁸

Evolving Management Strategies

A number of management strategies have been proposed to improve the safety and efficacy of long-term therapy with TCSs, including weekend-only or pulse therapy, dose reduction, rotating to another therapy, or combining with other topical therapies. Maintenance efficacy data are sparse. A small double-blind study in 44 patients with mild to moderate psoriasis was conducted wherein patients were treated with calcipotriene ointment in the morning and HP ointment in the evening for 2 weeks.¹⁶ Those patients who achieved at least a 50% improvement in disease severity (N=40) were randomized to receive HP ointment twice daily on weekends and calcipotriene ointment or placebo twice daily on weekdays for 6 months. Seventy-six percent of those patients treated with a HP/calcipotriene pulsed therapy maintained remission (achieving and maintaining a 75% improvement in physician global assessment) compared to 40% of those patients treated with HP only (P=.045). Mild AEs were reported in 4 patients treated with the combination regimen and 1 patient treated with HP only. No AE-related discontinuations occurred.¹⁶

In a real-world setting, a maintenance regimen that is less complicated enhances the potential for increased patient adherence and successful outcomes.¹⁷ After an initial 2-week regimen of twice-daily HP ointment 0.05% in combination with ammonium lactate lotion in patients with mild to moderate psoriasis (N=55), those rated clear or almost clear (41/55 [74.6%]) entered a maintenance phase, applying ammonium lactate lotion twice daily and either HP or placebo ointment twice daily on weekends. The probability of disease worsening by week 14 was 29% in the HP-treated group compared to 100% in the placebo group (P<.0001). By week 24, 12 patients (29.2%) remained clear or almost clear.¹⁷

Development of HP Lotion 0.01%

There are numerous examples in dermatology where advances in formulation development have made it possible to reduce the strength of active ingredients without compromising efficacy. Formulation advances also afford improved safety profiles that can extend a product’s utility. The vehicle affects not only the potency of an agent but also patient compliance, which is crucial for adequate response. Patients prefer lighter vehicles, such as lotions, over heavy ointments and creams.^18,19

Recently, a polymeric honeycomb matrix (carbomer cross-linked polymers), which helps structure the oil emulsion and provide a uniform distribution of both active and moisturizing/hydrating ingredients (ie, sorbitol, light mineral oil, diethyl sebacate) at the surface of the skin, has been deployed for topical delivery of HP (eFigure 1). Ninety percent of the oil droplets containing solubilized halobetasol are 13 µm or smaller, an ideal size for penetration through follicular openings (unpublished data, Bausch Health, 2018).

Comparison of Skin Penetration of HP Lotion 0.01% vs HP Cream 0.05%

Comparative percutaneous absorption of 2 HP formulations—0.01% lotion and 0.05% cream—was evaluated in vitro using human tissue from a single donor mounted on Bronaugh flow-through diffusion cells. Receptor phase samples were collected over the 24-hour study period and HP content assessed using liquid chromatography–mass spectrometry analysis. Halobetasol propionate lotion 0.01% demonstrated faster tissue permeation, with receptor phase levels of 0.91% of the applied dose at 24 hours compared to 0.28% of the applied dose with HP cream 0.05%. Although there was little differentiation of cumulative receptor fluid levels of HP at 6 hours, there was significant differentiation at 12 hours. Levels of HP were lowest in the receptor phase and highest in the epidermal layers of the skin, indicating limited permeation through the epidermis to the dermis. The mean (SD) for epidermal deposition of HP following the 24-hour duration of exposure was 6.17% (2.07%) and 1.72% (0.76%) for the 0.01% lotion and 0.05% cream, respectively (Figure 1)(unpublished data, Bausch Health, 2018).

Efficacy and Safety of HP Lotion 0.01% in Moderate to Severe Plaque Psoriasis

Two articles have been published on the use of HP lotion 0.01% in moderate to severe psoriasis: 2 pivotal studies comparing once-daily application with vehicle lotion over 8 weeks (N=430),²⁰ and a comparative “label-restricted” 2-week study with HP lotion 0.01% and HP cream 0.05% (N=150).²¹

HP Lotion 0.01% Compared to Vehicle
Two multicenter, randomized, double-blind, vehicle-controlled phase 3 studies investigated the safety and efficacy of once-daily HP lotion 0.01% in moderate to severe plaque psoriasis (N=430).²⁰ Patients were treated with HP lotion 0.01% or vehicle (randomized in a 2:1 ratio) for 8 weeks, with a 4-week posttreatment follow-up. Treatment success (defined as at least a 2-grade improvement in baseline IGA score and a score equating to clear or almost clear) was significantly greater with HP lotion 0.01% at all assessment points (Figure 2)(P=.003 for week 2; P<.001 for other time points). At week 8, 37.4% of patients receiving HP lotion 0.01% were treatment successes compared to 10.0% of patients receiving vehicle (P<.001). Additionally, a 2-grade improvement from baseline for each psoriasis sign—erythema, plaque elevation, and scaling—was achieved by 42.2% of patients receiving HP lotion 0.01% at week 8 compared to 11.4% of patients receiving vehicle (P<.001). Good efficacy was maintained posttreatment that was significant compared to vehicle (P<.001).²⁰

There were corresponding reductions in body surface area (BSA) affected following treatment with HP lotion 0.01%.²⁰ At baseline, the mean BSA was 6.1 (range, 3–12). By week 8, there was a 35.2% reduction in BSA compared to 5.9% with vehicle. Again, a significant reduction in BSA was maintained posttreatment compared to vehicle (P<.001).²⁰

Halobetasol propionate lotion 0.01% was well tolerated with few treatment-related AEs.²⁰ Most AEs were application-site reactions such as dermatitis (0.7%), infection, pruritus, and discoloration (0.4% each). Mild to moderate itching, dryness, burning, and stinging present at baseline all improved with treatment, and severity of local skin reactions was significantly lower than with vehicle at week 8 (P<.001). Quality-of-life data also highlighted the benefits of active treatment compared to vehicle for cutaneous tolerability. The Dermatology Life Quality Index (DLQI) is a 10-item patient-reported questionnaire consisting of questions concerning symptoms and feelings, daily activities, leisure, work and school, personal relationships, and treatment.²² Change from baseline for DLQI (how itchy, sore, painful, stinging) was significantly greater with HP lotion 0.01% at weeks 4 and 8 (P<.001). Changes in the overall DLQI score also were significantly greater with HP lotion 0.01% at both study visits (P=.006 and P=.014 at week 4 and P=.001 and P=.004 at week 8 for study 1 and study 2, respectively).²⁰

HP Lotion 0.01% Compared to HP Cream 0.05%
Treatment success with HP lotion 0.01% also was shown to be comparable to the higher-concentration HP cream 0.05% in patients with moderate to severe psoriasis over a 2-week “label-restricted” treatment period (Figure 3). Both products were well tolerated over the 2-week treatment period. One patient reported application-site dermatitis (1.7%) with HP lotion 0.01%.²¹

Conclusion

Halobetasol propionate 0.05%—cream, ointment, and lotion—has been shown to be a highly effective short-term topical treatment for psoriasis. Longer-term treatment strategies using HP, which are important when considering management of a chronic condition, have been limited by safety concerns and labelling. However, there are data to suggest weekend or pulsed therapy may be an option.

A novel formulation of HP lotion 0.01% has been developed using a polymerized matrix with active ingredients and moisturizing excipients suspended in oil droplets. The polymerized honeycomb matrix and vehicle formulation form a barrier by reducing epidermal water loss and improving skin hydration. The oil droplets deliver uniform amounts of active ingredient in an optimal size for follicular penetration. Skin penetration has been shown to be quicker with greater retention in the epidermis with HP lotion 0.01% compared to HP cream 0.05%, with corresponding considerably lower penetration into the dermis.

Although there have been a number of clinical studies of HP for psoriasis, until recently there have been no comparative trials, with studies label restricted to a 2- to 4-week duration. Three clinical studies with HP lotion 0.01% have now been reported.Not only has HP lotion 0.01% been shown to be as effective as HP cream 0.05% in a 2-week comparative study (despite having one-fifth the concentration of HP), it also has been shown to be very effective and well tolerated following 8 weeks of daily use.^20,21 Further studies involving longer treatment durations are required to better elucidate AEs, but HP lotion 0.01% may provide the first longer-term TCS treatment solution for moderate to severe psoriasis.

Acknowledgments
We thank Brian Bulley, MSc (Konic Limited, United Kingdom), for assistance with the preparation of the manuscript. Ortho Dermatologics funded Konic’s activities pertaining to this manuscript.

In clinical practice, for the majority of patients with psoriasis superpotent topical corticosteroids (TCSs) are used as initial therapy as well as ongoing breakthrough therapy to achieve quick resolution of target lesions. However, safe and effective long-term treatment and maintenance options are required for managing the chronic nature of psoriasis to improve patient satisfaction, adherence, and quality of life, especially given that package inserts advise no more than 2 to 4 weeks of continuous use to limit side effects. The long-term use of superpotent TCSs can have a multitude of unwanted cutaneous side effects, such as skin atrophy, telangiectases, striae, and allergic vehicle responses.^1,2 Tachyphylaxis, a decreased response to treatment over time, has been more controversial and may not occur with halobetasol propionate (HP) ointment 0.05%.³ In addition, TCSs are associated with relapse or rebound on withdrawal, which can be problematic but are poorly characterized.

We review the clinical data on HP, a superpotent TCS, in the treatment of psoriasis. We also explore both recent formulation developments and fixed-combination approaches to providing optimal treatment.

Clinical Experience With HP 0.05% in Various Formulations

Halobetasol propionate is a superpotent TCS with extensive clinical experience in treating psoriasis spanning nearly 30 years.^1,2,3-7 Most recently, a twice-daily HP lotion 0.05% formulation was evaluated in patients with moderate to severe disease.⁸ Halobetasol propionate lotion 0.05% applied morning and night was shown to be significantly more effective than vehicle after 2 weeks of treatment (P<.001) in 2 parallel-group studies of 443 patients.⁹ Treatment success (ie, at least a 2-grade improvement in investigator global assessment [IGA] and IGA score of clear or almost clear) was achieved in 44.5% of patients treated with HP lotion 0.05% compared to 6.3% and 7.1% in the 2 vehicle arms. Treatment-related adverse events (AEs) were uncommon, with application-site pain reported in 2 patients treated with HP lotion 0.05% compared to 5 patients treated with vehicle.⁹

Several earlier studies have evaluated the short-term efficacy of twice-daily HP cream 0.05% and HP ointment 0.05% in the treatment of plaque psoriasis, but only 2 placebo-controlled trials have been reported, and data are limited.

Two 2-week studies of twice-daily HP ointment 0.05% (paired-comparison and parallel-group designs) in 204 patients with moderate plaque psoriasis reported improvement in plaque elevation, erythema, and scaling compared to vehicle. Patient global responses and physician global evaluation favored HP ointment 0.05%, and reports of stinging and burning were similar with active treatment and vehicle.⁴

Similarly, HP cream 0.05% applied twice daily was shown to be significantly superior to vehicle in reducing overall disease severity, erythema, plaque elevation, and scaling after 1 and 2 weeks of treatment in a paired-comparison study of 110 patients (P=.0001).⁵ A clinically significant reduction (at least a 1-grade improvement) in erythema, plaque elevation, pruritus, and scaling was noted in 81% to 92% of patients (P=.0001). Patients’ self-assessment of effectiveness rated HP cream 0.05% as excellent, very good, or good in 69% of patients compared to 20% for vehicle. Treatment-related AEs were reported by 4 patients.⁵

A small, noncontrolled, 2-week pediatric study (N=11) demonstrated the efficacy of combined therapy with HP cream 0.05% every morning and HP ointment 0.05% every night due to the then-perceived preference for creams as being more pleasant to apply during the day and ointments being more efficacious. Reported side effects were relatively mild, with application-site burning being the most common.¹⁰

Potential local AEs associated with HP are similar to those seen with other superpotent TCSs. Overall, they were reported in 0% to 13% of patients. The most common AEs were burning, pruritus, erythema, hypopigmentation, dryness, and folliculitis.^5-8,10-14 Isolated cases of moderate telangiectasia and mild atrophy also have been reported.^8,10

Comparative Studies With Other TCSs

In comparative studies of patients with severe localized plaque psoriasis, HP ointment 0.05% applied twice daily for up to 4 weeks was significantly superior compared to clobetasol propionate ointment 0.05% for the number of patients with none or mild disease (P=.023⁷) or comparisons of global evaluation scores (P=.013¹⁵) at week 2, or compared to betamethasone valerate ointment 0.1% (P=.02).⁶ It also was more effective than betamethasone dipropionate ointment 0.05% with healing seen in 40% of patients treated with HP ointment 0.05% within 24 days compared to 25% of patients treated with betamethasone dipropionate ointment 0.05%.⁸ Patient acceptance of HP ointment 0.05% based on cosmetic acceptability and ease of application was better (very good in 90% vs 80% of patients⁷) or significantly better compared to clobetasol propionate ointment 0.05% (P=.042 and P=.019¹⁵) and betamethasone dipropionate ointment 0.05% (P=.02).⁸

Evolving Management Strategies

A number of management strategies have been proposed to improve the safety and efficacy of long-term therapy with TCSs, including weekend-only or pulse therapy, dose reduction, rotating to another therapy, or combining with other topical therapies. Maintenance efficacy data are sparse. A small double-blind study in 44 patients with mild to moderate psoriasis was conducted wherein patients were treated with calcipotriene ointment in the morning and HP ointment in the evening for 2 weeks.¹⁶ Those patients who achieved at least a 50% improvement in disease severity (N=40) were randomized to receive HP ointment twice daily on weekends and calcipotriene ointment or placebo twice daily on weekdays for 6 months. Seventy-six percent of those patients treated with a HP/calcipotriene pulsed therapy maintained remission (achieving and maintaining a 75% improvement in physician global assessment) compared to 40% of those patients treated with HP only (P=.045). Mild AEs were reported in 4 patients treated with the combination regimen and 1 patient treated with HP only. No AE-related discontinuations occurred.¹⁶

In a real-world setting, a maintenance regimen that is less complicated enhances the potential for increased patient adherence and successful outcomes.¹⁷ After an initial 2-week regimen of twice-daily HP ointment 0.05% in combination with ammonium lactate lotion in patients with mild to moderate psoriasis (N=55), those rated clear or almost clear (41/55 [74.6%]) entered a maintenance phase, applying ammonium lactate lotion twice daily and either HP or placebo ointment twice daily on weekends. The probability of disease worsening by week 14 was 29% in the HP-treated group compared to 100% in the placebo group (P<.0001). By week 24, 12 patients (29.2%) remained clear or almost clear.¹⁷

Development of HP Lotion 0.01%

There are numerous examples in dermatology where advances in formulation development have made it possible to reduce the strength of active ingredients without compromising efficacy. Formulation advances also afford improved safety profiles that can extend a product’s utility. The vehicle affects not only the potency of an agent but also patient compliance, which is crucial for adequate response. Patients prefer lighter vehicles, such as lotions, over heavy ointments and creams.^18,19

Recently, a polymeric honeycomb matrix (carbomer cross-linked polymers), which helps structure the oil emulsion and provide a uniform distribution of both active and moisturizing/hydrating ingredients (ie, sorbitol, light mineral oil, diethyl sebacate) at the surface of the skin, has been deployed for topical delivery of HP (eFigure 1). Ninety percent of the oil droplets containing solubilized halobetasol are 13 µm or smaller, an ideal size for penetration through follicular openings (unpublished data, Bausch Health, 2018).

Comparison of Skin Penetration of HP Lotion 0.01% vs HP Cream 0.05%

Comparative percutaneous absorption of 2 HP formulations—0.01% lotion and 0.05% cream—was evaluated in vitro using human tissue from a single donor mounted on Bronaugh flow-through diffusion cells. Receptor phase samples were collected over the 24-hour study period and HP content assessed using liquid chromatography–mass spectrometry analysis. Halobetasol propionate lotion 0.01% demonstrated faster tissue permeation, with receptor phase levels of 0.91% of the applied dose at 24 hours compared to 0.28% of the applied dose with HP cream 0.05%. Although there was little differentiation of cumulative receptor fluid levels of HP at 6 hours, there was significant differentiation at 12 hours. Levels of HP were lowest in the receptor phase and highest in the epidermal layers of the skin, indicating limited permeation through the epidermis to the dermis. The mean (SD) for epidermal deposition of HP following the 24-hour duration of exposure was 6.17% (2.07%) and 1.72% (0.76%) for the 0.01% lotion and 0.05% cream, respectively (Figure 1)(unpublished data, Bausch Health, 2018).

Efficacy and Safety of HP Lotion 0.01% in Moderate to Severe Plaque Psoriasis

Two articles have been published on the use of HP lotion 0.01% in moderate to severe psoriasis: 2 pivotal studies comparing once-daily application with vehicle lotion over 8 weeks (N=430),²⁰ and a comparative “label-restricted” 2-week study with HP lotion 0.01% and HP cream 0.05% (N=150).²¹

HP Lotion 0.01% Compared to Vehicle
Two multicenter, randomized, double-blind, vehicle-controlled phase 3 studies investigated the safety and efficacy of once-daily HP lotion 0.01% in moderate to severe plaque psoriasis (N=430).²⁰ Patients were treated with HP lotion 0.01% or vehicle (randomized in a 2:1 ratio) for 8 weeks, with a 4-week posttreatment follow-up. Treatment success (defined as at least a 2-grade improvement in baseline IGA score and a score equating to clear or almost clear) was significantly greater with HP lotion 0.01% at all assessment points (Figure 2)(P=.003 for week 2; P<.001 for other time points). At week 8, 37.4% of patients receiving HP lotion 0.01% were treatment successes compared to 10.0% of patients receiving vehicle (P<.001). Additionally, a 2-grade improvement from baseline for each psoriasis sign—erythema, plaque elevation, and scaling—was achieved by 42.2% of patients receiving HP lotion 0.01% at week 8 compared to 11.4% of patients receiving vehicle (P<.001). Good efficacy was maintained posttreatment that was significant compared to vehicle (P<.001).²⁰

There were corresponding reductions in body surface area (BSA) affected following treatment with HP lotion 0.01%.²⁰ At baseline, the mean BSA was 6.1 (range, 3–12). By week 8, there was a 35.2% reduction in BSA compared to 5.9% with vehicle. Again, a significant reduction in BSA was maintained posttreatment compared to vehicle (P<.001).²⁰

Halobetasol propionate lotion 0.01% was well tolerated with few treatment-related AEs.²⁰ Most AEs were application-site reactions such as dermatitis (0.7%), infection, pruritus, and discoloration (0.4% each). Mild to moderate itching, dryness, burning, and stinging present at baseline all improved with treatment, and severity of local skin reactions was significantly lower than with vehicle at week 8 (P<.001). Quality-of-life data also highlighted the benefits of active treatment compared to vehicle for cutaneous tolerability. The Dermatology Life Quality Index (DLQI) is a 10-item patient-reported questionnaire consisting of questions concerning symptoms and feelings, daily activities, leisure, work and school, personal relationships, and treatment.²² Change from baseline for DLQI (how itchy, sore, painful, stinging) was significantly greater with HP lotion 0.01% at weeks 4 and 8 (P<.001). Changes in the overall DLQI score also were significantly greater with HP lotion 0.01% at both study visits (P=.006 and P=.014 at week 4 and P=.001 and P=.004 at week 8 for study 1 and study 2, respectively).²⁰

HP Lotion 0.01% Compared to HP Cream 0.05%
Treatment success with HP lotion 0.01% also was shown to be comparable to the higher-concentration HP cream 0.05% in patients with moderate to severe psoriasis over a 2-week “label-restricted” treatment period (Figure 3). Both products were well tolerated over the 2-week treatment period. One patient reported application-site dermatitis (1.7%) with HP lotion 0.01%.²¹

Conclusion

Halobetasol propionate 0.05%—cream, ointment, and lotion—has been shown to be a highly effective short-term topical treatment for psoriasis. Longer-term treatment strategies using HP, which are important when considering management of a chronic condition, have been limited by safety concerns and labelling. However, there are data to suggest weekend or pulsed therapy may be an option.

A novel formulation of HP lotion 0.01% has been developed using a polymerized matrix with active ingredients and moisturizing excipients suspended in oil droplets. The polymerized honeycomb matrix and vehicle formulation form a barrier by reducing epidermal water loss and improving skin hydration. The oil droplets deliver uniform amounts of active ingredient in an optimal size for follicular penetration. Skin penetration has been shown to be quicker with greater retention in the epidermis with HP lotion 0.01% compared to HP cream 0.05%, with corresponding considerably lower penetration into the dermis.

Although there have been a number of clinical studies of HP for psoriasis, until recently there have been no comparative trials, with studies label restricted to a 2- to 4-week duration. Three clinical studies with HP lotion 0.01% have now been reported.Not only has HP lotion 0.01% been shown to be as effective as HP cream 0.05% in a 2-week comparative study (despite having one-fifth the concentration of HP), it also has been shown to be very effective and well tolerated following 8 weeks of daily use.^20,21 Further studies involving longer treatment durations are required to better elucidate AEs, but HP lotion 0.01% may provide the first longer-term TCS treatment solution for moderate to severe psoriasis.

Acknowledgments
We thank Brian Bulley, MSc (Konic Limited, United Kingdom), for assistance with the preparation of the manuscript. Ortho Dermatologics funded Konic’s activities pertaining to this manuscript.

In clinical practice, for the majority of patients with psoriasis superpotent topical corticosteroids (TCSs) are used as initial therapy as well as ongoing breakthrough therapy to achieve quick resolution of target lesions. However, safe and effective long-term treatment and maintenance options are required for managing the chronic nature of psoriasis to improve patient satisfaction, adherence, and quality of life, especially given that package inserts advise no more than 2 to 4 weeks of continuous use to limit side effects. The long-term use of superpotent TCSs can have a multitude of unwanted cutaneous side effects, such as skin atrophy, telangiectases, striae, and allergic vehicle responses.^1,2 Tachyphylaxis, a decreased response to treatment over time, has been more controversial and may not occur with halobetasol propionate (HP) ointment 0.05%.³ In addition, TCSs are associated with relapse or rebound on withdrawal, which can be problematic but are poorly characterized.

We review the clinical data on HP, a superpotent TCS, in the treatment of psoriasis. We also explore both recent formulation developments and fixed-combination approaches to providing optimal treatment.

Clinical Experience With HP 0.05% in Various Formulations

Halobetasol propionate is a superpotent TCS with extensive clinical experience in treating psoriasis spanning nearly 30 years.^1,2,3-7 Most recently, a twice-daily HP lotion 0.05% formulation was evaluated in patients with moderate to severe disease.⁸ Halobetasol propionate lotion 0.05% applied morning and night was shown to be significantly more effective than vehicle after 2 weeks of treatment (P<.001) in 2 parallel-group studies of 443 patients.⁹ Treatment success (ie, at least a 2-grade improvement in investigator global assessment [IGA] and IGA score of clear or almost clear) was achieved in 44.5% of patients treated with HP lotion 0.05% compared to 6.3% and 7.1% in the 2 vehicle arms. Treatment-related adverse events (AEs) were uncommon, with application-site pain reported in 2 patients treated with HP lotion 0.05% compared to 5 patients treated with vehicle.⁹

Several earlier studies have evaluated the short-term efficacy of twice-daily HP cream 0.05% and HP ointment 0.05% in the treatment of plaque psoriasis, but only 2 placebo-controlled trials have been reported, and data are limited.

Two 2-week studies of twice-daily HP ointment 0.05% (paired-comparison and parallel-group designs) in 204 patients with moderate plaque psoriasis reported improvement in plaque elevation, erythema, and scaling compared to vehicle. Patient global responses and physician global evaluation favored HP ointment 0.05%, and reports of stinging and burning were similar with active treatment and vehicle.⁴

Similarly, HP cream 0.05% applied twice daily was shown to be significantly superior to vehicle in reducing overall disease severity, erythema, plaque elevation, and scaling after 1 and 2 weeks of treatment in a paired-comparison study of 110 patients (P=.0001).⁵ A clinically significant reduction (at least a 1-grade improvement) in erythema, plaque elevation, pruritus, and scaling was noted in 81% to 92% of patients (P=.0001). Patients’ self-assessment of effectiveness rated HP cream 0.05% as excellent, very good, or good in 69% of patients compared to 20% for vehicle. Treatment-related AEs were reported by 4 patients.⁵

A small, noncontrolled, 2-week pediatric study (N=11) demonstrated the efficacy of combined therapy with HP cream 0.05% every morning and HP ointment 0.05% every night due to the then-perceived preference for creams as being more pleasant to apply during the day and ointments being more efficacious. Reported side effects were relatively mild, with application-site burning being the most common.¹⁰

Potential local AEs associated with HP are similar to those seen with other superpotent TCSs. Overall, they were reported in 0% to 13% of patients. The most common AEs were burning, pruritus, erythema, hypopigmentation, dryness, and folliculitis.^5-8,10-14 Isolated cases of moderate telangiectasia and mild atrophy also have been reported.^8,10

Comparative Studies With Other TCSs

In comparative studies of patients with severe localized plaque psoriasis, HP ointment 0.05% applied twice daily for up to 4 weeks was significantly superior compared to clobetasol propionate ointment 0.05% for the number of patients with none or mild disease (P=.023⁷) or comparisons of global evaluation scores (P=.013¹⁵) at week 2, or compared to betamethasone valerate ointment 0.1% (P=.02).⁶ It also was more effective than betamethasone dipropionate ointment 0.05% with healing seen in 40% of patients treated with HP ointment 0.05% within 24 days compared to 25% of patients treated with betamethasone dipropionate ointment 0.05%.⁸ Patient acceptance of HP ointment 0.05% based on cosmetic acceptability and ease of application was better (very good in 90% vs 80% of patients⁷) or significantly better compared to clobetasol propionate ointment 0.05% (P=.042 and P=.019¹⁵) and betamethasone dipropionate ointment 0.05% (P=.02).⁸

Evolving Management Strategies

A number of management strategies have been proposed to improve the safety and efficacy of long-term therapy with TCSs, including weekend-only or pulse therapy, dose reduction, rotating to another therapy, or combining with other topical therapies. Maintenance efficacy data are sparse. A small double-blind study in 44 patients with mild to moderate psoriasis was conducted wherein patients were treated with calcipotriene ointment in the morning and HP ointment in the evening for 2 weeks.¹⁶ Those patients who achieved at least a 50% improvement in disease severity (N=40) were randomized to receive HP ointment twice daily on weekends and calcipotriene ointment or placebo twice daily on weekdays for 6 months. Seventy-six percent of those patients treated with a HP/calcipotriene pulsed therapy maintained remission (achieving and maintaining a 75% improvement in physician global assessment) compared to 40% of those patients treated with HP only (P=.045). Mild AEs were reported in 4 patients treated with the combination regimen and 1 patient treated with HP only. No AE-related discontinuations occurred.¹⁶

In a real-world setting, a maintenance regimen that is less complicated enhances the potential for increased patient adherence and successful outcomes.¹⁷ After an initial 2-week regimen of twice-daily HP ointment 0.05% in combination with ammonium lactate lotion in patients with mild to moderate psoriasis (N=55), those rated clear or almost clear (41/55 [74.6%]) entered a maintenance phase, applying ammonium lactate lotion twice daily and either HP or placebo ointment twice daily on weekends. The probability of disease worsening by week 14 was 29% in the HP-treated group compared to 100% in the placebo group (P<.0001). By week 24, 12 patients (29.2%) remained clear or almost clear.¹⁷

Development of HP Lotion 0.01%

There are numerous examples in dermatology where advances in formulation development have made it possible to reduce the strength of active ingredients without compromising efficacy. Formulation advances also afford improved safety profiles that can extend a product’s utility. The vehicle affects not only the potency of an agent but also patient compliance, which is crucial for adequate response. Patients prefer lighter vehicles, such as lotions, over heavy ointments and creams.^18,19

Recently, a polymeric honeycomb matrix (carbomer cross-linked polymers), which helps structure the oil emulsion and provide a uniform distribution of both active and moisturizing/hydrating ingredients (ie, sorbitol, light mineral oil, diethyl sebacate) at the surface of the skin, has been deployed for topical delivery of HP (eFigure 1). Ninety percent of the oil droplets containing solubilized halobetasol are 13 µm or smaller, an ideal size for penetration through follicular openings (unpublished data, Bausch Health, 2018).

Comparison of Skin Penetration of HP Lotion 0.01% vs HP Cream 0.05%

Comparative percutaneous absorption of 2 HP formulations—0.01% lotion and 0.05% cream—was evaluated in vitro using human tissue from a single donor mounted on Bronaugh flow-through diffusion cells. Receptor phase samples were collected over the 24-hour study period and HP content assessed using liquid chromatography–mass spectrometry analysis. Halobetasol propionate lotion 0.01% demonstrated faster tissue permeation, with receptor phase levels of 0.91% of the applied dose at 24 hours compared to 0.28% of the applied dose with HP cream 0.05%. Although there was little differentiation of cumulative receptor fluid levels of HP at 6 hours, there was significant differentiation at 12 hours. Levels of HP were lowest in the receptor phase and highest in the epidermal layers of the skin, indicating limited permeation through the epidermis to the dermis. The mean (SD) for epidermal deposition of HP following the 24-hour duration of exposure was 6.17% (2.07%) and 1.72% (0.76%) for the 0.01% lotion and 0.05% cream, respectively (Figure 1)(unpublished data, Bausch Health, 2018).

Efficacy and Safety of HP Lotion 0.01% in Moderate to Severe Plaque Psoriasis

Two articles have been published on the use of HP lotion 0.01% in moderate to severe psoriasis: 2 pivotal studies comparing once-daily application with vehicle lotion over 8 weeks (N=430),²⁰ and a comparative “label-restricted” 2-week study with HP lotion 0.01% and HP cream 0.05% (N=150).²¹

HP Lotion 0.01% Compared to Vehicle
Two multicenter, randomized, double-blind, vehicle-controlled phase 3 studies investigated the safety and efficacy of once-daily HP lotion 0.01% in moderate to severe plaque psoriasis (N=430).²⁰ Patients were treated with HP lotion 0.01% or vehicle (randomized in a 2:1 ratio) for 8 weeks, with a 4-week posttreatment follow-up. Treatment success (defined as at least a 2-grade improvement in baseline IGA score and a score equating to clear or almost clear) was significantly greater with HP lotion 0.01% at all assessment points (Figure 2)(P=.003 for week 2; P<.001 for other time points). At week 8, 37.4% of patients receiving HP lotion 0.01% were treatment successes compared to 10.0% of patients receiving vehicle (P<.001). Additionally, a 2-grade improvement from baseline for each psoriasis sign—erythema, plaque elevation, and scaling—was achieved by 42.2% of patients receiving HP lotion 0.01% at week 8 compared to 11.4% of patients receiving vehicle (P<.001). Good efficacy was maintained posttreatment that was significant compared to vehicle (P<.001).²⁰

There were corresponding reductions in body surface area (BSA) affected following treatment with HP lotion 0.01%.²⁰ At baseline, the mean BSA was 6.1 (range, 3–12). By week 8, there was a 35.2% reduction in BSA compared to 5.9% with vehicle. Again, a significant reduction in BSA was maintained posttreatment compared to vehicle (P<.001).²⁰

Halobetasol propionate lotion 0.01% was well tolerated with few treatment-related AEs.²⁰ Most AEs were application-site reactions such as dermatitis (0.7%), infection, pruritus, and discoloration (0.4% each). Mild to moderate itching, dryness, burning, and stinging present at baseline all improved with treatment, and severity of local skin reactions was significantly lower than with vehicle at week 8 (P<.001). Quality-of-life data also highlighted the benefits of active treatment compared to vehicle for cutaneous tolerability. The Dermatology Life Quality Index (DLQI) is a 10-item patient-reported questionnaire consisting of questions concerning symptoms and feelings, daily activities, leisure, work and school, personal relationships, and treatment.²² Change from baseline for DLQI (how itchy, sore, painful, stinging) was significantly greater with HP lotion 0.01% at weeks 4 and 8 (P<.001). Changes in the overall DLQI score also were significantly greater with HP lotion 0.01% at both study visits (P=.006 and P=.014 at week 4 and P=.001 and P=.004 at week 8 for study 1 and study 2, respectively).²⁰

HP Lotion 0.01% Compared to HP Cream 0.05%
Treatment success with HP lotion 0.01% also was shown to be comparable to the higher-concentration HP cream 0.05% in patients with moderate to severe psoriasis over a 2-week “label-restricted” treatment period (Figure 3). Both products were well tolerated over the 2-week treatment period. One patient reported application-site dermatitis (1.7%) with HP lotion 0.01%.²¹

Conclusion

Halobetasol propionate 0.05%—cream, ointment, and lotion—has been shown to be a highly effective short-term topical treatment for psoriasis. Longer-term treatment strategies using HP, which are important when considering management of a chronic condition, have been limited by safety concerns and labelling. However, there are data to suggest weekend or pulsed therapy may be an option.

A novel formulation of HP lotion 0.01% has been developed using a polymerized matrix with active ingredients and moisturizing excipients suspended in oil droplets. The polymerized honeycomb matrix and vehicle formulation form a barrier by reducing epidermal water loss and improving skin hydration. The oil droplets deliver uniform amounts of active ingredient in an optimal size for follicular penetration. Skin penetration has been shown to be quicker with greater retention in the epidermis with HP lotion 0.01% compared to HP cream 0.05%, with corresponding considerably lower penetration into the dermis.

Although there have been a number of clinical studies of HP for psoriasis, until recently there have been no comparative trials, with studies label restricted to a 2- to 4-week duration. Three clinical studies with HP lotion 0.01% have now been reported.Not only has HP lotion 0.01% been shown to be as effective as HP cream 0.05% in a 2-week comparative study (despite having one-fifth the concentration of HP), it also has been shown to be very effective and well tolerated following 8 weeks of daily use.^20,21 Further studies involving longer treatment durations are required to better elucidate AEs, but HP lotion 0.01% may provide the first longer-term TCS treatment solution for moderate to severe psoriasis.

Acknowledgments
We thank Brian Bulley, MSc (Konic Limited, United Kingdom), for assistance with the preparation of the manuscript. Ortho Dermatologics funded Konic’s activities pertaining to this manuscript.

High-potency topical corticosteroids are first-line treatments for psoriasis, but many patients report that they are ineffective or lose effectiveness over time.^1-5 The mechanism underlying the lack or loss of activity is not well characterized but may be due to poor adherence to treatment. Adherence to topical treatment is poor in the short run and even worse in the long run.^6,7 We evaluated 12 patients with psoriasis resistant to topical corticosteroids to determine if they would respond to topical corticosteroids under conditions designed to promote adherence to treatment.

Methods

This open-label, randomized, single-center clinical study recruited 12 patients with plaque psoriasis that previously failed treatment with topical corticosteroids and other therapies (Table). We stratified disease by body surface area: mild (<3%), moderate (3%–10%), and severe (>10%). Inclusion criteria included adult patients with plaque psoriasis amenable to topical corticosteroid therapy, ability to comply with requirements of the study, and a history of failed topical corticosteroid treatment (Figure). Patients were excluded if they were pregnant, breastfeeding, had conditions that would affect adherence or potentially bias results (eg, dementia, Alzheimer disease), had a history of allergy or sensitivity to corticosteroids, and had a history of drug hypersensitivity.

All patients received desoximetasone spray 0.25% twice daily for 14 days. At the baseline visit, 6 patients were randomly selected to also receive a twice-daily reminder telephone call. Study visits occurred frequently—at baseline and on days 3, 7, and 14—to further assure good adherence to the treatment regimen.

During visits, disease severity was scored using the visual analog scale for pruritus, psoriasis area and severity index (PASI), total lesion severity score (TLSS), and investigator global assessment (IGA). Descriptive statistics were used to report the outcomes for each patient.

The study was designed to assess the number of topical treatment–resistant patients who would improve with topical treatment but was not designed or powered to test if the telephone call reminders increased adherence.

Results

All patients completed the study; 10 of 12 patients (83.3%) had previously used topical clobetasol and it failed (Table). At the 2-week end-of-study visit, most patients improved on all measures. Patients who received telephone call reminders improved more than patients who did not. All 12 patients (100%) reported relief of itching; 11 of 12 (91.7%) had an improved PASI; 10 of 12 (83.3%) had an improved TLSS; and 7 of 12 (58.3%) had an improved IGA (eTables 1 and 2).

The percentage reduction in pruritus ranged from 66.7% to 100% and 50.0% to 85.7% with and without telephone call reminders, respectively. Improvement in PASI ranged from 18.0% to 62.8% and 0% to 54.5% with and without telephone call reminders, respectively. Improvement in TLSS and IGA was of lower magnitude but showed a similar pattern, with numerically greater improvement in the telephone call reminders group compared to the group that was not called (eTable 2). No patients showed a worse score for pruritus on the visual analog scale, PASI, TLSS, or IGA.

Discussion

Topical corticosteroids are highly effective for psoriasis in clinical trials, with clearance in 2 to 4 weeks in 60% to 80% of patients, a rapidity of response not matched by even the most potent biologic treatments.^8,9 However, topical corticosteroids are not always effective in clinical practice. There may be primary inefficacy (they do not work at first) or secondary inefficacy (a previously effective treatment loses efficacy over time).¹⁰ Poor adherence can explain both phenomena. Primary adherence occurs when patients fill their prescription; secondary adherence occurs when patients follow the medication recommendations.¹¹ Primary nonadherence is common in patients with psoriasis; in one study, 50% of psoriasis prescriptions were not filled.¹² Secondary adherence also is poor and declines over time; electronic monitoring revealed adherence to topical treatments in psoriasis patients decreased from 85% initially to 51% at the end of 8 weeks.⁷ Given the high efficacy of topical corticosteroids in clinical trials and the poor adherence to topical treatment in patients with psoriasis, we anticipated that psoriasis that is resistant to topical corticosteroids would improve rapidly under conditions designed to promote adherence.

As expected, disease improved in almost every patient in this small cohort when they were given a potent topical corticosteroid, even though they previously reported that their psoriasis was resistant to potent topical corticosteroids. Although this study enrolled only a small cohort, it appears that the majority of patients with limited psoriasis that was reported to be resistant to topical treatment can see a response to topical treatment under conditions designed to encourage good adherence.

We believe that the good outcomes seen in our study were a result of good adherence. Although the desoximetasone spray 0.25% used in this study is a superpotent topical corticosteroid,⁸ the response to treatment was unlikely due to changing corticosteroid potency because 10 of 12 patients had tried another superpotent topical corticosteroid (clobetasol) and it failed. We chose a spray product for this study rather than an ointment to promote adherence; however, this choice limited the ability to assess adherence directly, as adherence-monitoring devices for spray delivery systems are not readily available.

Our study was limited by the small sample size and brief duration of treatment. However, the effect size is so large (ie, the topical treatment was so effective) that only a small sample size and brief treatment duration were needed to show that a high percentage of patients with psoriasis that had previously failed treatment with topical corticosteroids can in fact respond to this treatment.

We used telephone calls as reminders in 50% of patients to further encourage adherence. The study was not designed or powered to assess the effect of the telephone call reminders, but patients receiving those calls appeared to have slightly greater reduction in disease severity. Nonetheless, twice-daily telephone call reminders are unlikely to be a wanted or practical intervention; other approaches to encourage adherence are needed.

Frequent follow-up visits were incorporated in our study design to maximize adherence. Although it might not be feasible for clinical practices to schedule follow-up visits as often as in our study, other approaches such as virtual visits and electronic interaction might provide a practical alternative. Multifaceted approaches to increasing adherence include encouraging patients to participate in the treatment plan, prescribing therapy consistent with a patient’s preferred vehicle, and extensive patient education.¹³ If patients do not respond as expected, poor adherence can be considered. Other potential causes of poor outcomes include error in diagnosis; resistance to the prescribed treatment; concomitant infection; irritant exposure; and, in the case of biologics, antidrug antibody formation.^14,15

High-potency topical corticosteroids are first-line treatments for psoriasis, but many patients report that they are ineffective or lose effectiveness over time.^1-5 The mechanism underlying the lack or loss of activity is not well characterized but may be due to poor adherence to treatment. Adherence to topical treatment is poor in the short run and even worse in the long run.^6,7 We evaluated 12 patients with psoriasis resistant to topical corticosteroids to determine if they would respond to topical corticosteroids under conditions designed to promote adherence to treatment.

Methods

This open-label, randomized, single-center clinical study recruited 12 patients with plaque psoriasis that previously failed treatment with topical corticosteroids and other therapies (Table). We stratified disease by body surface area: mild (<3%), moderate (3%–10%), and severe (>10%). Inclusion criteria included adult patients with plaque psoriasis amenable to topical corticosteroid therapy, ability to comply with requirements of the study, and a history of failed topical corticosteroid treatment (Figure). Patients were excluded if they were pregnant, breastfeeding, had conditions that would affect adherence or potentially bias results (eg, dementia, Alzheimer disease), had a history of allergy or sensitivity to corticosteroids, and had a history of drug hypersensitivity.

All patients received desoximetasone spray 0.25% twice daily for 14 days. At the baseline visit, 6 patients were randomly selected to also receive a twice-daily reminder telephone call. Study visits occurred frequently—at baseline and on days 3, 7, and 14—to further assure good adherence to the treatment regimen.

During visits, disease severity was scored using the visual analog scale for pruritus, psoriasis area and severity index (PASI), total lesion severity score (TLSS), and investigator global assessment (IGA). Descriptive statistics were used to report the outcomes for each patient.

The study was designed to assess the number of topical treatment–resistant patients who would improve with topical treatment but was not designed or powered to test if the telephone call reminders increased adherence.

Results

All patients completed the study; 10 of 12 patients (83.3%) had previously used topical clobetasol and it failed (Table). At the 2-week end-of-study visit, most patients improved on all measures. Patients who received telephone call reminders improved more than patients who did not. All 12 patients (100%) reported relief of itching; 11 of 12 (91.7%) had an improved PASI; 10 of 12 (83.3%) had an improved TLSS; and 7 of 12 (58.3%) had an improved IGA (eTables 1 and 2).

The percentage reduction in pruritus ranged from 66.7% to 100% and 50.0% to 85.7% with and without telephone call reminders, respectively. Improvement in PASI ranged from 18.0% to 62.8% and 0% to 54.5% with and without telephone call reminders, respectively. Improvement in TLSS and IGA was of lower magnitude but showed a similar pattern, with numerically greater improvement in the telephone call reminders group compared to the group that was not called (eTable 2). No patients showed a worse score for pruritus on the visual analog scale, PASI, TLSS, or IGA.

Discussion

Topical corticosteroids are highly effective for psoriasis in clinical trials, with clearance in 2 to 4 weeks in 60% to 80% of patients, a rapidity of response not matched by even the most potent biologic treatments.^8,9 However, topical corticosteroids are not always effective in clinical practice. There may be primary inefficacy (they do not work at first) or secondary inefficacy (a previously effective treatment loses efficacy over time).¹⁰ Poor adherence can explain both phenomena. Primary adherence occurs when patients fill their prescription; secondary adherence occurs when patients follow the medication recommendations.¹¹ Primary nonadherence is common in patients with psoriasis; in one study, 50% of psoriasis prescriptions were not filled.¹² Secondary adherence also is poor and declines over time; electronic monitoring revealed adherence to topical treatments in psoriasis patients decreased from 85% initially to 51% at the end of 8 weeks.⁷ Given the high efficacy of topical corticosteroids in clinical trials and the poor adherence to topical treatment in patients with psoriasis, we anticipated that psoriasis that is resistant to topical corticosteroids would improve rapidly under conditions designed to promote adherence.

As expected, disease improved in almost every patient in this small cohort when they were given a potent topical corticosteroid, even though they previously reported that their psoriasis was resistant to potent topical corticosteroids. Although this study enrolled only a small cohort, it appears that the majority of patients with limited psoriasis that was reported to be resistant to topical treatment can see a response to topical treatment under conditions designed to encourage good adherence.

We believe that the good outcomes seen in our study were a result of good adherence. Although the desoximetasone spray 0.25% used in this study is a superpotent topical corticosteroid,⁸ the response to treatment was unlikely due to changing corticosteroid potency because 10 of 12 patients had tried another superpotent topical corticosteroid (clobetasol) and it failed. We chose a spray product for this study rather than an ointment to promote adherence; however, this choice limited the ability to assess adherence directly, as adherence-monitoring devices for spray delivery systems are not readily available.

Our study was limited by the small sample size and brief duration of treatment. However, the effect size is so large (ie, the topical treatment was so effective) that only a small sample size and brief treatment duration were needed to show that a high percentage of patients with psoriasis that had previously failed treatment with topical corticosteroids can in fact respond to this treatment.

We used telephone calls as reminders in 50% of patients to further encourage adherence. The study was not designed or powered to assess the effect of the telephone call reminders, but patients receiving those calls appeared to have slightly greater reduction in disease severity. Nonetheless, twice-daily telephone call reminders are unlikely to be a wanted or practical intervention; other approaches to encourage adherence are needed.

Frequent follow-up visits were incorporated in our study design to maximize adherence. Although it might not be feasible for clinical practices to schedule follow-up visits as often as in our study, other approaches such as virtual visits and electronic interaction might provide a practical alternative. Multifaceted approaches to increasing adherence include encouraging patients to participate in the treatment plan, prescribing therapy consistent with a patient’s preferred vehicle, and extensive patient education.¹³ If patients do not respond as expected, poor adherence can be considered. Other potential causes of poor outcomes include error in diagnosis; resistance to the prescribed treatment; concomitant infection; irritant exposure; and, in the case of biologics, antidrug antibody formation.^14,15

High-potency topical corticosteroids are first-line treatments for psoriasis, but many patients report that they are ineffective or lose effectiveness over time.^1-5 The mechanism underlying the lack or loss of activity is not well characterized but may be due to poor adherence to treatment. Adherence to topical treatment is poor in the short run and even worse in the long run.^6,7 We evaluated 12 patients with psoriasis resistant to topical corticosteroids to determine if they would respond to topical corticosteroids under conditions designed to promote adherence to treatment.

Methods

This open-label, randomized, single-center clinical study recruited 12 patients with plaque psoriasis that previously failed treatment with topical corticosteroids and other therapies (Table). We stratified disease by body surface area: mild (<3%), moderate (3%–10%), and severe (>10%). Inclusion criteria included adult patients with plaque psoriasis amenable to topical corticosteroid therapy, ability to comply with requirements of the study, and a history of failed topical corticosteroid treatment (Figure). Patients were excluded if they were pregnant, breastfeeding, had conditions that would affect adherence or potentially bias results (eg, dementia, Alzheimer disease), had a history of allergy or sensitivity to corticosteroids, and had a history of drug hypersensitivity.

All patients received desoximetasone spray 0.25% twice daily for 14 days. At the baseline visit, 6 patients were randomly selected to also receive a twice-daily reminder telephone call. Study visits occurred frequently—at baseline and on days 3, 7, and 14—to further assure good adherence to the treatment regimen.

During visits, disease severity was scored using the visual analog scale for pruritus, psoriasis area and severity index (PASI), total lesion severity score (TLSS), and investigator global assessment (IGA). Descriptive statistics were used to report the outcomes for each patient.

The study was designed to assess the number of topical treatment–resistant patients who would improve with topical treatment but was not designed or powered to test if the telephone call reminders increased adherence.

Results

All patients completed the study; 10 of 12 patients (83.3%) had previously used topical clobetasol and it failed (Table). At the 2-week end-of-study visit, most patients improved on all measures. Patients who received telephone call reminders improved more than patients who did not. All 12 patients (100%) reported relief of itching; 11 of 12 (91.7%) had an improved PASI; 10 of 12 (83.3%) had an improved TLSS; and 7 of 12 (58.3%) had an improved IGA (eTables 1 and 2).

The percentage reduction in pruritus ranged from 66.7% to 100% and 50.0% to 85.7% with and without telephone call reminders, respectively. Improvement in PASI ranged from 18.0% to 62.8% and 0% to 54.5% with and without telephone call reminders, respectively. Improvement in TLSS and IGA was of lower magnitude but showed a similar pattern, with numerically greater improvement in the telephone call reminders group compared to the group that was not called (eTable 2). No patients showed a worse score for pruritus on the visual analog scale, PASI, TLSS, or IGA.

Discussion

Topical corticosteroids are highly effective for psoriasis in clinical trials, with clearance in 2 to 4 weeks in 60% to 80% of patients, a rapidity of response not matched by even the most potent biologic treatments.^8,9 However, topical corticosteroids are not always effective in clinical practice. There may be primary inefficacy (they do not work at first) or secondary inefficacy (a previously effective treatment loses efficacy over time).¹⁰ Poor adherence can explain both phenomena. Primary adherence occurs when patients fill their prescription; secondary adherence occurs when patients follow the medication recommendations.¹¹ Primary nonadherence is common in patients with psoriasis; in one study, 50% of psoriasis prescriptions were not filled.¹² Secondary adherence also is poor and declines over time; electronic monitoring revealed adherence to topical treatments in psoriasis patients decreased from 85% initially to 51% at the end of 8 weeks.⁷ Given the high efficacy of topical corticosteroids in clinical trials and the poor adherence to topical treatment in patients with psoriasis, we anticipated that psoriasis that is resistant to topical corticosteroids would improve rapidly under conditions designed to promote adherence.

As expected, disease improved in almost every patient in this small cohort when they were given a potent topical corticosteroid, even though they previously reported that their psoriasis was resistant to potent topical corticosteroids. Although this study enrolled only a small cohort, it appears that the majority of patients with limited psoriasis that was reported to be resistant to topical treatment can see a response to topical treatment under conditions designed to encourage good adherence.

We believe that the good outcomes seen in our study were a result of good adherence. Although the desoximetasone spray 0.25% used in this study is a superpotent topical corticosteroid,⁸ the response to treatment was unlikely due to changing corticosteroid potency because 10 of 12 patients had tried another superpotent topical corticosteroid (clobetasol) and it failed. We chose a spray product for this study rather than an ointment to promote adherence; however, this choice limited the ability to assess adherence directly, as adherence-monitoring devices for spray delivery systems are not readily available.

Our study was limited by the small sample size and brief duration of treatment. However, the effect size is so large (ie, the topical treatment was so effective) that only a small sample size and brief treatment duration were needed to show that a high percentage of patients with psoriasis that had previously failed treatment with topical corticosteroids can in fact respond to this treatment.

We used telephone calls as reminders in 50% of patients to further encourage adherence. The study was not designed or powered to assess the effect of the telephone call reminders, but patients receiving those calls appeared to have slightly greater reduction in disease severity. Nonetheless, twice-daily telephone call reminders are unlikely to be a wanted or practical intervention; other approaches to encourage adherence are needed.

Frequent follow-up visits were incorporated in our study design to maximize adherence. Although it might not be feasible for clinical practices to schedule follow-up visits as often as in our study, other approaches such as virtual visits and electronic interaction might provide a practical alternative. Multifaceted approaches to increasing adherence include encouraging patients to participate in the treatment plan, prescribing therapy consistent with a patient’s preferred vehicle, and extensive patient education.¹³ If patients do not respond as expected, poor adherence can be considered. Other potential causes of poor outcomes include error in diagnosis; resistance to the prescribed treatment; concomitant infection; irritant exposure; and, in the case of biologics, antidrug antibody formation.^14,15

Psoriasis affects approximately 2% to 3% of the US population and is characterized by plaques that are red, scaly, and elevated.¹ Cutaneous symptoms of the disease are described by patients as itching, burning, and stinging sensations. Large multinational and US surveys have reported pruritus as patients’ most bothersome symptom, with scaling/flaking reported as the second most bothersome.^2,3 Reported incidence rates for itching range from 60.4% to 98.3%, with at least half of these patients reporting daily or constant pruritus.^2,4-7 Consequent effects on quality of life include impaired sleep,⁶ difficulty concentrating, lower sex drive, and depression.⁷ Despite these findings, pruritus is rarely included in the efficacy assessments of psoriasis treatments. In addition, 2 of the most commonly reported but difficult-to-treat locations for plaques are the outside of the elbows (45%) and the knees (32%),^1,2,8 areas where the stratum corneum typically is thicker, less hydrated, and less likely to absorb topical products.^9-11 Clinical studies have not focused specifically on these areas when assessing treatments.

Topical corticosteroids have been the mainstay of psoriasis therapy for decades because of their anti-inflammatory and antiproliferative properties.⁷ One large multinational physician survey indicated that 75% of patients are prescribed topical steroids,¹² which are important for first-line treatment and are often maintained as adjunctive therapy in combination with other treatments for patients with extensive disease or recalcitrant lesions.¹³ Topical corticosteroids are ranked into different classes based on their vasoconstrictor assay (VCA), a measure of skin blanching used as a marker for vasoconstriction. Topical agents with VCA ratings of mid-potency or superpotency are generally recommended for initial therapy, with superpotent agents required for the treatment of thick chronic plaques. However, longer durations of use may contribute to systemic absorption and adverse events.¹³ The vehicle composition is important for corticosteroid delivery and retention at the site of pathology, contributing to the efficacy of the steroid.^13,14 Selecting the appropriate steroid and vehicle is important to maximize efficacy and minimize adverse events.

Betamethasone dipropionate (BD) spray 0.05% is an emollient formulation of 0.05% BD that can be sprayed onto psoriatic plaques. The BD spray formulation was designed to penetrate the stratum corneum and be retained within the dermis and epidermis, the site of T-cell activity that drives the psoriatic disease process.¹⁴ In 2 phase 3 studies, BD spray demonstrated the ability to reduce the signs of plaque psoriasis with indication of improvement by day 4.^15,16 These studies also showed improvement in the local cutaneous symptoms of itching, burning and stinging, and pain. As a mid-potent steroid, BD spray displays less systemic absorption but similar efficacy compared to a superpotent augmented BD (AugBD) lotion in relieving the signs and symptoms of plaque psoriasis.^15-17

The objective of the current investigation was to assess the ability of BD spray to relieve itching and to clear plaque psoriasis on the knees and elbows utilizing post hoc analyses of the 2 phase 3 trials. The goal of these analyses was to demonstrate BD spray as effective at relieving the most troublesome signs and symptoms affecting patients with plaque psoriasis.

Methods

Study Design

Two phase 3 studies were conducted to demonstrate the efficacy and safety of BD spray.^15,16 The design of the studies was similar^15,16 to allow the data to be pooled for post hoc analyses.

Both were US multicenter, randomized, vehicle-controlled, double-blind, parallel-group studies comparing the safety and efficacy of BD spray 0.05% (Sernivo, Promius Pharma) with its vehicle formulation spray (identical to BD spray, but lacking the active steroid component).^15,16 One of the studies also compared BD spray with an AugBD lotion 0.05% (Diprolene,Merck & Co). Adults with moderate plaque psoriasis (investigator global assessment of 3; 10%–20% body surface area) were randomized to apply BD spray, vehicle spray, or AugBD lotion (1 study only) twice daily to all affected areas, excluding the face, scalp, and intertriginous areas for 28 days (BD spray and vehicle) or 14 days (AugBD lotion, per product label).¹⁵

Assessments

Two post hoc analyses were conducted on data pooled from the 2 phase 3 trials: (1) incidence of itching, and (2) total sign score (TSS) for lesions located on the knees and elbows.

Itching
Itching was assessed proactively by asking patients if they were experiencing itching (yes/no) at each visit (baseline and days 4, 8, 15, and 29) or had experienced itching since their last visit. As itching could be an adverse event of topical application, application-site pruritus was also recorded.

Total Sign Score
For each patient, a target plaque was selected that was representative of their psoriasis. The plaque was assessed on a 3-point grading scale for each of 3 key signs of plaque psoriasis: erythema, scaling, and plaque elevation (Table 1) at baseline and days 4, 8, 15, and 29. Total sign score was calculated by summing the scores for these 3 signs, resulting in a score ranging from 0 to 9. Treatment success was measured as (1) achieving a score of 0 or 1 (ie, reducing the plaque to clear or slight to mild) for the individual signs of erythema, scaling, and plaque elevation; and (2) achieving a TSS of 0 or 1 for all 3 signs—erythema, scaling, and plaque elevation—for each target lesion. Total sign score was assessed proactively for all patients.^15,16 The post hoc analysis reported here examined patients whose target lesion was located on either the knee or the elbow.

Statistical Analyses

Because both study protocols were identical, data were pooled from the 2 phase 3 trials. All statistical analyses were performed using SAS software (SAS Institute). Two-sided hypothesis testing was conducted for all analyses using a significance level of P=.05. Post hoc analyses used Fisher exact test. No imputations were made for missing data.

Statistical analyses of itching compared the incidence of itching at each assessment time point (baseline and days 4, 8, 15, and 29) between BD spray and vehicle and between BD spray and AugBD lotion. Additional analysis included a statistical test on the incidence of itching in the subgroup of patients who reported itching at baseline.

Statistical analyses for the knees and elbows included only patients with their target lesion located on either the knee or the elbow. Analyses compared BD spray with vehicle and BD spray with AugBD lotion at days 4, 8, 15, and 29. Comparison with AugBD lotion treatment was up to day 14 only, consistent with application time limits in the AugBD lotion product label.¹⁸

Results

Patients

These analyses included data from the 628 patients enrolled in the 2 phase 3 trials. Patients had similar baseline characteristics across treatment groups (Table 2). Itching was the most common cutaneous symptom at baseline, reported by almost two-thirds (n=392, 62.4%) of patients. Of the 628 patients, 236 (37.6%) had a target lesion located on the elbow or knee selected for assessment. The mean baseline body surface area was 13% to 14% across groups.

A post hoc analysis was performed on the subgroup of patients who reported itching at baseline (N=392)(eFigure 1). For these patients, almost half were itch free by day 4 across all groups (49.3% BD spray, 48.2% AugBD lotion, and 47.4% vehicle). By the end of treatment, 65.9% of patients using BD spray and 58.3% of patients using vehicle were itch free at day 29, with 56.9% of AugBD lotion patients itch free at day 15.

Psoriasis Individual Sign Scores for Knee and Elbow Plaques

Target lesions located on the knee or elbow represented 37.6% of all target lesions assessed. Efficacy analysis of the pooled data on knee and elbow lesions revealed that BD spray was similar to AugBD lotion in reducing sign scores to 0 or 1 (Figures 1 and 2).

The percentage of patients reporting improvements in erythema, scaling, and plaque elevation scores at day 4 were numerically but not statistically significantly greater with BD spray vs AugBD lotion (eFigure 2).

Total Sign Score

Total sign score results showed that the mean percentage of patients achieving a TSS of 0 or 1 for all signs for lesions located on the knees or elbows was numerically higher for BD spray vs AugBD lotion at day 4, but this difference was not statistically significant (Figure 2). Day 15 outcomes for TSS also showed a numerically greater success rate for BD spray, but again this difference was not statistically significant (53.4% BD spray vs 43.8% AugBD lotion). At days 15 and 29, significantly more patients treated with BD spray achieved TSS of 0 or 1 for all 3 signs compared to those treated with vehicle (P<.001). Improvement in TSS with BD spray continued through to day 29 of the study.

Comment

In these post hoc analyses, mid-potency BD spray demonstrated early relief of itching and early efficacy in the treatment of psoriasis plaques on the elbows and knees with minimal systemic absorption and a low rate of adverse events.

Betamethasone dipropionate spray and its vehicle formulation relieved psoriatic itching with similar efficacy to the superpotent AugBD steroid lotion. Notably, relief was rapid, with approximately half of responding patients reporting relief of itching by day 4. The results seen with vehicle suggest that the emollient formulation of BD spray is responsible for hydrating dry skin, contributing to the relief of this cutaneous symptom. Dry skin can exacerbate itching, and emollients are recognized as being able to alleviate itching by hydrating and soothing the skin.⁷

The second set of post hoc analyses reported here demonstrated that BD spray was efficacious in clearing the signs of psoriatic lesions on the difficult-to-treat areas of the knees and elbows. Efficacy with BD spray was similar to the superpotent steroid AugBD lotion, with no statistical difference between the 2 products at any time point. Betamethasone dipropionate spray was significantly more effective than its vehicle in reducing the signs of erythema and scaling from day 8 and plaque elevation from day 15.

Rapid relief of symptoms is important for patient comfort and to improve treatment adherence. These analyses showed that by day 4, BD spray resulted in numerically higher percentages of patients achieving a score of 0 or 1 for the individual signs of erythema, scaling, and plaque elevation compared to AugBD lotion. Of particular note, 37.6% of patients treated with BD spray had scaling scores of clear or almost clear by day 4 compared to 25.0% of patients treated with AugBD lotion. Scaling has been consistently reported as the second most bothersome symptom experienced by patients^2,3 and has been shown to be associated with decreased quality of life and work productivity.¹⁹

Betamethasone dipropionate spray has a rationally designed vehicle, with the formulation selected specifically to maximize penetration of the product through the stratum corneum and retention of BD steroid in the epidermis and upper dermis while reducing absorption into the systemic circulation.¹⁴ The reduced absorption into the systemic circulation leads to less vasoconstriction; fewer adverse events; and a “medium potent” VCA designation compared to the “superpotent” designation of the AugBD formulation, despite containing the same active ingredient.

These analyses demonstrate that BD spray is effective at addressing 2 symptoms that patients with psoriasis consider most bothersome: itching and scaling. Notably, BD spray was able to achieve these results rapidly, with many patients experiencing improvements in 4 days. In these analyses, mid-potent BD spray demonstrated similar efficacy to AugBD lotion, a superpotent steroid formulation.

This analysis is limited by being post hoc. Although the statistical methodology is valid, the AugBD lotion arm of the analyses was relatively small compared with the BD spray and vehicle arms, as it was only included in 1 of 2 studies pooled.

Conclusion

Mid-potency BD spray effectively improved the symptom of itching and cleared hard-to-treat lesions on knees and elbows with efficacy similar to a superpotent AugBD formulation but with less systemic absorption. Improvements were seen in erythema, scaling, and plaque elevation. Reductions in psoriatic signs were observed as early as day 4, with continued improvement seen throughout the study period. These findings provide evidence that BD spray can rapidly relieve 2 of the most troublesome symptoms affecting patients with psoriasis (itching and scaling), potentially improving quality of life.

Acknowledgments
The authors wish to thank Alix Bennett, PhD, formerly of Promius Pharma, a subsidiary of Dr. Reddy’s Laboratories, Inc (Princeton, New Jersey), and Jodie Macoun, PhD, of CUBE Information (Katonah, New York), for their review and assistance with the preparation of this manuscript. Manuscript preparation was supported by Promius Pharma (Princeton, New Jersey)(DRL #866).

Psoriasis affects approximately 2% to 3% of the US population and is characterized by plaques that are red, scaly, and elevated.¹ Cutaneous symptoms of the disease are described by patients as itching, burning, and stinging sensations. Large multinational and US surveys have reported pruritus as patients’ most bothersome symptom, with scaling/flaking reported as the second most bothersome.^2,3 Reported incidence rates for itching range from 60.4% to 98.3%, with at least half of these patients reporting daily or constant pruritus.^2,4-7 Consequent effects on quality of life include impaired sleep,⁶ difficulty concentrating, lower sex drive, and depression.⁷ Despite these findings, pruritus is rarely included in the efficacy assessments of psoriasis treatments. In addition, 2 of the most commonly reported but difficult-to-treat locations for plaques are the outside of the elbows (45%) and the knees (32%),^1,2,8 areas where the stratum corneum typically is thicker, less hydrated, and less likely to absorb topical products.^9-11 Clinical studies have not focused specifically on these areas when assessing treatments.

Topical corticosteroids have been the mainstay of psoriasis therapy for decades because of their anti-inflammatory and antiproliferative properties.⁷ One large multinational physician survey indicated that 75% of patients are prescribed topical steroids,¹² which are important for first-line treatment and are often maintained as adjunctive therapy in combination with other treatments for patients with extensive disease or recalcitrant lesions.¹³ Topical corticosteroids are ranked into different classes based on their vasoconstrictor assay (VCA), a measure of skin blanching used as a marker for vasoconstriction. Topical agents with VCA ratings of mid-potency or superpotency are generally recommended for initial therapy, with superpotent agents required for the treatment of thick chronic plaques. However, longer durations of use may contribute to systemic absorption and adverse events.¹³ The vehicle composition is important for corticosteroid delivery and retention at the site of pathology, contributing to the efficacy of the steroid.^13,14 Selecting the appropriate steroid and vehicle is important to maximize efficacy and minimize adverse events.

Betamethasone dipropionate (BD) spray 0.05% is an emollient formulation of 0.05% BD that can be sprayed onto psoriatic plaques. The BD spray formulation was designed to penetrate the stratum corneum and be retained within the dermis and epidermis, the site of T-cell activity that drives the psoriatic disease process.¹⁴ In 2 phase 3 studies, BD spray demonstrated the ability to reduce the signs of plaque psoriasis with indication of improvement by day 4.^15,16 These studies also showed improvement in the local cutaneous symptoms of itching, burning and stinging, and pain. As a mid-potent steroid, BD spray displays less systemic absorption but similar efficacy compared to a superpotent augmented BD (AugBD) lotion in relieving the signs and symptoms of plaque psoriasis.^15-17

The objective of the current investigation was to assess the ability of BD spray to relieve itching and to clear plaque psoriasis on the knees and elbows utilizing post hoc analyses of the 2 phase 3 trials. The goal of these analyses was to demonstrate BD spray as effective at relieving the most troublesome signs and symptoms affecting patients with plaque psoriasis.

Methods

Study Design

Two phase 3 studies were conducted to demonstrate the efficacy and safety of BD spray.^15,16 The design of the studies was similar^15,16 to allow the data to be pooled for post hoc analyses.

Both were US multicenter, randomized, vehicle-controlled, double-blind, parallel-group studies comparing the safety and efficacy of BD spray 0.05% (Sernivo, Promius Pharma) with its vehicle formulation spray (identical to BD spray, but lacking the active steroid component).^15,16 One of the studies also compared BD spray with an AugBD lotion 0.05% (Diprolene,Merck & Co). Adults with moderate plaque psoriasis (investigator global assessment of 3; 10%–20% body surface area) were randomized to apply BD spray, vehicle spray, or AugBD lotion (1 study only) twice daily to all affected areas, excluding the face, scalp, and intertriginous areas for 28 days (BD spray and vehicle) or 14 days (AugBD lotion, per product label).¹⁵

Assessments

Two post hoc analyses were conducted on data pooled from the 2 phase 3 trials: (1) incidence of itching, and (2) total sign score (TSS) for lesions located on the knees and elbows.

Itching
Itching was assessed proactively by asking patients if they were experiencing itching (yes/no) at each visit (baseline and days 4, 8, 15, and 29) or had experienced itching since their last visit. As itching could be an adverse event of topical application, application-site pruritus was also recorded.

Total Sign Score
For each patient, a target plaque was selected that was representative of their psoriasis. The plaque was assessed on a 3-point grading scale for each of 3 key signs of plaque psoriasis: erythema, scaling, and plaque elevation (Table 1) at baseline and days 4, 8, 15, and 29. Total sign score was calculated by summing the scores for these 3 signs, resulting in a score ranging from 0 to 9. Treatment success was measured as (1) achieving a score of 0 or 1 (ie, reducing the plaque to clear or slight to mild) for the individual signs of erythema, scaling, and plaque elevation; and (2) achieving a TSS of 0 or 1 for all 3 signs—erythema, scaling, and plaque elevation—for each target lesion. Total sign score was assessed proactively for all patients.^15,16 The post hoc analysis reported here examined patients whose target lesion was located on either the knee or the elbow.

Statistical Analyses

Because both study protocols were identical, data were pooled from the 2 phase 3 trials. All statistical analyses were performed using SAS software (SAS Institute). Two-sided hypothesis testing was conducted for all analyses using a significance level of P=.05. Post hoc analyses used Fisher exact test. No imputations were made for missing data.

Statistical analyses of itching compared the incidence of itching at each assessment time point (baseline and days 4, 8, 15, and 29) between BD spray and vehicle and between BD spray and AugBD lotion. Additional analysis included a statistical test on the incidence of itching in the subgroup of patients who reported itching at baseline.

Statistical analyses for the knees and elbows included only patients with their target lesion located on either the knee or the elbow. Analyses compared BD spray with vehicle and BD spray with AugBD lotion at days 4, 8, 15, and 29. Comparison with AugBD lotion treatment was up to day 14 only, consistent with application time limits in the AugBD lotion product label.¹⁸

Results

Patients

These analyses included data from the 628 patients enrolled in the 2 phase 3 trials. Patients had similar baseline characteristics across treatment groups (Table 2). Itching was the most common cutaneous symptom at baseline, reported by almost two-thirds (n=392, 62.4%) of patients. Of the 628 patients, 236 (37.6%) had a target lesion located on the elbow or knee selected for assessment. The mean baseline body surface area was 13% to 14% across groups.

A post hoc analysis was performed on the subgroup of patients who reported itching at baseline (N=392)(eFigure 1). For these patients, almost half were itch free by day 4 across all groups (49.3% BD spray, 48.2% AugBD lotion, and 47.4% vehicle). By the end of treatment, 65.9% of patients using BD spray and 58.3% of patients using vehicle were itch free at day 29, with 56.9% of AugBD lotion patients itch free at day 15.

Psoriasis Individual Sign Scores for Knee and Elbow Plaques

Target lesions located on the knee or elbow represented 37.6% of all target lesions assessed. Efficacy analysis of the pooled data on knee and elbow lesions revealed that BD spray was similar to AugBD lotion in reducing sign scores to 0 or 1 (Figures 1 and 2).

The percentage of patients reporting improvements in erythema, scaling, and plaque elevation scores at day 4 were numerically but not statistically significantly greater with BD spray vs AugBD lotion (eFigure 2).

Total Sign Score

Total sign score results showed that the mean percentage of patients achieving a TSS of 0 or 1 for all signs for lesions located on the knees or elbows was numerically higher for BD spray vs AugBD lotion at day 4, but this difference was not statistically significant (Figure 2). Day 15 outcomes for TSS also showed a numerically greater success rate for BD spray, but again this difference was not statistically significant (53.4% BD spray vs 43.8% AugBD lotion). At days 15 and 29, significantly more patients treated with BD spray achieved TSS of 0 or 1 for all 3 signs compared to those treated with vehicle (P<.001). Improvement in TSS with BD spray continued through to day 29 of the study.

Comment

In these post hoc analyses, mid-potency BD spray demonstrated early relief of itching and early efficacy in the treatment of psoriasis plaques on the elbows and knees with minimal systemic absorption and a low rate of adverse events.

Betamethasone dipropionate spray and its vehicle formulation relieved psoriatic itching with similar efficacy to the superpotent AugBD steroid lotion. Notably, relief was rapid, with approximately half of responding patients reporting relief of itching by day 4. The results seen with vehicle suggest that the emollient formulation of BD spray is responsible for hydrating dry skin, contributing to the relief of this cutaneous symptom. Dry skin can exacerbate itching, and emollients are recognized as being able to alleviate itching by hydrating and soothing the skin.⁷

The second set of post hoc analyses reported here demonstrated that BD spray was efficacious in clearing the signs of psoriatic lesions on the difficult-to-treat areas of the knees and elbows. Efficacy with BD spray was similar to the superpotent steroid AugBD lotion, with no statistical difference between the 2 products at any time point. Betamethasone dipropionate spray was significantly more effective than its vehicle in reducing the signs of erythema and scaling from day 8 and plaque elevation from day 15.

Rapid relief of symptoms is important for patient comfort and to improve treatment adherence. These analyses showed that by day 4, BD spray resulted in numerically higher percentages of patients achieving a score of 0 or 1 for the individual signs of erythema, scaling, and plaque elevation compared to AugBD lotion. Of particular note, 37.6% of patients treated with BD spray had scaling scores of clear or almost clear by day 4 compared to 25.0% of patients treated with AugBD lotion. Scaling has been consistently reported as the second most bothersome symptom experienced by patients^2,3 and has been shown to be associated with decreased quality of life and work productivity.¹⁹

Betamethasone dipropionate spray has a rationally designed vehicle, with the formulation selected specifically to maximize penetration of the product through the stratum corneum and retention of BD steroid in the epidermis and upper dermis while reducing absorption into the systemic circulation.¹⁴ The reduced absorption into the systemic circulation leads to less vasoconstriction; fewer adverse events; and a “medium potent” VCA designation compared to the “superpotent” designation of the AugBD formulation, despite containing the same active ingredient.

These analyses demonstrate that BD spray is effective at addressing 2 symptoms that patients with psoriasis consider most bothersome: itching and scaling. Notably, BD spray was able to achieve these results rapidly, with many patients experiencing improvements in 4 days. In these analyses, mid-potent BD spray demonstrated similar efficacy to AugBD lotion, a superpotent steroid formulation.

This analysis is limited by being post hoc. Although the statistical methodology is valid, the AugBD lotion arm of the analyses was relatively small compared with the BD spray and vehicle arms, as it was only included in 1 of 2 studies pooled.

Conclusion

Mid-potency BD spray effectively improved the symptom of itching and cleared hard-to-treat lesions on knees and elbows with efficacy similar to a superpotent AugBD formulation but with less systemic absorption. Improvements were seen in erythema, scaling, and plaque elevation. Reductions in psoriatic signs were observed as early as day 4, with continued improvement seen throughout the study period. These findings provide evidence that BD spray can rapidly relieve 2 of the most troublesome symptoms affecting patients with psoriasis (itching and scaling), potentially improving quality of life.

Acknowledgments
The authors wish to thank Alix Bennett, PhD, formerly of Promius Pharma, a subsidiary of Dr. Reddy’s Laboratories, Inc (Princeton, New Jersey), and Jodie Macoun, PhD, of CUBE Information (Katonah, New York), for their review and assistance with the preparation of this manuscript. Manuscript preparation was supported by Promius Pharma (Princeton, New Jersey)(DRL #866).

Psoriasis affects approximately 2% to 3% of the US population and is characterized by plaques that are red, scaly, and elevated.¹ Cutaneous symptoms of the disease are described by patients as itching, burning, and stinging sensations. Large multinational and US surveys have reported pruritus as patients’ most bothersome symptom, with scaling/flaking reported as the second most bothersome.^2,3 Reported incidence rates for itching range from 60.4% to 98.3%, with at least half of these patients reporting daily or constant pruritus.^2,4-7 Consequent effects on quality of life include impaired sleep,⁶ difficulty concentrating, lower sex drive, and depression.⁷ Despite these findings, pruritus is rarely included in the efficacy assessments of psoriasis treatments. In addition, 2 of the most commonly reported but difficult-to-treat locations for plaques are the outside of the elbows (45%) and the knees (32%),^1,2,8 areas where the stratum corneum typically is thicker, less hydrated, and less likely to absorb topical products.^9-11 Clinical studies have not focused specifically on these areas when assessing treatments.

Topical corticosteroids have been the mainstay of psoriasis therapy for decades because of their anti-inflammatory and antiproliferative properties.⁷ One large multinational physician survey indicated that 75% of patients are prescribed topical steroids,¹² which are important for first-line treatment and are often maintained as adjunctive therapy in combination with other treatments for patients with extensive disease or recalcitrant lesions.¹³ Topical corticosteroids are ranked into different classes based on their vasoconstrictor assay (VCA), a measure of skin blanching used as a marker for vasoconstriction. Topical agents with VCA ratings of mid-potency or superpotency are generally recommended for initial therapy, with superpotent agents required for the treatment of thick chronic plaques. However, longer durations of use may contribute to systemic absorption and adverse events.¹³ The vehicle composition is important for corticosteroid delivery and retention at the site of pathology, contributing to the efficacy of the steroid.^13,14 Selecting the appropriate steroid and vehicle is important to maximize efficacy and minimize adverse events.

Betamethasone dipropionate (BD) spray 0.05% is an emollient formulation of 0.05% BD that can be sprayed onto psoriatic plaques. The BD spray formulation was designed to penetrate the stratum corneum and be retained within the dermis and epidermis, the site of T-cell activity that drives the psoriatic disease process.¹⁴ In 2 phase 3 studies, BD spray demonstrated the ability to reduce the signs of plaque psoriasis with indication of improvement by day 4.^15,16 These studies also showed improvement in the local cutaneous symptoms of itching, burning and stinging, and pain. As a mid-potent steroid, BD spray displays less systemic absorption but similar efficacy compared to a superpotent augmented BD (AugBD) lotion in relieving the signs and symptoms of plaque psoriasis.^15-17

The objective of the current investigation was to assess the ability of BD spray to relieve itching and to clear plaque psoriasis on the knees and elbows utilizing post hoc analyses of the 2 phase 3 trials. The goal of these analyses was to demonstrate BD spray as effective at relieving the most troublesome signs and symptoms affecting patients with plaque psoriasis.

Methods

Study Design

Two phase 3 studies were conducted to demonstrate the efficacy and safety of BD spray.^15,16 The design of the studies was similar^15,16 to allow the data to be pooled for post hoc analyses.

Both were US multicenter, randomized, vehicle-controlled, double-blind, parallel-group studies comparing the safety and efficacy of BD spray 0.05% (Sernivo, Promius Pharma) with its vehicle formulation spray (identical to BD spray, but lacking the active steroid component).^15,16 One of the studies also compared BD spray with an AugBD lotion 0.05% (Diprolene,Merck & Co). Adults with moderate plaque psoriasis (investigator global assessment of 3; 10%–20% body surface area) were randomized to apply BD spray, vehicle spray, or AugBD lotion (1 study only) twice daily to all affected areas, excluding the face, scalp, and intertriginous areas for 28 days (BD spray and vehicle) or 14 days (AugBD lotion, per product label).¹⁵

Assessments

Two post hoc analyses were conducted on data pooled from the 2 phase 3 trials: (1) incidence of itching, and (2) total sign score (TSS) for lesions located on the knees and elbows.

Itching
Itching was assessed proactively by asking patients if they were experiencing itching (yes/no) at each visit (baseline and days 4, 8, 15, and 29) or had experienced itching since their last visit. As itching could be an adverse event of topical application, application-site pruritus was also recorded.

Total Sign Score
For each patient, a target plaque was selected that was representative of their psoriasis. The plaque was assessed on a 3-point grading scale for each of 3 key signs of plaque psoriasis: erythema, scaling, and plaque elevation (Table 1) at baseline and days 4, 8, 15, and 29. Total sign score was calculated by summing the scores for these 3 signs, resulting in a score ranging from 0 to 9. Treatment success was measured as (1) achieving a score of 0 or 1 (ie, reducing the plaque to clear or slight to mild) for the individual signs of erythema, scaling, and plaque elevation; and (2) achieving a TSS of 0 or 1 for all 3 signs—erythema, scaling, and plaque elevation—for each target lesion. Total sign score was assessed proactively for all patients.^15,16 The post hoc analysis reported here examined patients whose target lesion was located on either the knee or the elbow.

Statistical Analyses

Because both study protocols were identical, data were pooled from the 2 phase 3 trials. All statistical analyses were performed using SAS software (SAS Institute). Two-sided hypothesis testing was conducted for all analyses using a significance level of P=.05. Post hoc analyses used Fisher exact test. No imputations were made for missing data.

Statistical analyses of itching compared the incidence of itching at each assessment time point (baseline and days 4, 8, 15, and 29) between BD spray and vehicle and between BD spray and AugBD lotion. Additional analysis included a statistical test on the incidence of itching in the subgroup of patients who reported itching at baseline.

Statistical analyses for the knees and elbows included only patients with their target lesion located on either the knee or the elbow. Analyses compared BD spray with vehicle and BD spray with AugBD lotion at days 4, 8, 15, and 29. Comparison with AugBD lotion treatment was up to day 14 only, consistent with application time limits in the AugBD lotion product label.¹⁸

Results

Patients

These analyses included data from the 628 patients enrolled in the 2 phase 3 trials. Patients had similar baseline characteristics across treatment groups (Table 2). Itching was the most common cutaneous symptom at baseline, reported by almost two-thirds (n=392, 62.4%) of patients. Of the 628 patients, 236 (37.6%) had a target lesion located on the elbow or knee selected for assessment. The mean baseline body surface area was 13% to 14% across groups.

A post hoc analysis was performed on the subgroup of patients who reported itching at baseline (N=392)(eFigure 1). For these patients, almost half were itch free by day 4 across all groups (49.3% BD spray, 48.2% AugBD lotion, and 47.4% vehicle). By the end of treatment, 65.9% of patients using BD spray and 58.3% of patients using vehicle were itch free at day 29, with 56.9% of AugBD lotion patients itch free at day 15.

Psoriasis Individual Sign Scores for Knee and Elbow Plaques

Target lesions located on the knee or elbow represented 37.6% of all target lesions assessed. Efficacy analysis of the pooled data on knee and elbow lesions revealed that BD spray was similar to AugBD lotion in reducing sign scores to 0 or 1 (Figures 1 and 2).

The percentage of patients reporting improvements in erythema, scaling, and plaque elevation scores at day 4 were numerically but not statistically significantly greater with BD spray vs AugBD lotion (eFigure 2).

Total Sign Score

Total sign score results showed that the mean percentage of patients achieving a TSS of 0 or 1 for all signs for lesions located on the knees or elbows was numerically higher for BD spray vs AugBD lotion at day 4, but this difference was not statistically significant (Figure 2). Day 15 outcomes for TSS also showed a numerically greater success rate for BD spray, but again this difference was not statistically significant (53.4% BD spray vs 43.8% AugBD lotion). At days 15 and 29, significantly more patients treated with BD spray achieved TSS of 0 or 1 for all 3 signs compared to those treated with vehicle (P<.001). Improvement in TSS with BD spray continued through to day 29 of the study.

Comment

In these post hoc analyses, mid-potency BD spray demonstrated early relief of itching and early efficacy in the treatment of psoriasis plaques on the elbows and knees with minimal systemic absorption and a low rate of adverse events.

Betamethasone dipropionate spray and its vehicle formulation relieved psoriatic itching with similar efficacy to the superpotent AugBD steroid lotion. Notably, relief was rapid, with approximately half of responding patients reporting relief of itching by day 4. The results seen with vehicle suggest that the emollient formulation of BD spray is responsible for hydrating dry skin, contributing to the relief of this cutaneous symptom. Dry skin can exacerbate itching, and emollients are recognized as being able to alleviate itching by hydrating and soothing the skin.⁷

The second set of post hoc analyses reported here demonstrated that BD spray was efficacious in clearing the signs of psoriatic lesions on the difficult-to-treat areas of the knees and elbows. Efficacy with BD spray was similar to the superpotent steroid AugBD lotion, with no statistical difference between the 2 products at any time point. Betamethasone dipropionate spray was significantly more effective than its vehicle in reducing the signs of erythema and scaling from day 8 and plaque elevation from day 15.

Rapid relief of symptoms is important for patient comfort and to improve treatment adherence. These analyses showed that by day 4, BD spray resulted in numerically higher percentages of patients achieving a score of 0 or 1 for the individual signs of erythema, scaling, and plaque elevation compared to AugBD lotion. Of particular note, 37.6% of patients treated with BD spray had scaling scores of clear or almost clear by day 4 compared to 25.0% of patients treated with AugBD lotion. Scaling has been consistently reported as the second most bothersome symptom experienced by patients^2,3 and has been shown to be associated with decreased quality of life and work productivity.¹⁹

Betamethasone dipropionate spray has a rationally designed vehicle, with the formulation selected specifically to maximize penetration of the product through the stratum corneum and retention of BD steroid in the epidermis and upper dermis while reducing absorption into the systemic circulation.¹⁴ The reduced absorption into the systemic circulation leads to less vasoconstriction; fewer adverse events; and a “medium potent” VCA designation compared to the “superpotent” designation of the AugBD formulation, despite containing the same active ingredient.

These analyses demonstrate that BD spray is effective at addressing 2 symptoms that patients with psoriasis consider most bothersome: itching and scaling. Notably, BD spray was able to achieve these results rapidly, with many patients experiencing improvements in 4 days. In these analyses, mid-potent BD spray demonstrated similar efficacy to AugBD lotion, a superpotent steroid formulation.

This analysis is limited by being post hoc. Although the statistical methodology is valid, the AugBD lotion arm of the analyses was relatively small compared with the BD spray and vehicle arms, as it was only included in 1 of 2 studies pooled.

Conclusion

Mid-potency BD spray effectively improved the symptom of itching and cleared hard-to-treat lesions on knees and elbows with efficacy similar to a superpotent AugBD formulation but with less systemic absorption. Improvements were seen in erythema, scaling, and plaque elevation. Reductions in psoriatic signs were observed as early as day 4, with continued improvement seen throughout the study period. These findings provide evidence that BD spray can rapidly relieve 2 of the most troublesome symptoms affecting patients with psoriasis (itching and scaling), potentially improving quality of life.

Acknowledgments
The authors wish to thank Alix Bennett, PhD, formerly of Promius Pharma, a subsidiary of Dr. Reddy’s Laboratories, Inc (Princeton, New Jersey), and Jodie Macoun, PhD, of CUBE Information (Katonah, New York), for their review and assistance with the preparation of this manuscript. Manuscript preparation was supported by Promius Pharma (Princeton, New Jersey)(DRL #866).

The personal statement is a narrative written by an applicant to residency programs to discuss his/her interests. It is one of the few places in the residency application process where applicants can express their personalities.¹ Applicants believe the personal statement is an important opportunity to distinguish themselves from others, thus increasing their chances of successful matching, particularly in competitive specialties.^1,2

Dermatology is a highly competitive specialty, with 614 medical students applying for 440 total dermatology positions in 2016.³ According to the results of the 2016 National Resident Matching program director survey, 82% (27/33) of dermatology program directors reported that the personal statement was a factor in selecting applicants to interview. Furthermore, dermatology program directors, on average, rated personal statements as more important than the Medical Student Performance Evaluation/Dean’s Letter, US Medical Licensing Examination (USMLE) Step 2 scores, and class ranking/quartile.⁴

Prior studies have sought to evaluate the impact of personal statements on the application process. A 2014 study of personal statements submitted by dermatology residency applicants found that the prevalence of certain themes differed according to match outcome.⁵ However, some of the conclusions drawn in this study were not supported by the reported results or were based on low numbers of participants. The purpose of our study was to examine personal statements from applications to a dermatology program at a major academic institution. This study identified common themes in personal statements, allowing for an analysis of their association with successful matching into dermatology.

Methods

All applications to the dermatology residency program at UNC School of Medicine (Chapel Hill, North Carolina) during the 2012 application cycle (N=422) were eligible. All submitted personal statements (N=422) were included with all personal identifiers removed prior to analysis. The investigator (D.S.M.) was blinded to other Electronic Residency Application Service data and match outcome.

The investigator initially reviewed a small, randomly selected subset of 20 personal statements to identify characteristics and common themes. The investigator then analyzed each of the personal statements to quantify the frequency of each theme. All personal statements submitted to the dermatology residency program at UNC School of Medicine were analyzed in this manner. Dermatology match outcomes for each applicant were confirmed later using dermatology program websites.

Differences in the prevalence of common themes between matched and unmatched applicants were calculated. Analysis of variance tests were used to determine if the differences in prevalence were statistically significant (P≤.05).

Results

All 422 submitted personal statements were evaluated, with 308 personal statements from applicants who matched and 114 personal statements from unmatched applicants. The screening of the initial subset of 20 personal statements resulted in a total of 9 content themes. The prevalence of each theme among matched and unmatched applicants is shown in the Table.

The most common themes among both matched and unmatched groups were personal accomplishments or attributes and positive qualities of dermatology. The prevalence of certain themes varied between matched and unmatched groups. Dermatologic cases were discussed significantly more frequently in the matched group compared to the unmatched group (60.06% vs 46.49%, P=.013). Name-dropping was more prevalent in the unmatched group (37.72%) compared to the matched group (26.95%). This difference in prevalence reached statistical significance (P=.014). Religious influences also were discussed more frequently in the unmatched group (5.26%) vs the matched group (0.65%) with statistical significance (P=.002).

Comment

This study of 422 personal statements submitted to a major academic institution showed that certain themes were common in personal statements among both matched and unmatched applicants. These themes included personal accomplishments/attributes and positive qualities of dermatology. This finding is consistent with prior studies that show common themes in the personal statements of applicants across a wide variety of specialties, including dermatology, anesthesiology, pediatrics, general surgery, internal medicine, and radiology.^5-10 Most commonly, applicants feel the need to justify why they chose their particular specialty, with Olazagasti et al⁵ (N=332) reporting that 70% of submitted dermatology personal statements explained why the applicant chose dermatology.

Certain themes, however, varied in prevalence between matched and unmatched groups in our study. Discussion of dermatologic cases was significantly more prevalent in the matched group compared to the unmatched group (P=.013), possibly because dermatology faculty enjoy hearing about cases and how the applicant responds and interacts with the cases. These data suggest that matched applicants focus more on characteristics specific to the clinical aspects of dermatology.

Conversely, name-dropping was significantly more prevalent in the unmatched group (P=.014). Dermatology is a highly competitive specialty. In 2016, applicants who matched into dermatology had a mean USMLE Step 1 score of 249 with a mean number of 4.7 research experiences and 11.7 abstracts, presentations, or publications, which is higher than the average USMLE Step 1 score of 239 with a mean number of 3.8 research experiences and 8.7 abstracts, presentations, or publications for unmatched applicants.³ It is possible that residency selection committees may view name-dropping negatively if applicants choose to name-drop to strengthen their applications in comparison to more competitive candidates. Religious influences also were significantly more prevalent in the unmatched group (P=.002), but the overall frequency of religious influences was low (approximately 2% of all applicants).

The 422 personal statements examined in our study represent 83.1% of the total pool of applicants to postgraduate year 2 dermatology positions in 2012 (N=508).¹¹ Our data differed somewhat from an analysis of same-year dermatology personal statements of 65% of the national applicant pool.⁵ Olazagasti et al⁵ found that themes of a family member in medicine (more in unmatched), a desire to contribute to decreasing literature gap (more in matched), and a desire to better understand dermatologic pathophysiology (more in matched) to be statistically significant (P≤.05 for all). Unfortunately, these themes were found in a small number of applicants, with each being reported in less than 7%.⁵ Our study included 23% more unmatched candidates and likely better estimated potential significant differences between matched and unmatched applicants.

In the Results section, Olazagasti et al⁵ reported that matched applicants emphasized the study of cutaneous manifestations of systemic disease significantly more frequently than unmatched applicants. However, the P value in their report did not support this statement (P=.054). In addition, their Conclusion section discussed matched candidates including themes of “why dermatology” and unmatched candidates including a “personal story” as differences between groups. Again, their results did not show any statistical significance to support these recommendations.⁵ When providing medical student mentorship in a field as competitive as dermatology, faculty must be careful in giving accurate advice that, if at all possible, is supported by objective data rather than personal preference or anecdotes.

Our study was limited in that only personal statements of applicants to a single program in a specific specialty were analyzed. Applicants may have submitted personalized versions of their personal statements to specific schools, which may have biased the themes present in this subset of personal statements. Given these limitations, we are unable to determine if these results are generalizable to all dermatology residency applicants. Further limitation is that the analysis of personal statements is in itself a subjective process.

This study included a larger number of personal statements representing a larger proportion of the total pool of applicants in 2012 than prior studies examining personal statements of dermatology residency applicants. In addition, this study examined the ultimate dermatology match outcome for each applicant during the 2012 application cycle. Future investigations could explore the role of other factors in the residency selection process such as USMLE Step scores, community service, research experiences, and Alpha Omega Alpha Honor Medical Society status.

Conclusion

There are common themes in the personal statements of dermatology residency applicants, including personal accomplishments/attributes and positive qualities of dermatology. In addition, discussion of dermatologic cases was statistically more prevalent in applicants who ultimately matched, whereas name-dropping and religious influences were more prevalent in applicants who did not match. This information may be useful to effectively mentor medical students about the writing process for the personal statement. Further investigation is needed to explore these associations and the role of other aspects of the application in the residency selection process.

The personal statement is a narrative written by an applicant to residency programs to discuss his/her interests. It is one of the few places in the residency application process where applicants can express their personalities.¹ Applicants believe the personal statement is an important opportunity to distinguish themselves from others, thus increasing their chances of successful matching, particularly in competitive specialties.^1,2

Dermatology is a highly competitive specialty, with 614 medical students applying for 440 total dermatology positions in 2016.³ According to the results of the 2016 National Resident Matching program director survey, 82% (27/33) of dermatology program directors reported that the personal statement was a factor in selecting applicants to interview. Furthermore, dermatology program directors, on average, rated personal statements as more important than the Medical Student Performance Evaluation/Dean’s Letter, US Medical Licensing Examination (USMLE) Step 2 scores, and class ranking/quartile.⁴

Prior studies have sought to evaluate the impact of personal statements on the application process. A 2014 study of personal statements submitted by dermatology residency applicants found that the prevalence of certain themes differed according to match outcome.⁵ However, some of the conclusions drawn in this study were not supported by the reported results or were based on low numbers of participants. The purpose of our study was to examine personal statements from applications to a dermatology program at a major academic institution. This study identified common themes in personal statements, allowing for an analysis of their association with successful matching into dermatology.

Methods

All applications to the dermatology residency program at UNC School of Medicine (Chapel Hill, North Carolina) during the 2012 application cycle (N=422) were eligible. All submitted personal statements (N=422) were included with all personal identifiers removed prior to analysis. The investigator (D.S.M.) was blinded to other Electronic Residency Application Service data and match outcome.

The investigator initially reviewed a small, randomly selected subset of 20 personal statements to identify characteristics and common themes. The investigator then analyzed each of the personal statements to quantify the frequency of each theme. All personal statements submitted to the dermatology residency program at UNC School of Medicine were analyzed in this manner. Dermatology match outcomes for each applicant were confirmed later using dermatology program websites.

Differences in the prevalence of common themes between matched and unmatched applicants were calculated. Analysis of variance tests were used to determine if the differences in prevalence were statistically significant (P≤.05).

Results

All 422 submitted personal statements were evaluated, with 308 personal statements from applicants who matched and 114 personal statements from unmatched applicants. The screening of the initial subset of 20 personal statements resulted in a total of 9 content themes. The prevalence of each theme among matched and unmatched applicants is shown in the Table.

The most common themes among both matched and unmatched groups were personal accomplishments or attributes and positive qualities of dermatology. The prevalence of certain themes varied between matched and unmatched groups. Dermatologic cases were discussed significantly more frequently in the matched group compared to the unmatched group (60.06% vs 46.49%, P=.013). Name-dropping was more prevalent in the unmatched group (37.72%) compared to the matched group (26.95%). This difference in prevalence reached statistical significance (P=.014). Religious influences also were discussed more frequently in the unmatched group (5.26%) vs the matched group (0.65%) with statistical significance (P=.002).

Comment

This study of 422 personal statements submitted to a major academic institution showed that certain themes were common in personal statements among both matched and unmatched applicants. These themes included personal accomplishments/attributes and positive qualities of dermatology. This finding is consistent with prior studies that show common themes in the personal statements of applicants across a wide variety of specialties, including dermatology, anesthesiology, pediatrics, general surgery, internal medicine, and radiology.^5-10 Most commonly, applicants feel the need to justify why they chose their particular specialty, with Olazagasti et al⁵ (N=332) reporting that 70% of submitted dermatology personal statements explained why the applicant chose dermatology.

Certain themes, however, varied in prevalence between matched and unmatched groups in our study. Discussion of dermatologic cases was significantly more prevalent in the matched group compared to the unmatched group (P=.013), possibly because dermatology faculty enjoy hearing about cases and how the applicant responds and interacts with the cases. These data suggest that matched applicants focus more on characteristics specific to the clinical aspects of dermatology.

Conversely, name-dropping was significantly more prevalent in the unmatched group (P=.014). Dermatology is a highly competitive specialty. In 2016, applicants who matched into dermatology had a mean USMLE Step 1 score of 249 with a mean number of 4.7 research experiences and 11.7 abstracts, presentations, or publications, which is higher than the average USMLE Step 1 score of 239 with a mean number of 3.8 research experiences and 8.7 abstracts, presentations, or publications for unmatched applicants.³ It is possible that residency selection committees may view name-dropping negatively if applicants choose to name-drop to strengthen their applications in comparison to more competitive candidates. Religious influences also were significantly more prevalent in the unmatched group (P=.002), but the overall frequency of religious influences was low (approximately 2% of all applicants).

The 422 personal statements examined in our study represent 83.1% of the total pool of applicants to postgraduate year 2 dermatology positions in 2012 (N=508).¹¹ Our data differed somewhat from an analysis of same-year dermatology personal statements of 65% of the national applicant pool.⁵ Olazagasti et al⁵ found that themes of a family member in medicine (more in unmatched), a desire to contribute to decreasing literature gap (more in matched), and a desire to better understand dermatologic pathophysiology (more in matched) to be statistically significant (P≤.05 for all). Unfortunately, these themes were found in a small number of applicants, with each being reported in less than 7%.⁵ Our study included 23% more unmatched candidates and likely better estimated potential significant differences between matched and unmatched applicants.

In the Results section, Olazagasti et al⁵ reported that matched applicants emphasized the study of cutaneous manifestations of systemic disease significantly more frequently than unmatched applicants. However, the P value in their report did not support this statement (P=.054). In addition, their Conclusion section discussed matched candidates including themes of “why dermatology” and unmatched candidates including a “personal story” as differences between groups. Again, their results did not show any statistical significance to support these recommendations.⁵ When providing medical student mentorship in a field as competitive as dermatology, faculty must be careful in giving accurate advice that, if at all possible, is supported by objective data rather than personal preference or anecdotes.

Our study was limited in that only personal statements of applicants to a single program in a specific specialty were analyzed. Applicants may have submitted personalized versions of their personal statements to specific schools, which may have biased the themes present in this subset of personal statements. Given these limitations, we are unable to determine if these results are generalizable to all dermatology residency applicants. Further limitation is that the analysis of personal statements is in itself a subjective process.

This study included a larger number of personal statements representing a larger proportion of the total pool of applicants in 2012 than prior studies examining personal statements of dermatology residency applicants. In addition, this study examined the ultimate dermatology match outcome for each applicant during the 2012 application cycle. Future investigations could explore the role of other factors in the residency selection process such as USMLE Step scores, community service, research experiences, and Alpha Omega Alpha Honor Medical Society status.

Conclusion

There are common themes in the personal statements of dermatology residency applicants, including personal accomplishments/attributes and positive qualities of dermatology. In addition, discussion of dermatologic cases was statistically more prevalent in applicants who ultimately matched, whereas name-dropping and religious influences were more prevalent in applicants who did not match. This information may be useful to effectively mentor medical students about the writing process for the personal statement. Further investigation is needed to explore these associations and the role of other aspects of the application in the residency selection process.

The personal statement is a narrative written by an applicant to residency programs to discuss his/her interests. It is one of the few places in the residency application process where applicants can express their personalities.¹ Applicants believe the personal statement is an important opportunity to distinguish themselves from others, thus increasing their chances of successful matching, particularly in competitive specialties.^1,2

Dermatology is a highly competitive specialty, with 614 medical students applying for 440 total dermatology positions in 2016.³ According to the results of the 2016 National Resident Matching program director survey, 82% (27/33) of dermatology program directors reported that the personal statement was a factor in selecting applicants to interview. Furthermore, dermatology program directors, on average, rated personal statements as more important than the Medical Student Performance Evaluation/Dean’s Letter, US Medical Licensing Examination (USMLE) Step 2 scores, and class ranking/quartile.⁴

Prior studies have sought to evaluate the impact of personal statements on the application process. A 2014 study of personal statements submitted by dermatology residency applicants found that the prevalence of certain themes differed according to match outcome.⁵ However, some of the conclusions drawn in this study were not supported by the reported results or were based on low numbers of participants. The purpose of our study was to examine personal statements from applications to a dermatology program at a major academic institution. This study identified common themes in personal statements, allowing for an analysis of their association with successful matching into dermatology.

Methods

All applications to the dermatology residency program at UNC School of Medicine (Chapel Hill, North Carolina) during the 2012 application cycle (N=422) were eligible. All submitted personal statements (N=422) were included with all personal identifiers removed prior to analysis. The investigator (D.S.M.) was blinded to other Electronic Residency Application Service data and match outcome.

The investigator initially reviewed a small, randomly selected subset of 20 personal statements to identify characteristics and common themes. The investigator then analyzed each of the personal statements to quantify the frequency of each theme. All personal statements submitted to the dermatology residency program at UNC School of Medicine were analyzed in this manner. Dermatology match outcomes for each applicant were confirmed later using dermatology program websites.

Differences in the prevalence of common themes between matched and unmatched applicants were calculated. Analysis of variance tests were used to determine if the differences in prevalence were statistically significant (P≤.05).

Results

All 422 submitted personal statements were evaluated, with 308 personal statements from applicants who matched and 114 personal statements from unmatched applicants. The screening of the initial subset of 20 personal statements resulted in a total of 9 content themes. The prevalence of each theme among matched and unmatched applicants is shown in the Table.

The most common themes among both matched and unmatched groups were personal accomplishments or attributes and positive qualities of dermatology. The prevalence of certain themes varied between matched and unmatched groups. Dermatologic cases were discussed significantly more frequently in the matched group compared to the unmatched group (60.06% vs 46.49%, P=.013). Name-dropping was more prevalent in the unmatched group (37.72%) compared to the matched group (26.95%). This difference in prevalence reached statistical significance (P=.014). Religious influences also were discussed more frequently in the unmatched group (5.26%) vs the matched group (0.65%) with statistical significance (P=.002).

Comment

This study of 422 personal statements submitted to a major academic institution showed that certain themes were common in personal statements among both matched and unmatched applicants. These themes included personal accomplishments/attributes and positive qualities of dermatology. This finding is consistent with prior studies that show common themes in the personal statements of applicants across a wide variety of specialties, including dermatology, anesthesiology, pediatrics, general surgery, internal medicine, and radiology.^5-10 Most commonly, applicants feel the need to justify why they chose their particular specialty, with Olazagasti et al⁵ (N=332) reporting that 70% of submitted dermatology personal statements explained why the applicant chose dermatology.

Certain themes, however, varied in prevalence between matched and unmatched groups in our study. Discussion of dermatologic cases was significantly more prevalent in the matched group compared to the unmatched group (P=.013), possibly because dermatology faculty enjoy hearing about cases and how the applicant responds and interacts with the cases. These data suggest that matched applicants focus more on characteristics specific to the clinical aspects of dermatology.

Conversely, name-dropping was significantly more prevalent in the unmatched group (P=.014). Dermatology is a highly competitive specialty. In 2016, applicants who matched into dermatology had a mean USMLE Step 1 score of 249 with a mean number of 4.7 research experiences and 11.7 abstracts, presentations, or publications, which is higher than the average USMLE Step 1 score of 239 with a mean number of 3.8 research experiences and 8.7 abstracts, presentations, or publications for unmatched applicants.³ It is possible that residency selection committees may view name-dropping negatively if applicants choose to name-drop to strengthen their applications in comparison to more competitive candidates. Religious influences also were significantly more prevalent in the unmatched group (P=.002), but the overall frequency of religious influences was low (approximately 2% of all applicants).

The 422 personal statements examined in our study represent 83.1% of the total pool of applicants to postgraduate year 2 dermatology positions in 2012 (N=508).¹¹ Our data differed somewhat from an analysis of same-year dermatology personal statements of 65% of the national applicant pool.⁵ Olazagasti et al⁵ found that themes of a family member in medicine (more in unmatched), a desire to contribute to decreasing literature gap (more in matched), and a desire to better understand dermatologic pathophysiology (more in matched) to be statistically significant (P≤.05 for all). Unfortunately, these themes were found in a small number of applicants, with each being reported in less than 7%.⁵ Our study included 23% more unmatched candidates and likely better estimated potential significant differences between matched and unmatched applicants.

In the Results section, Olazagasti et al⁵ reported that matched applicants emphasized the study of cutaneous manifestations of systemic disease significantly more frequently than unmatched applicants. However, the P value in their report did not support this statement (P=.054). In addition, their Conclusion section discussed matched candidates including themes of “why dermatology” and unmatched candidates including a “personal story” as differences between groups. Again, their results did not show any statistical significance to support these recommendations.⁵ When providing medical student mentorship in a field as competitive as dermatology, faculty must be careful in giving accurate advice that, if at all possible, is supported by objective data rather than personal preference or anecdotes.

Our study was limited in that only personal statements of applicants to a single program in a specific specialty were analyzed. Applicants may have submitted personalized versions of their personal statements to specific schools, which may have biased the themes present in this subset of personal statements. Given these limitations, we are unable to determine if these results are generalizable to all dermatology residency applicants. Further limitation is that the analysis of personal statements is in itself a subjective process.

This study included a larger number of personal statements representing a larger proportion of the total pool of applicants in 2012 than prior studies examining personal statements of dermatology residency applicants. In addition, this study examined the ultimate dermatology match outcome for each applicant during the 2012 application cycle. Future investigations could explore the role of other factors in the residency selection process such as USMLE Step scores, community service, research experiences, and Alpha Omega Alpha Honor Medical Society status.

Conclusion

There are common themes in the personal statements of dermatology residency applicants, including personal accomplishments/attributes and positive qualities of dermatology. In addition, discussion of dermatologic cases was statistically more prevalent in applicants who ultimately matched, whereas name-dropping and religious influences were more prevalent in applicants who did not match. This information may be useful to effectively mentor medical students about the writing process for the personal statement. Further investigation is needed to explore these associations and the role of other aspects of the application in the residency selection process.

Practice Gap

Myxoid cysts are among the most common space-occupying lesions involving the nail unit. Their etiology has not been fully elucidated, but these cysts likely form due to leakage of synovial fluid following trauma or chronic wear and tear. They are highly associated with osteoarthritis and typically are found in close proximity to the distal interphalangeal joints.¹ Myxoid cysts often extend into the eponychium, where mechanical stress on the nail matrix may lead to nail dystrophy, most commonly resulting in a longitudinal groove in the nail plate (Figure, A). The presence of multiple myxoid cysts is not uncommon. Differentiation of this lesion from other nodules of the digits, including epidermoid cysts, acquired digital fibrokeratomas, and giant cell tendon sheath tumors often is challenging without a biopsy.

Technique

The normal nail unit transmits light to some extent, and masses may be identified by how easily they transmit light relative to the adjacent skin. Solid tumors of the nail unit, such as acquired digital fibrokeratomas and giant cell tendon sheath tumors, will not transmit light, while myxoid cysts transmit light easily. A dermatoscope can be used to project light from the dorsal digit through the nail unit. The area occupied by the myxoid cyst will appear bright compared to the surrounding skin (Figure, B). Drainage of the lesion using an 18-gauge needle yielded a clear jellylike fluid that was consistent with a myxoid cyst. This technique aids in localizing and characterizing the myxoid cyst for treatment or drainage. Physician assessment of transillumination has been shown to demonstrate clinical accuracy and high intraobserver reliability in differentiating between cystic and solid tumors.²

Practice Implications

Transillumination is a valuable technique that may aid dermatologists in both the diagnosis and subsequent treatment of myxoid cysts. Location is important to consider when choosing a treatment option. Although lower recurrence rates are achieved with nail surgery, permanent nail dystrophy is likely when cysts are in close proximity to the nail matrix.³ When multiple cysts are present, only the largest may be apparent. Transillumination can guide the physician in achieving more accurate and thorough drainage of the cyst contents, negating the need for more costly imaging modalities. Dermatologists may utilize transillumination as a rapid and economical diagnostic method for space-occupying lesions involving the nail unit.

Practice Gap

Myxoid cysts are among the most common space-occupying lesions involving the nail unit. Their etiology has not been fully elucidated, but these cysts likely form due to leakage of synovial fluid following trauma or chronic wear and tear. They are highly associated with osteoarthritis and typically are found in close proximity to the distal interphalangeal joints.¹ Myxoid cysts often extend into the eponychium, where mechanical stress on the nail matrix may lead to nail dystrophy, most commonly resulting in a longitudinal groove in the nail plate (Figure, A). The presence of multiple myxoid cysts is not uncommon. Differentiation of this lesion from other nodules of the digits, including epidermoid cysts, acquired digital fibrokeratomas, and giant cell tendon sheath tumors often is challenging without a biopsy.

Technique

The normal nail unit transmits light to some extent, and masses may be identified by how easily they transmit light relative to the adjacent skin. Solid tumors of the nail unit, such as acquired digital fibrokeratomas and giant cell tendon sheath tumors, will not transmit light, while myxoid cysts transmit light easily. A dermatoscope can be used to project light from the dorsal digit through the nail unit. The area occupied by the myxoid cyst will appear bright compared to the surrounding skin (Figure, B). Drainage of the lesion using an 18-gauge needle yielded a clear jellylike fluid that was consistent with a myxoid cyst. This technique aids in localizing and characterizing the myxoid cyst for treatment or drainage. Physician assessment of transillumination has been shown to demonstrate clinical accuracy and high intraobserver reliability in differentiating between cystic and solid tumors.²

Practice Implications

Transillumination is a valuable technique that may aid dermatologists in both the diagnosis and subsequent treatment of myxoid cysts. Location is important to consider when choosing a treatment option. Although lower recurrence rates are achieved with nail surgery, permanent nail dystrophy is likely when cysts are in close proximity to the nail matrix.³ When multiple cysts are present, only the largest may be apparent. Transillumination can guide the physician in achieving more accurate and thorough drainage of the cyst contents, negating the need for more costly imaging modalities. Dermatologists may utilize transillumination as a rapid and economical diagnostic method for space-occupying lesions involving the nail unit.

Practice Gap

Myxoid cysts are among the most common space-occupying lesions involving the nail unit. Their etiology has not been fully elucidated, but these cysts likely form due to leakage of synovial fluid following trauma or chronic wear and tear. They are highly associated with osteoarthritis and typically are found in close proximity to the distal interphalangeal joints.¹ Myxoid cysts often extend into the eponychium, where mechanical stress on the nail matrix may lead to nail dystrophy, most commonly resulting in a longitudinal groove in the nail plate (Figure, A). The presence of multiple myxoid cysts is not uncommon. Differentiation of this lesion from other nodules of the digits, including epidermoid cysts, acquired digital fibrokeratomas, and giant cell tendon sheath tumors often is challenging without a biopsy.

Technique

The normal nail unit transmits light to some extent, and masses may be identified by how easily they transmit light relative to the adjacent skin. Solid tumors of the nail unit, such as acquired digital fibrokeratomas and giant cell tendon sheath tumors, will not transmit light, while myxoid cysts transmit light easily. A dermatoscope can be used to project light from the dorsal digit through the nail unit. The area occupied by the myxoid cyst will appear bright compared to the surrounding skin (Figure, B). Drainage of the lesion using an 18-gauge needle yielded a clear jellylike fluid that was consistent with a myxoid cyst. This technique aids in localizing and characterizing the myxoid cyst for treatment or drainage. Physician assessment of transillumination has been shown to demonstrate clinical accuracy and high intraobserver reliability in differentiating between cystic and solid tumors.²

Practice Implications

Transillumination is a valuable technique that may aid dermatologists in both the diagnosis and subsequent treatment of myxoid cysts. Location is important to consider when choosing a treatment option. Although lower recurrence rates are achieved with nail surgery, permanent nail dystrophy is likely when cysts are in close proximity to the nail matrix.³ When multiple cysts are present, only the largest may be apparent. Transillumination can guide the physician in achieving more accurate and thorough drainage of the cyst contents, negating the need for more costly imaging modalities. Dermatologists may utilize transillumination as a rapid and economical diagnostic method for space-occupying lesions involving the nail unit.

Fitzpatrick skin type (FST) is the most commonly used classification system in dermatologic practice. It was developed by Thomas B. Fitzpatrick, MD, PhD, in 1975 to assess the propensity of the skin to burn during phototherapy.¹ Fitzpatrick skin type also can be used to assess the clinical benefits and efficacy of cosmetic procedures, including laser hair removal, chemical peel and dermabrasion, tattoo removal, spray tanning, and laser resurfacing for acne scarring.² The original FST classifications included skin types I through IV; skin types V and VI were later added to include individuals of Asian, Indian, and African origin.¹ As a result, FST often is used by providers as a means of describing constitutive skin color and ethnicity.³

How did FST transition from describing the propensity of the skin to burn from UV light exposure to categorizing skin color, thereby becoming a proxy for race? It most likely occurred because there has not been another widely adopted classification system for describing skin color that can be applied to all skin types. Even when the FST classification scale is used as intended, there are inconsistencies with its accuracy; for example, self-reported FSTs have correlated poorly with sunburn risk as well as physician-reported FSTs.^4,5 Although physician-reported FSTs have been demonstrated to correlate with race, race does not consistently correlate with objective measures of pigmentation or self-reported FSTs.⁵ For example, Japanese women often self-identify as FST type II, but Asian skin generally is considered to be nonwhite.¹ Fitzpatrick himself acknowledged that race and ethnicity are cultural and political terms with no scientific basis.⁶ Fitzpatrick skin type also has been demonstrated to correlate poorly with constitutive skin color and minimal erythema dose values.⁷

We conducted an anonymous survey of dermatologists and dermatology trainees to evaluate how providers use FST in their clinical practice as well as how it is used to describe race and ethnicity.

Methods

The survey was distributed electronically to dermatologists and dermatology trainees from March 13 to March 28, 2019, using the Association of Professors of Dermatology listserv, as well as in person at the annual Skin of Color Society meeting in Washington, DC, on February 28, 2019. The 8-item survey included questions about physician demographics (ie, primary practice setting, board certification, and geographic location); whether the respondent identified as an individual with skin of color; and how the respondent utilized FST in clinical notes (ie, describing race/ethnicity, skin cancer risk, and constitutive [baseline] skin color; determining initial phototherapy dosage and suitability for laser treatments, and likelihood of skin burning). A t test was used to determine whether dermatologists who identified as having skin of color utilized FST differently.

Results

A total of 141 surveys were returned, and 140 respondents were included in the final analysis. Given the methods used to distribute the survey, a response rate could not be calculated. The respondents included more board-certified dermatologists (70%) than dermatology trainees (30%). Ninety-three percent of respondents indicated an academic institution as their primary practice location. Notably, 26% of respondents self-identified as having skin of color.

Forty-one percent of all respondents agreed that FST should be included in their clinical documentation. In response to the question “In what scenarios would you refer to FST in a clinical note?” 31% said they used FST to describe patients’ race or ethnicity, 47% used it to describe patients’ constitutive skin color, and 22% utilized it in both scenarios. Respondents who did not identify as having skin of color were more likely to use FST to describe constitutive skin color, though this finding was not statistically significant (P=.063). Anecdotally, providers also included FST in clinical notes on postinflammatory hyperpigmentation, melasma, and treatment with cryotherapy.

Comment

The US Census Bureau has estimated that half of the US population will be of non-European descent by 2050.⁸ As racial and ethnic distinctions continue to be blurred, attempts to include all nonwhite skin types under the umbrella term skin of color becomes increasingly problematic. The true number of skin colors is unknown but likely is infinite, as Brazilian artist Angélica Dass has demonstrated with her photographic project “Humanae” (Figure). Given this shift in demographics and the limitations of the FST, alternative methods of describing skin color must be developed.

The results of our survey suggest that approximately one-third to half of academic dermatologists/dermatology trainees use FST to describe race/ethnicity and/or constitutive skin color. This misuse of FST may occur more frequently among physicians who do not identify as having skin of color. Additionally, misuse of FST in academic settings may be problematic and confusing for medical students who may learn to use this common dermatologic tool outside of its original intent.

We acknowledge that the conundrum of how to classify individuals with nonwhite skin or skin of color is not simply answered. Several alternative skin classification models have been proposed to improve the sensitivity and specificity of identifying patients with skin of color (Table). Refining FST classification is one approach. Employing terms such as skin irritation, tenderness, itching, or skin becoming darker from sun exposure rather than painful burn or tanning may result in better identification.^1,4 A study conducted in India modified the FST questionnaire to acknowledge cultural behaviors.¹⁵ Because lighter skin is culturally valued in this population, patient experience with purposeful sun exposure was limited; thus, the questionnaire was modified to remove questions on the use of tanning booths and/or creams as well as sun exposure and instead included more objective questions regarding dark brown eye color, black and dark brown hair color, and dark brown skin color.¹⁵ Other studies have suggested that patient-reported photosensitivity assessed via a questionnaire is a valid measure for assessing FST but is associated with an overestimation of skin color, known as “the dark shift.”²⁰

Conclusion

Other investigators have criticized the various limitations of FST, including physician vs patient assessment, interview vs questionnaire, and phrasing of questions on skin type.²³ Our findings suggest that medical providers should be cognizant of conflating race and ethnicity with FST. Two authors of this report (O.R.W. and J.E.D.) are medical students with skin of color and frequently have observed the addition of FST to the medical records of patients who were not receiving phototherapy as a proxy for race. We believe that more culturally appropriate and clinically relevant methods for describing skin of color need to be developed and, in the interim, the original intent of FST should be emphasized and incorporated in medical school and resident education.

Acknowledgment
The authors thank Adewole Adamson, MD (Austin, Texas), for discussion and feedback.

Fitzpatrick skin type (FST) is the most commonly used classification system in dermatologic practice. It was developed by Thomas B. Fitzpatrick, MD, PhD, in 1975 to assess the propensity of the skin to burn during phototherapy.¹ Fitzpatrick skin type also can be used to assess the clinical benefits and efficacy of cosmetic procedures, including laser hair removal, chemical peel and dermabrasion, tattoo removal, spray tanning, and laser resurfacing for acne scarring.² The original FST classifications included skin types I through IV; skin types V and VI were later added to include individuals of Asian, Indian, and African origin.¹ As a result, FST often is used by providers as a means of describing constitutive skin color and ethnicity.³

How did FST transition from describing the propensity of the skin to burn from UV light exposure to categorizing skin color, thereby becoming a proxy for race? It most likely occurred because there has not been another widely adopted classification system for describing skin color that can be applied to all skin types. Even when the FST classification scale is used as intended, there are inconsistencies with its accuracy; for example, self-reported FSTs have correlated poorly with sunburn risk as well as physician-reported FSTs.^4,5 Although physician-reported FSTs have been demonstrated to correlate with race, race does not consistently correlate with objective measures of pigmentation or self-reported FSTs.⁵ For example, Japanese women often self-identify as FST type II, but Asian skin generally is considered to be nonwhite.¹ Fitzpatrick himself acknowledged that race and ethnicity are cultural and political terms with no scientific basis.⁶ Fitzpatrick skin type also has been demonstrated to correlate poorly with constitutive skin color and minimal erythema dose values.⁷

We conducted an anonymous survey of dermatologists and dermatology trainees to evaluate how providers use FST in their clinical practice as well as how it is used to describe race and ethnicity.

Methods

The survey was distributed electronically to dermatologists and dermatology trainees from March 13 to March 28, 2019, using the Association of Professors of Dermatology listserv, as well as in person at the annual Skin of Color Society meeting in Washington, DC, on February 28, 2019. The 8-item survey included questions about physician demographics (ie, primary practice setting, board certification, and geographic location); whether the respondent identified as an individual with skin of color; and how the respondent utilized FST in clinical notes (ie, describing race/ethnicity, skin cancer risk, and constitutive [baseline] skin color; determining initial phototherapy dosage and suitability for laser treatments, and likelihood of skin burning). A t test was used to determine whether dermatologists who identified as having skin of color utilized FST differently.

Results

A total of 141 surveys were returned, and 140 respondents were included in the final analysis. Given the methods used to distribute the survey, a response rate could not be calculated. The respondents included more board-certified dermatologists (70%) than dermatology trainees (30%). Ninety-three percent of respondents indicated an academic institution as their primary practice location. Notably, 26% of respondents self-identified as having skin of color.

Forty-one percent of all respondents agreed that FST should be included in their clinical documentation. In response to the question “In what scenarios would you refer to FST in a clinical note?” 31% said they used FST to describe patients’ race or ethnicity, 47% used it to describe patients’ constitutive skin color, and 22% utilized it in both scenarios. Respondents who did not identify as having skin of color were more likely to use FST to describe constitutive skin color, though this finding was not statistically significant (P=.063). Anecdotally, providers also included FST in clinical notes on postinflammatory hyperpigmentation, melasma, and treatment with cryotherapy.

Comment

The US Census Bureau has estimated that half of the US population will be of non-European descent by 2050.⁸ As racial and ethnic distinctions continue to be blurred, attempts to include all nonwhite skin types under the umbrella term skin of color becomes increasingly problematic. The true number of skin colors is unknown but likely is infinite, as Brazilian artist Angélica Dass has demonstrated with her photographic project “Humanae” (Figure). Given this shift in demographics and the limitations of the FST, alternative methods of describing skin color must be developed.

The results of our survey suggest that approximately one-third to half of academic dermatologists/dermatology trainees use FST to describe race/ethnicity and/or constitutive skin color. This misuse of FST may occur more frequently among physicians who do not identify as having skin of color. Additionally, misuse of FST in academic settings may be problematic and confusing for medical students who may learn to use this common dermatologic tool outside of its original intent.

We acknowledge that the conundrum of how to classify individuals with nonwhite skin or skin of color is not simply answered. Several alternative skin classification models have been proposed to improve the sensitivity and specificity of identifying patients with skin of color (Table). Refining FST classification is one approach. Employing terms such as skin irritation, tenderness, itching, or skin becoming darker from sun exposure rather than painful burn or tanning may result in better identification.^1,4 A study conducted in India modified the FST questionnaire to acknowledge cultural behaviors.¹⁵ Because lighter skin is culturally valued in this population, patient experience with purposeful sun exposure was limited; thus, the questionnaire was modified to remove questions on the use of tanning booths and/or creams as well as sun exposure and instead included more objective questions regarding dark brown eye color, black and dark brown hair color, and dark brown skin color.¹⁵ Other studies have suggested that patient-reported photosensitivity assessed via a questionnaire is a valid measure for assessing FST but is associated with an overestimation of skin color, known as “the dark shift.”²⁰

Conclusion

Other investigators have criticized the various limitations of FST, including physician vs patient assessment, interview vs questionnaire, and phrasing of questions on skin type.²³ Our findings suggest that medical providers should be cognizant of conflating race and ethnicity with FST. Two authors of this report (O.R.W. and J.E.D.) are medical students with skin of color and frequently have observed the addition of FST to the medical records of patients who were not receiving phototherapy as a proxy for race. We believe that more culturally appropriate and clinically relevant methods for describing skin of color need to be developed and, in the interim, the original intent of FST should be emphasized and incorporated in medical school and resident education.

Acknowledgment
The authors thank Adewole Adamson, MD (Austin, Texas), for discussion and feedback.

Fitzpatrick skin type (FST) is the most commonly used classification system in dermatologic practice. It was developed by Thomas B. Fitzpatrick, MD, PhD, in 1975 to assess the propensity of the skin to burn during phototherapy.¹ Fitzpatrick skin type also can be used to assess the clinical benefits and efficacy of cosmetic procedures, including laser hair removal, chemical peel and dermabrasion, tattoo removal, spray tanning, and laser resurfacing for acne scarring.² The original FST classifications included skin types I through IV; skin types V and VI were later added to include individuals of Asian, Indian, and African origin.¹ As a result, FST often is used by providers as a means of describing constitutive skin color and ethnicity.³

How did FST transition from describing the propensity of the skin to burn from UV light exposure to categorizing skin color, thereby becoming a proxy for race? It most likely occurred because there has not been another widely adopted classification system for describing skin color that can be applied to all skin types. Even when the FST classification scale is used as intended, there are inconsistencies with its accuracy; for example, self-reported FSTs have correlated poorly with sunburn risk as well as physician-reported FSTs.^4,5 Although physician-reported FSTs have been demonstrated to correlate with race, race does not consistently correlate with objective measures of pigmentation or self-reported FSTs.⁵ For example, Japanese women often self-identify as FST type II, but Asian skin generally is considered to be nonwhite.¹ Fitzpatrick himself acknowledged that race and ethnicity are cultural and political terms with no scientific basis.⁶ Fitzpatrick skin type also has been demonstrated to correlate poorly with constitutive skin color and minimal erythema dose values.⁷

We conducted an anonymous survey of dermatologists and dermatology trainees to evaluate how providers use FST in their clinical practice as well as how it is used to describe race and ethnicity.

Methods

The survey was distributed electronically to dermatologists and dermatology trainees from March 13 to March 28, 2019, using the Association of Professors of Dermatology listserv, as well as in person at the annual Skin of Color Society meeting in Washington, DC, on February 28, 2019. The 8-item survey included questions about physician demographics (ie, primary practice setting, board certification, and geographic location); whether the respondent identified as an individual with skin of color; and how the respondent utilized FST in clinical notes (ie, describing race/ethnicity, skin cancer risk, and constitutive [baseline] skin color; determining initial phototherapy dosage and suitability for laser treatments, and likelihood of skin burning). A t test was used to determine whether dermatologists who identified as having skin of color utilized FST differently.

Results

A total of 141 surveys were returned, and 140 respondents were included in the final analysis. Given the methods used to distribute the survey, a response rate could not be calculated. The respondents included more board-certified dermatologists (70%) than dermatology trainees (30%). Ninety-three percent of respondents indicated an academic institution as their primary practice location. Notably, 26% of respondents self-identified as having skin of color.

Forty-one percent of all respondents agreed that FST should be included in their clinical documentation. In response to the question “In what scenarios would you refer to FST in a clinical note?” 31% said they used FST to describe patients’ race or ethnicity, 47% used it to describe patients’ constitutive skin color, and 22% utilized it in both scenarios. Respondents who did not identify as having skin of color were more likely to use FST to describe constitutive skin color, though this finding was not statistically significant (P=.063). Anecdotally, providers also included FST in clinical notes on postinflammatory hyperpigmentation, melasma, and treatment with cryotherapy.

Comment

The US Census Bureau has estimated that half of the US population will be of non-European descent by 2050.⁸ As racial and ethnic distinctions continue to be blurred, attempts to include all nonwhite skin types under the umbrella term skin of color becomes increasingly problematic. The true number of skin colors is unknown but likely is infinite, as Brazilian artist Angélica Dass has demonstrated with her photographic project “Humanae” (Figure). Given this shift in demographics and the limitations of the FST, alternative methods of describing skin color must be developed.

The results of our survey suggest that approximately one-third to half of academic dermatologists/dermatology trainees use FST to describe race/ethnicity and/or constitutive skin color. This misuse of FST may occur more frequently among physicians who do not identify as having skin of color. Additionally, misuse of FST in academic settings may be problematic and confusing for medical students who may learn to use this common dermatologic tool outside of its original intent.

We acknowledge that the conundrum of how to classify individuals with nonwhite skin or skin of color is not simply answered. Several alternative skin classification models have been proposed to improve the sensitivity and specificity of identifying patients with skin of color (Table). Refining FST classification is one approach. Employing terms such as skin irritation, tenderness, itching, or skin becoming darker from sun exposure rather than painful burn or tanning may result in better identification.^1,4 A study conducted in India modified the FST questionnaire to acknowledge cultural behaviors.¹⁵ Because lighter skin is culturally valued in this population, patient experience with purposeful sun exposure was limited; thus, the questionnaire was modified to remove questions on the use of tanning booths and/or creams as well as sun exposure and instead included more objective questions regarding dark brown eye color, black and dark brown hair color, and dark brown skin color.¹⁵ Other studies have suggested that patient-reported photosensitivity assessed via a questionnaire is a valid measure for assessing FST but is associated with an overestimation of skin color, known as “the dark shift.”²⁰

Conclusion

Other investigators have criticized the various limitations of FST, including physician vs patient assessment, interview vs questionnaire, and phrasing of questions on skin type.²³ Our findings suggest that medical providers should be cognizant of conflating race and ethnicity with FST. Two authors of this report (O.R.W. and J.E.D.) are medical students with skin of color and frequently have observed the addition of FST to the medical records of patients who were not receiving phototherapy as a proxy for race. We believe that more culturally appropriate and clinically relevant methods for describing skin of color need to be developed and, in the interim, the original intent of FST should be emphasized and incorporated in medical school and resident education.

Acknowledgment
The authors thank Adewole Adamson, MD (Austin, Texas), for discussion and feedback.

Hypersensitivity to metal implants remains a controversial field in contact dermatitis and patch testing. With positive reactions to nickel hovering around 20% in patch-tested populations,¹ the question remains whether metal-allergic patients can safely receive metal implants. Unfortunately, large controlled studies are lacking, in part due to ethical concerns of knowingly placing a metal implant in a metal-allergic patient. Much of the focus of implant hypersensitivity reactions (IHRs) has been on orthopedic joints including hips, knees, and shoulders, as well as fixed orthopedic implanted materials such as screws and plates. However, there have been reports of IHRs to cardiac devices including defibrillators, pacemakers, and intracardiac devices; dental hardware including implants, crowns, dentures, and braces; and neurologic and gynecologic devices. For the purposes of this review, we will focus on IHRs to orthopedic implants.

Making the Case for IHRs

There are multiple case reports and series documenting likely orthopedic IHRs in the literature^2-5; however, large prospective studies are lacking. Some of the largest series are from Danish registry studies. In 2009, Thyssen et al⁶ reviewed356 patients who had undergone both total hip arthroplasty and patch testing. Metal allergy frequencies were similar between patch-tested registry patients and patch test controls, showing no increase in positive patch tests to metals after receiving implants. Additionally, implant revision rates were comparable between registry patients with and without patch testing. The group concluded that the risk for revision after hip implantation in metal-allergic patients and the risk for development of metal allergy after implantation were both low.⁶ In 2015, Münch et al⁷ compared 327 patients who had undergone both total knee arthroplasty and patch testing and found that prevalence of allergy to nickel, cobalt, and chromium was similar between patients who had undergone revision surgery and those who had not; however, for patients who had 2 or more knee revisions, there was a higher prevalence of postimplant metal allergy. This study also showed that metal allergy identified before implantation did not increase the risk for postimplantation knee revision surgery or implant failure.⁷ These larger studies suggest that although individual cases of IHR exist, it is likely quite rare.

Patients have been found to have increased levels of chromium (serum and urine) and titanium (serum) following total hip arthroplasty.⁸ Additionally, metal wear particles have been identified in postmortem livers and spleens, which was more prevalent in patients with a history of failed hip arthroplasty.⁹ It is difficult to determine the meaning of this data, as the presence of metal ions does not necessarily indicate allergy or IHR. In 2001, Hallab et al¹⁰ pooled data from several implant cohort studies and concluded that in comparison to a baseline metal sensitivity prevalence of approximately 10%, patients with well-functioning implants had a metal sensitivity–weighted average of 25%, and those with poorly functioning implants had a weighted average of 60%. Again, positive patch testing to metals does not necessarily implicate allergy as the cause of implant failure.

Some small studies have shown that patients with evidence of metal hypersensitivity improve with revision. Zondervan et al¹¹ reviewed results of 46 orthopedic revisions following painful total knee arthroplasty. Patients with knee pain and lymphocyte transformation testing (LTT) positive for metals received hypoallergenic revisions, and those with LTT negative for metals received standard revisions. The group who received hypoallergenic revisions had more pain reduction compared to the standard revision group (37.8% reduction in pain vs 27%). However, this study was limited in that the diagnosis of metal allergy was made entirely on results of LTT.¹¹ In 2012, Atanaskova Mesinkovska et al¹² described 41 patients who underwent orthopedic patch testing following implantation for symptoms including pain, dermatitis, pruritus, joint loosening, edema, and impaired wound healing. Fifteen (37%) patients had positive patch test reactions to metals, and 10 (67%) of them had reactions to metals that were present in their implants. Six (60%) of these patients had their implants removed and their symptoms resolved; the remaining 4 continued to experience implant symptoms.¹² These studies support the existence of rare metal-related orthopedic IHRs and support the concept of proceeding with orthopedic implant revision when indicated, safe, and agreed upon by the surgeon and patient. However, as noted in the series by Zondervan et al,¹¹ not every patient with confirmed metal allergy who undergoes revision improves, so an informed conversation between the patient and surgeon is mandatory.

Types of Orthopedic Implants

Orthopedic implanted materials consist of either dynamic (knees, hips) or static (screws, plates) components. Several generations of hip implants have evolved since the 1960s. First-generation implanted hips were metal-on-metal and had high rates of metal release and sensitization. Metal-on-plastic implants may be less likely to release metal but instead release large polyethylene wear particles. Second-generation metal-on-metal implants reportedly have lower wear rates. With these implants, wear particles are generated but are reportedly smaller than first-generation particles.¹³

Allergens in IHRs

Metals
Metals are the most commonly implicated allergens in orthopedic IHRs. Potentially relevant metal alloys include 316L stainless steel, cobalt-chromium-molybdenum steel, Vitallium alloy, titanium alloy, titanium-tantalum-niobium alloy, and Oxinium (Smith & Nephew).^14,15 Each alloy contains several metals, which can include nickel, chromium, cobalt, manganese, molybdenum, iron, titanium, aluminum, vanadium, niobium, tantalum, and zirconium, among others. For example, 316L stainless steel contains iron, nickel, chromium, manganese, molybdenum, nitrogen, carbon, sulfur, silicon, and phosphorus, whereas Oxinium contains only oxidized zirconium and niobium.

Bone Cement
Bone cement also has been reported in cases of orthopedic IHRs and can contain several chemicals, including methyl methacrylate, N,N-dimethyl-p-toluidine, benzoyl peroxide, hydroquinone, and gentamicin.¹⁴ Other potential exposures include adhesives (cyanoacrylates) and topical antibiotics.

Clinical Presentation

Several clinical presentations of orthopedic IHRs have been described. Perhaps the most commonly recognized is a localized cutaneous eczematous eruption, with dermatitis typically overlying the site of the implanted material.^1,2,16 Generalized cutaneous eczematous IHRs also have been reported, including diffuse generalized dermatitis from a stainless steel orthopedic screw⁴ and nummular dermatitis attributed to vanadium in an orthopedic plate.⁵ Urticaria, vasculitis, and bullous cutaneous reactions, as well as extracutaneous complications, also have been reported.^14,15 Pain, edema, joint loosening or failure, and poor wound healing have been reported,¹² but it remains unclear whether these symptoms represent IHR.

Patch Testing for IHR

Several groups have published recommended patch test series for IHR.^12,14,15 Common components of implant patch testing panels include metals, adhesives (acrylates, epoxy resins) and antibiotics. Importantly, obtaining product information from the manufacturer of the suspected implant can guide which allergens to include in patch testing. Implant and metal panels also are available for commercial purchase.

Other Diagnostic Tests

We rarely (almost never) order LTTs in the workup for potential IHRs. This is an in vitro test that includes lymphocytes, metal ions, and the radioactive marker methyl-3H-thymidine. The goal of the test is to evaluate if patient lymphocytes are reactive or responsive to metal ions. A positive LTT suggests that lymphocytes can respond to the presence of metal ions but does not confirm allergy or the presence of IHR.

Typically, skin or tissue biopsies are not required to make a diagnosis of IHR; however, if performed, histopathology suggestive of IHR can support a suspected diagnosis. Typical findings include but are not limited to spongiotic dermatitis. Eosinophils may or may not be present. Metal disc testing has been utilized for orthopedic IHR but is not currently recommended due to low diagnostic yield. Prick testing rarely is used and also is not a primary method for diagnosis of IHR.¹⁷

Preimplantation Patch Testing

Expert opinion guidelines published by the American Contact Dermatitis Society (ACDS) state that routine preimplantation patch testing is not necessary; however, for those patients with a clear history of contact reactions to metal, preimplantation patch testing can be considered.¹⁷

Patch test results can influence the orthopedic surgeon’s choice of implant material. In one study, when preimplantation patch testing showed a positive patch test reaction to metals, the results influenced the surgeon’s decision-making in all cases.¹²

Postimplantation Patch Testing: Diagnostic Criteria for Metal IHR After Implantation

From 2012 to 2013, Schalock and Thyssen¹⁸ surveyed expert attendees at meetings of the European Society of Contact Dermatitis and the ACDS for their opinions on proposed diagnostic criteria for metal IHRs. Based on these results (N=119), the authors stratified 4 major and 5 minor diagnostic criteria, which were defined based on overall responses of meeting attendees. Major criteria included (1) chronic dermatitis beginning weeks to months after metallic implantation, (2) complete recovery after removal of the offending implant, (3) eruption overlying the metal implant, and (4) positive patch test reaction to a metal used in the implant. Minor criteria included (1) histology consistent with allergic contact dermatitis, (2) morphology consistent with dermatitis (ie, erythema, induration, papules, vesicles), (3) positive in vitro test to metals (eg, lymphocyte transformation test), (4) systemic allergic dermatitis reaction, and (5) therapy-resistant dermatitis reaction. The authors did not describe a scoring system for evaluation and confirmation of a diagnosis of IHR. Instead, the criteria should be used as general guidelines when evaluating patients for possible IHRs. From a standpoint of available diagnostic tests for metal IHR, 86.1% of experts agreed that a positive patch test reaction to a metal used in the implant was suggestive of a diagnosis, whereas a positive in vitro test to metals (LTT) was suggestive of a diagnosis for only 32.2% of respondents. This study was designed specifically for metal IHRs and therefore is not necessarily generalizable for nonmetal IHRs.¹⁸

Final Interpretation

We follow the 2016 ACDS guidelines¹⁷ and complete preimplantation patch testing only in the setting of suspected metal allergy and postimplantation patch testing based on the guidelines described by Schalock and Thyssen.¹⁸ However, an extended conversation is warranted prior to patch testing to ensure the patient fully understands the limitations of the test. Although we have both ordered the LTT, interpretation remains murky, and until this test is standardized, routine use is unlikely to benefit the patient. Until we are more reliably able to predict who will develop hypersensitivity to implanted metals, the decision to remove or revise an implant is one that should be made by a multidisciplinary team that includes the surgeon and the patient.

Hypersensitivity to metal implants remains a controversial field in contact dermatitis and patch testing. With positive reactions to nickel hovering around 20% in patch-tested populations,¹ the question remains whether metal-allergic patients can safely receive metal implants. Unfortunately, large controlled studies are lacking, in part due to ethical concerns of knowingly placing a metal implant in a metal-allergic patient. Much of the focus of implant hypersensitivity reactions (IHRs) has been on orthopedic joints including hips, knees, and shoulders, as well as fixed orthopedic implanted materials such as screws and plates. However, there have been reports of IHRs to cardiac devices including defibrillators, pacemakers, and intracardiac devices; dental hardware including implants, crowns, dentures, and braces; and neurologic and gynecologic devices. For the purposes of this review, we will focus on IHRs to orthopedic implants.

Making the Case for IHRs

There are multiple case reports and series documenting likely orthopedic IHRs in the literature^2-5; however, large prospective studies are lacking. Some of the largest series are from Danish registry studies. In 2009, Thyssen et al⁶ reviewed356 patients who had undergone both total hip arthroplasty and patch testing. Metal allergy frequencies were similar between patch-tested registry patients and patch test controls, showing no increase in positive patch tests to metals after receiving implants. Additionally, implant revision rates were comparable between registry patients with and without patch testing. The group concluded that the risk for revision after hip implantation in metal-allergic patients and the risk for development of metal allergy after implantation were both low.⁶ In 2015, Münch et al⁷ compared 327 patients who had undergone both total knee arthroplasty and patch testing and found that prevalence of allergy to nickel, cobalt, and chromium was similar between patients who had undergone revision surgery and those who had not; however, for patients who had 2 or more knee revisions, there was a higher prevalence of postimplant metal allergy. This study also showed that metal allergy identified before implantation did not increase the risk for postimplantation knee revision surgery or implant failure.⁷ These larger studies suggest that although individual cases of IHR exist, it is likely quite rare.

Patients have been found to have increased levels of chromium (serum and urine) and titanium (serum) following total hip arthroplasty.⁸ Additionally, metal wear particles have been identified in postmortem livers and spleens, which was more prevalent in patients with a history of failed hip arthroplasty.⁹ It is difficult to determine the meaning of this data, as the presence of metal ions does not necessarily indicate allergy or IHR. In 2001, Hallab et al¹⁰ pooled data from several implant cohort studies and concluded that in comparison to a baseline metal sensitivity prevalence of approximately 10%, patients with well-functioning implants had a metal sensitivity–weighted average of 25%, and those with poorly functioning implants had a weighted average of 60%. Again, positive patch testing to metals does not necessarily implicate allergy as the cause of implant failure.

Some small studies have shown that patients with evidence of metal hypersensitivity improve with revision. Zondervan et al¹¹ reviewed results of 46 orthopedic revisions following painful total knee arthroplasty. Patients with knee pain and lymphocyte transformation testing (LTT) positive for metals received hypoallergenic revisions, and those with LTT negative for metals received standard revisions. The group who received hypoallergenic revisions had more pain reduction compared to the standard revision group (37.8% reduction in pain vs 27%). However, this study was limited in that the diagnosis of metal allergy was made entirely on results of LTT.¹¹ In 2012, Atanaskova Mesinkovska et al¹² described 41 patients who underwent orthopedic patch testing following implantation for symptoms including pain, dermatitis, pruritus, joint loosening, edema, and impaired wound healing. Fifteen (37%) patients had positive patch test reactions to metals, and 10 (67%) of them had reactions to metals that were present in their implants. Six (60%) of these patients had their implants removed and their symptoms resolved; the remaining 4 continued to experience implant symptoms.¹² These studies support the existence of rare metal-related orthopedic IHRs and support the concept of proceeding with orthopedic implant revision when indicated, safe, and agreed upon by the surgeon and patient. However, as noted in the series by Zondervan et al,¹¹ not every patient with confirmed metal allergy who undergoes revision improves, so an informed conversation between the patient and surgeon is mandatory.

Types of Orthopedic Implants

Orthopedic implanted materials consist of either dynamic (knees, hips) or static (screws, plates) components. Several generations of hip implants have evolved since the 1960s. First-generation implanted hips were metal-on-metal and had high rates of metal release and sensitization. Metal-on-plastic implants may be less likely to release metal but instead release large polyethylene wear particles. Second-generation metal-on-metal implants reportedly have lower wear rates. With these implants, wear particles are generated but are reportedly smaller than first-generation particles.¹³

Allergens in IHRs

Metals
Metals are the most commonly implicated allergens in orthopedic IHRs. Potentially relevant metal alloys include 316L stainless steel, cobalt-chromium-molybdenum steel, Vitallium alloy, titanium alloy, titanium-tantalum-niobium alloy, and Oxinium (Smith & Nephew).^14,15 Each alloy contains several metals, which can include nickel, chromium, cobalt, manganese, molybdenum, iron, titanium, aluminum, vanadium, niobium, tantalum, and zirconium, among others. For example, 316L stainless steel contains iron, nickel, chromium, manganese, molybdenum, nitrogen, carbon, sulfur, silicon, and phosphorus, whereas Oxinium contains only oxidized zirconium and niobium.

Bone Cement
Bone cement also has been reported in cases of orthopedic IHRs and can contain several chemicals, including methyl methacrylate, N,N-dimethyl-p-toluidine, benzoyl peroxide, hydroquinone, and gentamicin.¹⁴ Other potential exposures include adhesives (cyanoacrylates) and topical antibiotics.

Clinical Presentation

Several clinical presentations of orthopedic IHRs have been described. Perhaps the most commonly recognized is a localized cutaneous eczematous eruption, with dermatitis typically overlying the site of the implanted material.^1,2,16 Generalized cutaneous eczematous IHRs also have been reported, including diffuse generalized dermatitis from a stainless steel orthopedic screw⁴ and nummular dermatitis attributed to vanadium in an orthopedic plate.⁵ Urticaria, vasculitis, and bullous cutaneous reactions, as well as extracutaneous complications, also have been reported.^14,15 Pain, edema, joint loosening or failure, and poor wound healing have been reported,¹² but it remains unclear whether these symptoms represent IHR.

Patch Testing for IHR

Several groups have published recommended patch test series for IHR.^12,14,15 Common components of implant patch testing panels include metals, adhesives (acrylates, epoxy resins) and antibiotics. Importantly, obtaining product information from the manufacturer of the suspected implant can guide which allergens to include in patch testing. Implant and metal panels also are available for commercial purchase.

Other Diagnostic Tests

We rarely (almost never) order LTTs in the workup for potential IHRs. This is an in vitro test that includes lymphocytes, metal ions, and the radioactive marker methyl-3H-thymidine. The goal of the test is to evaluate if patient lymphocytes are reactive or responsive to metal ions. A positive LTT suggests that lymphocytes can respond to the presence of metal ions but does not confirm allergy or the presence of IHR.

Typically, skin or tissue biopsies are not required to make a diagnosis of IHR; however, if performed, histopathology suggestive of IHR can support a suspected diagnosis. Typical findings include but are not limited to spongiotic dermatitis. Eosinophils may or may not be present. Metal disc testing has been utilized for orthopedic IHR but is not currently recommended due to low diagnostic yield. Prick testing rarely is used and also is not a primary method for diagnosis of IHR.¹⁷

Preimplantation Patch Testing

Expert opinion guidelines published by the American Contact Dermatitis Society (ACDS) state that routine preimplantation patch testing is not necessary; however, for those patients with a clear history of contact reactions to metal, preimplantation patch testing can be considered.¹⁷

Patch test results can influence the orthopedic surgeon’s choice of implant material. In one study, when preimplantation patch testing showed a positive patch test reaction to metals, the results influenced the surgeon’s decision-making in all cases.¹²

Postimplantation Patch Testing: Diagnostic Criteria for Metal IHR After Implantation

From 2012 to 2013, Schalock and Thyssen¹⁸ surveyed expert attendees at meetings of the European Society of Contact Dermatitis and the ACDS for their opinions on proposed diagnostic criteria for metal IHRs. Based on these results (N=119), the authors stratified 4 major and 5 minor diagnostic criteria, which were defined based on overall responses of meeting attendees. Major criteria included (1) chronic dermatitis beginning weeks to months after metallic implantation, (2) complete recovery after removal of the offending implant, (3) eruption overlying the metal implant, and (4) positive patch test reaction to a metal used in the implant. Minor criteria included (1) histology consistent with allergic contact dermatitis, (2) morphology consistent with dermatitis (ie, erythema, induration, papules, vesicles), (3) positive in vitro test to metals (eg, lymphocyte transformation test), (4) systemic allergic dermatitis reaction, and (5) therapy-resistant dermatitis reaction. The authors did not describe a scoring system for evaluation and confirmation of a diagnosis of IHR. Instead, the criteria should be used as general guidelines when evaluating patients for possible IHRs. From a standpoint of available diagnostic tests for metal IHR, 86.1% of experts agreed that a positive patch test reaction to a metal used in the implant was suggestive of a diagnosis, whereas a positive in vitro test to metals (LTT) was suggestive of a diagnosis for only 32.2% of respondents. This study was designed specifically for metal IHRs and therefore is not necessarily generalizable for nonmetal IHRs.¹⁸

Final Interpretation

We follow the 2016 ACDS guidelines¹⁷ and complete preimplantation patch testing only in the setting of suspected metal allergy and postimplantation patch testing based on the guidelines described by Schalock and Thyssen.¹⁸ However, an extended conversation is warranted prior to patch testing to ensure the patient fully understands the limitations of the test. Although we have both ordered the LTT, interpretation remains murky, and until this test is standardized, routine use is unlikely to benefit the patient. Until we are more reliably able to predict who will develop hypersensitivity to implanted metals, the decision to remove or revise an implant is one that should be made by a multidisciplinary team that includes the surgeon and the patient.

Hypersensitivity to metal implants remains a controversial field in contact dermatitis and patch testing. With positive reactions to nickel hovering around 20% in patch-tested populations,¹ the question remains whether metal-allergic patients can safely receive metal implants. Unfortunately, large controlled studies are lacking, in part due to ethical concerns of knowingly placing a metal implant in a metal-allergic patient. Much of the focus of implant hypersensitivity reactions (IHRs) has been on orthopedic joints including hips, knees, and shoulders, as well as fixed orthopedic implanted materials such as screws and plates. However, there have been reports of IHRs to cardiac devices including defibrillators, pacemakers, and intracardiac devices; dental hardware including implants, crowns, dentures, and braces; and neurologic and gynecologic devices. For the purposes of this review, we will focus on IHRs to orthopedic implants.

Making the Case for IHRs

There are multiple case reports and series documenting likely orthopedic IHRs in the literature^2-5; however, large prospective studies are lacking. Some of the largest series are from Danish registry studies. In 2009, Thyssen et al⁶ reviewed356 patients who had undergone both total hip arthroplasty and patch testing. Metal allergy frequencies were similar between patch-tested registry patients and patch test controls, showing no increase in positive patch tests to metals after receiving implants. Additionally, implant revision rates were comparable between registry patients with and without patch testing. The group concluded that the risk for revision after hip implantation in metal-allergic patients and the risk for development of metal allergy after implantation were both low.⁶ In 2015, Münch et al⁷ compared 327 patients who had undergone both total knee arthroplasty and patch testing and found that prevalence of allergy to nickel, cobalt, and chromium was similar between patients who had undergone revision surgery and those who had not; however, for patients who had 2 or more knee revisions, there was a higher prevalence of postimplant metal allergy. This study also showed that metal allergy identified before implantation did not increase the risk for postimplantation knee revision surgery or implant failure.⁷ These larger studies suggest that although individual cases of IHR exist, it is likely quite rare.

Patients have been found to have increased levels of chromium (serum and urine) and titanium (serum) following total hip arthroplasty.⁸ Additionally, metal wear particles have been identified in postmortem livers and spleens, which was more prevalent in patients with a history of failed hip arthroplasty.⁹ It is difficult to determine the meaning of this data, as the presence of metal ions does not necessarily indicate allergy or IHR. In 2001, Hallab et al¹⁰ pooled data from several implant cohort studies and concluded that in comparison to a baseline metal sensitivity prevalence of approximately 10%, patients with well-functioning implants had a metal sensitivity–weighted average of 25%, and those with poorly functioning implants had a weighted average of 60%. Again, positive patch testing to metals does not necessarily implicate allergy as the cause of implant failure.

Some small studies have shown that patients with evidence of metal hypersensitivity improve with revision. Zondervan et al¹¹ reviewed results of 46 orthopedic revisions following painful total knee arthroplasty. Patients with knee pain and lymphocyte transformation testing (LTT) positive for metals received hypoallergenic revisions, and those with LTT negative for metals received standard revisions. The group who received hypoallergenic revisions had more pain reduction compared to the standard revision group (37.8% reduction in pain vs 27%). However, this study was limited in that the diagnosis of metal allergy was made entirely on results of LTT.¹¹ In 2012, Atanaskova Mesinkovska et al¹² described 41 patients who underwent orthopedic patch testing following implantation for symptoms including pain, dermatitis, pruritus, joint loosening, edema, and impaired wound healing. Fifteen (37%) patients had positive patch test reactions to metals, and 10 (67%) of them had reactions to metals that were present in their implants. Six (60%) of these patients had their implants removed and their symptoms resolved; the remaining 4 continued to experience implant symptoms.¹² These studies support the existence of rare metal-related orthopedic IHRs and support the concept of proceeding with orthopedic implant revision when indicated, safe, and agreed upon by the surgeon and patient. However, as noted in the series by Zondervan et al,¹¹ not every patient with confirmed metal allergy who undergoes revision improves, so an informed conversation between the patient and surgeon is mandatory.

Types of Orthopedic Implants

Orthopedic implanted materials consist of either dynamic (knees, hips) or static (screws, plates) components. Several generations of hip implants have evolved since the 1960s. First-generation implanted hips were metal-on-metal and had high rates of metal release and sensitization. Metal-on-plastic implants may be less likely to release metal but instead release large polyethylene wear particles. Second-generation metal-on-metal implants reportedly have lower wear rates. With these implants, wear particles are generated but are reportedly smaller than first-generation particles.¹³

Allergens in IHRs

Metals
Metals are the most commonly implicated allergens in orthopedic IHRs. Potentially relevant metal alloys include 316L stainless steel, cobalt-chromium-molybdenum steel, Vitallium alloy, titanium alloy, titanium-tantalum-niobium alloy, and Oxinium (Smith & Nephew).^14,15 Each alloy contains several metals, which can include nickel, chromium, cobalt, manganese, molybdenum, iron, titanium, aluminum, vanadium, niobium, tantalum, and zirconium, among others. For example, 316L stainless steel contains iron, nickel, chromium, manganese, molybdenum, nitrogen, carbon, sulfur, silicon, and phosphorus, whereas Oxinium contains only oxidized zirconium and niobium.

Bone Cement
Bone cement also has been reported in cases of orthopedic IHRs and can contain several chemicals, including methyl methacrylate, N,N-dimethyl-p-toluidine, benzoyl peroxide, hydroquinone, and gentamicin.¹⁴ Other potential exposures include adhesives (cyanoacrylates) and topical antibiotics.

Clinical Presentation

Several clinical presentations of orthopedic IHRs have been described. Perhaps the most commonly recognized is a localized cutaneous eczematous eruption, with dermatitis typically overlying the site of the implanted material.^1,2,16 Generalized cutaneous eczematous IHRs also have been reported, including diffuse generalized dermatitis from a stainless steel orthopedic screw⁴ and nummular dermatitis attributed to vanadium in an orthopedic plate.⁵ Urticaria, vasculitis, and bullous cutaneous reactions, as well as extracutaneous complications, also have been reported.^14,15 Pain, edema, joint loosening or failure, and poor wound healing have been reported,¹² but it remains unclear whether these symptoms represent IHR.

Patch Testing for IHR

Several groups have published recommended patch test series for IHR.^12,14,15 Common components of implant patch testing panels include metals, adhesives (acrylates, epoxy resins) and antibiotics. Importantly, obtaining product information from the manufacturer of the suspected implant can guide which allergens to include in patch testing. Implant and metal panels also are available for commercial purchase.

Other Diagnostic Tests

We rarely (almost never) order LTTs in the workup for potential IHRs. This is an in vitro test that includes lymphocytes, metal ions, and the radioactive marker methyl-3H-thymidine. The goal of the test is to evaluate if patient lymphocytes are reactive or responsive to metal ions. A positive LTT suggests that lymphocytes can respond to the presence of metal ions but does not confirm allergy or the presence of IHR.

Typically, skin or tissue biopsies are not required to make a diagnosis of IHR; however, if performed, histopathology suggestive of IHR can support a suspected diagnosis. Typical findings include but are not limited to spongiotic dermatitis. Eosinophils may or may not be present. Metal disc testing has been utilized for orthopedic IHR but is not currently recommended due to low diagnostic yield. Prick testing rarely is used and also is not a primary method for diagnosis of IHR.¹⁷

Preimplantation Patch Testing

Expert opinion guidelines published by the American Contact Dermatitis Society (ACDS) state that routine preimplantation patch testing is not necessary; however, for those patients with a clear history of contact reactions to metal, preimplantation patch testing can be considered.¹⁷

Patch test results can influence the orthopedic surgeon’s choice of implant material. In one study, when preimplantation patch testing showed a positive patch test reaction to metals, the results influenced the surgeon’s decision-making in all cases.¹²

Postimplantation Patch Testing: Diagnostic Criteria for Metal IHR After Implantation

From 2012 to 2013, Schalock and Thyssen¹⁸ surveyed expert attendees at meetings of the European Society of Contact Dermatitis and the ACDS for their opinions on proposed diagnostic criteria for metal IHRs. Based on these results (N=119), the authors stratified 4 major and 5 minor diagnostic criteria, which were defined based on overall responses of meeting attendees. Major criteria included (1) chronic dermatitis beginning weeks to months after metallic implantation, (2) complete recovery after removal of the offending implant, (3) eruption overlying the metal implant, and (4) positive patch test reaction to a metal used in the implant. Minor criteria included (1) histology consistent with allergic contact dermatitis, (2) morphology consistent with dermatitis (ie, erythema, induration, papules, vesicles), (3) positive in vitro test to metals (eg, lymphocyte transformation test), (4) systemic allergic dermatitis reaction, and (5) therapy-resistant dermatitis reaction. The authors did not describe a scoring system for evaluation and confirmation of a diagnosis of IHR. Instead, the criteria should be used as general guidelines when evaluating patients for possible IHRs. From a standpoint of available diagnostic tests for metal IHR, 86.1% of experts agreed that a positive patch test reaction to a metal used in the implant was suggestive of a diagnosis, whereas a positive in vitro test to metals (LTT) was suggestive of a diagnosis for only 32.2% of respondents. This study was designed specifically for metal IHRs and therefore is not necessarily generalizable for nonmetal IHRs.¹⁸

Final Interpretation

We follow the 2016 ACDS guidelines¹⁷ and complete preimplantation patch testing only in the setting of suspected metal allergy and postimplantation patch testing based on the guidelines described by Schalock and Thyssen.¹⁸ However, an extended conversation is warranted prior to patch testing to ensure the patient fully understands the limitations of the test. Although we have both ordered the LTT, interpretation remains murky, and until this test is standardized, routine use is unlikely to benefit the patient. Until we are more reliably able to predict who will develop hypersensitivity to implanted metals, the decision to remove or revise an implant is one that should be made by a multidisciplinary team that includes the surgeon and the patient.