MDedge Dermatology

NEW ORLEANS – As the study of cutaneous dysbiosis and its role in the pathogenesis of dermatoses continues to evolve, how the mounting evidence on this topic translates into clinical practice remains largely unknown.

“There’s still a lot for us to learn,” Adam Friedman, MD, professor and chair of dermatology at George Washington University, Washington, said at the annual meeting of the American Academy of Dermatology. “Multiple factors contribute to the variability in the skin microbiota, including age, sex, environment, immune system, host genotype, lifestyle, and pathobiology. The question becomes, when do these factors or impacts on the microbiota become clinically significant?”

According to Dr. Friedman, there are 10 times more bacteria cells than human cells in the human body, “but it’s not a fight to the finish; it’s not us versus them,” he said. “Together, we are a super organism.” There are also more than 500 species of bacteria on human skin excluding viruses and fungi, and each person carries up to 5 pounds of bacteria, which is akin to finding a new organ in the body.

Credit: Daryl Leja, NHGRI (National Human Genome Research Institute)

“What’s so unique is that we each have our own bacterial fingerprint,” he said. “Whoever is sitting next to you? Their microbiota makeup is different than yours.”

Beyond genetics and environment, activities that can contribute to alterations in skin flora or skin dysbiosis include topical application of steroids, antibiotics, retinoids, harsh soaps, chemical and physical exfoliants, and resurfacing techniques. “With anything we apply or do to the skin, we are literally changing the home of many microorganisms, for good or bad,” he said.

In the realm of atopic dermatitis (AD), Staphylococcus aureus has been implicated as an offender in the pathophysiology of the disease. “It’s not about one single species of Staphylococcus, though,” said Dr. Friedman, who also is director of translational research at George Washington University. “We’re finding out that, depending on the severity of disease, Staph. epidermis may be part of the problem as opposed to it just being about Staph. aureus. Furthermore, and more importantly, these changes in the microbiota, specifically a decrease in microbial diversity, has been shown to precede a disease flare, highlighting the central role of maintaining microbial diversity and by definition, supporting the living barrier in our management of AD.”

With this in mind, researchers in one study used high-throughput sequencing to evaluate the microbial communities associated with affected and unaffected skin of 49 patients with AD before and after emollient treatment. Following 84 days of emollient application, clinical symptoms of AD improved in 72% of the study population and Stenotrophomonas species were significantly more abundant among responders.
 

Prebiotics, probiotics

“Our treatments certainly can positively impact the microbiota, as we have seen even recently with some of our new targeted therapies, but we can also directly provide support,” he continued. Prebiotics, which he defined as supplements or foods that contain a nondigestible ingredient that selectively stimulates the growth and/or activity of indigenous bacteria, can be found in many over-the-counter moisturizers.

For example, colloidal oatmeal has been found to support the growth of S. epidermidis and enhance the production of lactic acid. “We really don’t know much about what these induced changes mean from a clinical perspective; that has yet to be elucidated,” Dr. Friedman said.

In light of the recent attention to the early application of moisturizers in infants at high risk of developing AD in an effort to prevent or limit AD, “maybe part of this has to do with applying something that’s nurturing an evolving microbiota,” Dr. Friedman noted. “It’s something to think about.”

Yet another area of study involves the use of probiotics, which Dr. Friedman defined as supplements or foods that contain viable microorganisms that alter the microflora of the host. In a first-of-its-kind trial, researchers evaluated the safety and efficacy of self-administered topical Roseomonas mucosa in 10 adults and 5 children with AD. No adverse events or treatment complications were observed, and the topical R. mucosa was associated with significant decreases in measures of disease severity, topical steroid requirement, and S. aureus burden

In a more recent randomized trial of 11 patients with AD, Richard L. Gallo, MD, PhD, chair of dermatology, University of California, San Diego, and colleagues found that application of a personalized topical cream formulated from coagulase-negative Staphylococcus with antimicrobial activity against S. aureus reduced colonization of S. aureus and improved disease severity.

And in another randomized, controlled trial, Italian researchers enrolled 80 adults with mild to severe AD to receive a placebo or a supplement that was a mixture of lactobacilli for 56 days. They found that adults in the treatment arm showed an improvement in skin smoothness, skin moisturization, self-perception, and a decrease in the SCORing Atopic Dermatitis (SCORAD) index as well as in levels of inflammatory markers associated with AD.

Dr. Friedman also discussed postbiotics, nonviable bacterial products or metabolic byproducts from probiotic microorganisms that have biologic activity in the host. In one trial, French researchers enrolled 75 people with AD who ranged in age from 6 to 70 years to receive a cream containing a 5% lysate of the nonpathogenic bacteria Vitreoscilla filiformis, or a vehicle cream for 30 days. They found that compared with the vehicle, V. filiformis lysate significantly decreased SCORAD levels and pruritus; active cream was shown to significantly decrease loss of sleep from day 0 to day 29.

Dr. Friedman characterized these novel approaches to AD as “an exciting area, one we need to pay attention to. But what I really want to know is, aside from these purposefully made and marketed products that have pre- and postprobiotics, is there a difference with some of the products we use already? My assumption is that there is, but we need to see that data.”

Dr. Friedman disclosed that he is a consultant and/or advisory board member for Medscape/SanovaWorks, Oakstone Institute, L’Oréal, La Roche Posay, Galderma, Aveeno, Ortho Dermatologic, Microcures, Pfizer, Novartis, Lilly, Hoth Therapeutics, Zylo Therapeutics, BMS, Vial, Janssen, Novocure, Dermavant, Regeneron/Sanofi, and Incyte. He has also received grants from Pfizer, the Dermatology Foundation, Lilly, Janssen, Incyte, and Galderma.

NEW ORLEANS – As the study of cutaneous dysbiosis and its role in the pathogenesis of dermatoses continues to evolve, how the mounting evidence on this topic translates into clinical practice remains largely unknown.

“There’s still a lot for us to learn,” Adam Friedman, MD, professor and chair of dermatology at George Washington University, Washington, said at the annual meeting of the American Academy of Dermatology. “Multiple factors contribute to the variability in the skin microbiota, including age, sex, environment, immune system, host genotype, lifestyle, and pathobiology. The question becomes, when do these factors or impacts on the microbiota become clinically significant?”

According to Dr. Friedman, there are 10 times more bacteria cells than human cells in the human body, “but it’s not a fight to the finish; it’s not us versus them,” he said. “Together, we are a super organism.” There are also more than 500 species of bacteria on human skin excluding viruses and fungi, and each person carries up to 5 pounds of bacteria, which is akin to finding a new organ in the body.

Credit: Daryl Leja, NHGRI (National Human Genome Research Institute)

“What’s so unique is that we each have our own bacterial fingerprint,” he said. “Whoever is sitting next to you? Their microbiota makeup is different than yours.”

Beyond genetics and environment, activities that can contribute to alterations in skin flora or skin dysbiosis include topical application of steroids, antibiotics, retinoids, harsh soaps, chemical and physical exfoliants, and resurfacing techniques. “With anything we apply or do to the skin, we are literally changing the home of many microorganisms, for good or bad,” he said.

In the realm of atopic dermatitis (AD), Staphylococcus aureus has been implicated as an offender in the pathophysiology of the disease. “It’s not about one single species of Staphylococcus, though,” said Dr. Friedman, who also is director of translational research at George Washington University. “We’re finding out that, depending on the severity of disease, Staph. epidermis may be part of the problem as opposed to it just being about Staph. aureus. Furthermore, and more importantly, these changes in the microbiota, specifically a decrease in microbial diversity, has been shown to precede a disease flare, highlighting the central role of maintaining microbial diversity and by definition, supporting the living barrier in our management of AD.”

With this in mind, researchers in one study used high-throughput sequencing to evaluate the microbial communities associated with affected and unaffected skin of 49 patients with AD before and after emollient treatment. Following 84 days of emollient application, clinical symptoms of AD improved in 72% of the study population and Stenotrophomonas species were significantly more abundant among responders.
 

Prebiotics, probiotics

“Our treatments certainly can positively impact the microbiota, as we have seen even recently with some of our new targeted therapies, but we can also directly provide support,” he continued. Prebiotics, which he defined as supplements or foods that contain a nondigestible ingredient that selectively stimulates the growth and/or activity of indigenous bacteria, can be found in many over-the-counter moisturizers.

For example, colloidal oatmeal has been found to support the growth of S. epidermidis and enhance the production of lactic acid. “We really don’t know much about what these induced changes mean from a clinical perspective; that has yet to be elucidated,” Dr. Friedman said.

In light of the recent attention to the early application of moisturizers in infants at high risk of developing AD in an effort to prevent or limit AD, “maybe part of this has to do with applying something that’s nurturing an evolving microbiota,” Dr. Friedman noted. “It’s something to think about.”

Yet another area of study involves the use of probiotics, which Dr. Friedman defined as supplements or foods that contain viable microorganisms that alter the microflora of the host. In a first-of-its-kind trial, researchers evaluated the safety and efficacy of self-administered topical Roseomonas mucosa in 10 adults and 5 children with AD. No adverse events or treatment complications were observed, and the topical R. mucosa was associated with significant decreases in measures of disease severity, topical steroid requirement, and S. aureus burden

In a more recent randomized trial of 11 patients with AD, Richard L. Gallo, MD, PhD, chair of dermatology, University of California, San Diego, and colleagues found that application of a personalized topical cream formulated from coagulase-negative Staphylococcus with antimicrobial activity against S. aureus reduced colonization of S. aureus and improved disease severity.

And in another randomized, controlled trial, Italian researchers enrolled 80 adults with mild to severe AD to receive a placebo or a supplement that was a mixture of lactobacilli for 56 days. They found that adults in the treatment arm showed an improvement in skin smoothness, skin moisturization, self-perception, and a decrease in the SCORing Atopic Dermatitis (SCORAD) index as well as in levels of inflammatory markers associated with AD.

Dr. Friedman also discussed postbiotics, nonviable bacterial products or metabolic byproducts from probiotic microorganisms that have biologic activity in the host. In one trial, French researchers enrolled 75 people with AD who ranged in age from 6 to 70 years to receive a cream containing a 5% lysate of the nonpathogenic bacteria Vitreoscilla filiformis, or a vehicle cream for 30 days. They found that compared with the vehicle, V. filiformis lysate significantly decreased SCORAD levels and pruritus; active cream was shown to significantly decrease loss of sleep from day 0 to day 29.

Dr. Friedman characterized these novel approaches to AD as “an exciting area, one we need to pay attention to. But what I really want to know is, aside from these purposefully made and marketed products that have pre- and postprobiotics, is there a difference with some of the products we use already? My assumption is that there is, but we need to see that data.”

Dr. Friedman disclosed that he is a consultant and/or advisory board member for Medscape/SanovaWorks, Oakstone Institute, L’Oréal, La Roche Posay, Galderma, Aveeno, Ortho Dermatologic, Microcures, Pfizer, Novartis, Lilly, Hoth Therapeutics, Zylo Therapeutics, BMS, Vial, Janssen, Novocure, Dermavant, Regeneron/Sanofi, and Incyte. He has also received grants from Pfizer, the Dermatology Foundation, Lilly, Janssen, Incyte, and Galderma.

NEW ORLEANS – As the study of cutaneous dysbiosis and its role in the pathogenesis of dermatoses continues to evolve, how the mounting evidence on this topic translates into clinical practice remains largely unknown.

“There’s still a lot for us to learn,” Adam Friedman, MD, professor and chair of dermatology at George Washington University, Washington, said at the annual meeting of the American Academy of Dermatology. “Multiple factors contribute to the variability in the skin microbiota, including age, sex, environment, immune system, host genotype, lifestyle, and pathobiology. The question becomes, when do these factors or impacts on the microbiota become clinically significant?”

According to Dr. Friedman, there are 10 times more bacteria cells than human cells in the human body, “but it’s not a fight to the finish; it’s not us versus them,” he said. “Together, we are a super organism.” There are also more than 500 species of bacteria on human skin excluding viruses and fungi, and each person carries up to 5 pounds of bacteria, which is akin to finding a new organ in the body.

Credit: Daryl Leja, NHGRI (National Human Genome Research Institute)

“What’s so unique is that we each have our own bacterial fingerprint,” he said. “Whoever is sitting next to you? Their microbiota makeup is different than yours.”

Beyond genetics and environment, activities that can contribute to alterations in skin flora or skin dysbiosis include topical application of steroids, antibiotics, retinoids, harsh soaps, chemical and physical exfoliants, and resurfacing techniques. “With anything we apply or do to the skin, we are literally changing the home of many microorganisms, for good or bad,” he said.

In the realm of atopic dermatitis (AD), Staphylococcus aureus has been implicated as an offender in the pathophysiology of the disease. “It’s not about one single species of Staphylococcus, though,” said Dr. Friedman, who also is director of translational research at George Washington University. “We’re finding out that, depending on the severity of disease, Staph. epidermis may be part of the problem as opposed to it just being about Staph. aureus. Furthermore, and more importantly, these changes in the microbiota, specifically a decrease in microbial diversity, has been shown to precede a disease flare, highlighting the central role of maintaining microbial diversity and by definition, supporting the living barrier in our management of AD.”

With this in mind, researchers in one study used high-throughput sequencing to evaluate the microbial communities associated with affected and unaffected skin of 49 patients with AD before and after emollient treatment. Following 84 days of emollient application, clinical symptoms of AD improved in 72% of the study population and Stenotrophomonas species were significantly more abundant among responders.
 

Prebiotics, probiotics

“Our treatments certainly can positively impact the microbiota, as we have seen even recently with some of our new targeted therapies, but we can also directly provide support,” he continued. Prebiotics, which he defined as supplements or foods that contain a nondigestible ingredient that selectively stimulates the growth and/or activity of indigenous bacteria, can be found in many over-the-counter moisturizers.

For example, colloidal oatmeal has been found to support the growth of S. epidermidis and enhance the production of lactic acid. “We really don’t know much about what these induced changes mean from a clinical perspective; that has yet to be elucidated,” Dr. Friedman said.

In light of the recent attention to the early application of moisturizers in infants at high risk of developing AD in an effort to prevent or limit AD, “maybe part of this has to do with applying something that’s nurturing an evolving microbiota,” Dr. Friedman noted. “It’s something to think about.”

Yet another area of study involves the use of probiotics, which Dr. Friedman defined as supplements or foods that contain viable microorganisms that alter the microflora of the host. In a first-of-its-kind trial, researchers evaluated the safety and efficacy of self-administered topical Roseomonas mucosa in 10 adults and 5 children with AD. No adverse events or treatment complications were observed, and the topical R. mucosa was associated with significant decreases in measures of disease severity, topical steroid requirement, and S. aureus burden

In a more recent randomized trial of 11 patients with AD, Richard L. Gallo, MD, PhD, chair of dermatology, University of California, San Diego, and colleagues found that application of a personalized topical cream formulated from coagulase-negative Staphylococcus with antimicrobial activity against S. aureus reduced colonization of S. aureus and improved disease severity.

And in another randomized, controlled trial, Italian researchers enrolled 80 adults with mild to severe AD to receive a placebo or a supplement that was a mixture of lactobacilli for 56 days. They found that adults in the treatment arm showed an improvement in skin smoothness, skin moisturization, self-perception, and a decrease in the SCORing Atopic Dermatitis (SCORAD) index as well as in levels of inflammatory markers associated with AD.

Dr. Friedman also discussed postbiotics, nonviable bacterial products or metabolic byproducts from probiotic microorganisms that have biologic activity in the host. In one trial, French researchers enrolled 75 people with AD who ranged in age from 6 to 70 years to receive a cream containing a 5% lysate of the nonpathogenic bacteria Vitreoscilla filiformis, or a vehicle cream for 30 days. They found that compared with the vehicle, V. filiformis lysate significantly decreased SCORAD levels and pruritus; active cream was shown to significantly decrease loss of sleep from day 0 to day 29.

Dr. Friedman characterized these novel approaches to AD as “an exciting area, one we need to pay attention to. But what I really want to know is, aside from these purposefully made and marketed products that have pre- and postprobiotics, is there a difference with some of the products we use already? My assumption is that there is, but we need to see that data.”

Dr. Friedman disclosed that he is a consultant and/or advisory board member for Medscape/SanovaWorks, Oakstone Institute, L’Oréal, La Roche Posay, Galderma, Aveeno, Ortho Dermatologic, Microcures, Pfizer, Novartis, Lilly, Hoth Therapeutics, Zylo Therapeutics, BMS, Vial, Janssen, Novocure, Dermavant, Regeneron/Sanofi, and Incyte. He has also received grants from Pfizer, the Dermatology Foundation, Lilly, Janssen, Incyte, and Galderma.

Court cases show that physicians continually underestimate their liability in supervising nurse practitioners (NPs) and physician assistants (PAs).

Even in states that have abolished requirements that NPs be physician-supervised, physicians may still be liable by virtue of employing the NP, according to William P. Sullivan, DO, an attorney and emergency physician in Frankfort, Ill.

Indeed, the vast majority of lawsuits against NPs and PAs name the supervising physician. According to a study of claims against NPs from 2011 to 2016, 82% of the cases also named the supervising physician.

Employed or contracted physicians assigned to supervise NPs or PAs are also affected, Dr. Sullivan said. “The employed physicians’ contract with a hospital or staffing company may require them to assist in the selection, supervision, and/or training of NPs or PAs,” he said. He added that supervisory duties may also be assigned through hospital bylaws.

“The physician is usually not paid anything extra for this work and may not be given extra time to perform it,” Dr. Sullivan said. But still, he said, that physician could be named in a lawsuit and wind up bearing some responsibility for an NP’s or PA’s mistake.

In addition to facing medical malpractice suits, Dr. Sullivan said, doctors are often sanctioned by state licensure boards for improperly supervising NPs and PAs. Licensure boards often require extensive protocols for supervision of NPs and PAs.
 

Yet more states are removing supervision requirements

With the addition of Kansas and New York in 2022 and California in 2023, 27 states no longer require supervision for all or most NPs. Sixteen of those states, including New York and California, have instituted progressive practice authority that requires temporary supervision of new NPs but then removes supervision after a period of 6 months to 4 years, depending on the state, for the rest of their career.

“When it comes to NP independence, the horse is already out of the barn,” Dr. Sullivan said. “It’s unlikely that states will repeal laws granting NPs independence, and in fact, more states are likely to pass them.”

*PAs, in contrast, are well behind NPs in achieving independence, but the American Academy of Physician Associates (AAPA) is calling to eliminate a mandated relationship with a specific physician. So far, Utah, North Dakota and Wyoming have ended physician supervision of PAs, while California and Hawaii have eliminated mandated chart review. Other states are considering eliminating physician supervision of PAs, according to the AAPA.

In states that have abolished oversight requirements for NPs, “liability can then shift to the NP when the NP is fully independent,” Cathy Klein, an advanced practice registered nurse who helped found the NP profession 50 years ago, told this news organization. “More NPs are starting their own practices, and in many cases, patients actually prefer to see an NP.”

As more NPs became more autonomous, the average payment that NPs incurred in professional liability lawsuits rose by 10.5% from 2017 to 2022, to $332,187, according to the Nurses Service Organization (NSO), a nursing malpractice insurer.

The number of malpractice judgments against autonomous NPs alone has also been rising. From 2012 to 2017, autonomous NPs’ share of all NP cases rose from 7% to 16.4%, the NSO reported.

The good news for physicians is that states’ removal of restrictions on NPs has reduced physicians’ liability to some extent. A 2017 study found that enacting less restrictive scope-of-practice laws for NPs decreased the number of payments made by physicians in NP cases by as much as 31%.

However, the top location for NP payouts remains the physician’s office, not the autonomous NP’s practice, according to the latter NSO report. Plaintiffs sue NPs’ and PAs’ supervising physicians on the basis of legal concepts, such as vicarious liability and respondeat superior. Even if the physician-employer never saw the patient, he or she can be held liable.

Court cases in which supervising physician was found liable

There are plenty of judgments against supervising or collaborating physicians when the NP or PA made the error. Typically, the doctor was faulted for paying little attention to the NP or PA he or she was supposed to supervise.

Dr. Sullivan points to a 2016 case in which a New York jury held a physician 40% liable for a $7 million judgment in a malpractice case involving a PA’s care of a patient in the emergency department. The case is Shajan v. South Nassau Community Hospital in New York.

“The patient presented with nontraumatic leg pain to his lower leg, was diagnosed by the PA with a muscle strain, and discharged without a physician evaluation,” Dr. Sullivan said. The next day, the patient visited an orthopedist who immediately diagnosed compartment syndrome, an emergent condition in which pressure builds up in an affected extremity, damaging the muscles and nerves. “The patient developed irreversible nerve damage and chronic regional pain syndrome,” he said.

A malpractice lawsuit named the PA and the emergency physician he was supposed to be reporting to. Even though the physician had never seen the patient, he had signed off on the PA’s note from a patient’s ED visit. “Testimony during the trial focused on hospital protocols that the supervising physician was supposed to take,” Dr. Sullivan said.

When doctors share fault, they frequently failed to follow the collaborative agreement with the NP or PA. In Collip v. Ratts, a 2015 Indiana case in which the patient died from a drug interaction, the doctor’s certified public accountant stated that the doctor was required to review at least 5% of the NP’s charts every week to evaluate her prescriptive practices.

The doctor admitted that he never reviewed the NP’s charts on a weekly basis. He did conduct some cursory reviews of some of the NP’s notes, and in them he noted concerns for her prescribing practices and suggested she attend a narcotics-prescribing seminar, but he did not follow up to make sure she had done this.

Sometimes the NP or PA who made the mistake may actually be dropped from the lawsuit, leaving the supervising physician fully liable. In these cases, courts reason that a fully engaged supervisor could have prevented the error. In the 2006 case of  Husak v. Siegal, the Florida Supreme Court dropped the NP from the case, ruling that the NP had provided the supervising doctor all the information he needed in order to tell her what to do for the patient.

The court noted the physician had failed to look at the chart, even though he was required to do so under his supervisory agreement with the NP. The doctor “could have made the correct diagnosis or referral had he been attentive,” the court said. Therefore, there was “no evidence of independent negligence” by the NP, even though she was the one who had made the incorrect diagnosis that harmed the patient.

When states require an autonomous NP to have a supervisory relationship with a doctor, the supervisor may be unavailable and may fail to designate a substitute. In Texas in January 2019, a 7-year-old girl died of pneumonia after being treated by an NP in an urgent care clinic. The NP had told the parents that the child could safely go home and only needed ibuprofen. The parents brought the girl back home, and she died 15 hours later. The Wattenbargers sued the NP, and the doctor’s supervision was a topic in the trial.

The supervising physician for the NP was out of the country at the time. He said that he had found a substitute, but the substitute doctor testified she had no idea she was designated to be the substitute, according to Niran Al-Agba, MD, a family physician in Silverdale, Wash., who has written on the Texas case. Dr. Al-Agba told this news organization the case appears to have been settled confidentially.
 

Different standards for expert witnesses

In many states, courts do not allow physicians to testify as expert witnesses in malpractice cases against NPs, arguing that nurses have a different set of standards than doctors have, Dr. Sullivan reported.

These states include Arkansas, Illinois, North Carolina, and New York, according to a report by SEAK Inc., an expert witness training program. The report said most other states allow physician experts in these cases, but they may still require that they have experience with the nursing standard of care.

Dr. Sullivan said some courts are whittling away at the ban on physician experts, and the ban may eventually disappear. He reported that in Oklahoma, which normally upholds the ban, a judge recently allowed a physician-expert to testify in a case involving the death of a 19-year-old woman, Alexus Ochoa, in an ED staffed by an NP. The judge reasoned that Ms. Ochoa’s parents assumed the ED was staffed by physicians and would adhere to medical standards.
 

Supervision pointers from a physician

Physicians who supervise NPs or PAs say it is important to keep track of their skills and help them sharpen their expertise. Their scope of practice and physicians’ supervisory responsibilities are included in the collaborative agreement.

Arthur Apolinario, MD, a family physician in Clinton, N.C., says his 10-physician practice, which employs six NPs and one PA, works under a collaborative agreement. “The agreement defines each person’s scope of practice. They can’t do certain procedures, such as surgery, and they need extra training before doing certain tasks alone, such as joint injection.

“You have to always figure that if there is a lawsuit against one of them, you as the supervising physician would be named,” said Dr. Apolinario, who is also president of the North Carolina Medical Society. “We try to avert mistakes by meeting regularly with our NPs and PAs and making sure they keep up to date.”
 

Collaborating with autonomous NPs

Even when NPs operate independently in states that have abolished supervision, physicians may still have some liability if they give NPs advice, Dr. Al-Agba said.

At her Washington state practice, Dr. Al-Agba shares an office with an autonomous NP. “We share overhead and a front desk, but we have separate patients,” Dr. Al-Agba said. “This arrangement works very well for both of us.”

The NP sometimes asks her for advice. When this occurs, Dr. Al-Agba said she always makes sure to see the patient first. “If you don’t actually see the patient, there could be a misunderstanding that could lead to an error,” she said.
 

Conclusion

Even though NPs now have autonomy in most states, supervising physicians may still be liable for NP malpractice by virtue of being their employers, and physicians in the remaining states are liable for NPs through state law and for PAs in virtually all the states. To determine the supervising physician’s fault, courts often study whether the physician has met the terms of the collaborative agreement.

Physicians can reduce collaborating NPs’ and PAs’ liability by properly training them, by verifying their scope of practice, by making themselves easily available for consultation, and by occasionally seeing their patients. If their NPs and PAs do commit malpractice, supervising physicians may be able to protect themselves from liability by adhering to all requirements of the collaborative agreement.

*Correction, 4/19/2023: An earlier version of this story misstated the name of the AAPA and the states that have ended physician supervision of PAs.

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

Court cases show that physicians continually underestimate their liability in supervising nurse practitioners (NPs) and physician assistants (PAs).

Even in states that have abolished requirements that NPs be physician-supervised, physicians may still be liable by virtue of employing the NP, according to William P. Sullivan, DO, an attorney and emergency physician in Frankfort, Ill.

Indeed, the vast majority of lawsuits against NPs and PAs name the supervising physician. According to a study of claims against NPs from 2011 to 2016, 82% of the cases also named the supervising physician.

Employed or contracted physicians assigned to supervise NPs or PAs are also affected, Dr. Sullivan said. “The employed physicians’ contract with a hospital or staffing company may require them to assist in the selection, supervision, and/or training of NPs or PAs,” he said. He added that supervisory duties may also be assigned through hospital bylaws.

“The physician is usually not paid anything extra for this work and may not be given extra time to perform it,” Dr. Sullivan said. But still, he said, that physician could be named in a lawsuit and wind up bearing some responsibility for an NP’s or PA’s mistake.

In addition to facing medical malpractice suits, Dr. Sullivan said, doctors are often sanctioned by state licensure boards for improperly supervising NPs and PAs. Licensure boards often require extensive protocols for supervision of NPs and PAs.
 

Yet more states are removing supervision requirements

With the addition of Kansas and New York in 2022 and California in 2023, 27 states no longer require supervision for all or most NPs. Sixteen of those states, including New York and California, have instituted progressive practice authority that requires temporary supervision of new NPs but then removes supervision after a period of 6 months to 4 years, depending on the state, for the rest of their career.

“When it comes to NP independence, the horse is already out of the barn,” Dr. Sullivan said. “It’s unlikely that states will repeal laws granting NPs independence, and in fact, more states are likely to pass them.”

*PAs, in contrast, are well behind NPs in achieving independence, but the American Academy of Physician Associates (AAPA) is calling to eliminate a mandated relationship with a specific physician. So far, Utah, North Dakota and Wyoming have ended physician supervision of PAs, while California and Hawaii have eliminated mandated chart review. Other states are considering eliminating physician supervision of PAs, according to the AAPA.

In states that have abolished oversight requirements for NPs, “liability can then shift to the NP when the NP is fully independent,” Cathy Klein, an advanced practice registered nurse who helped found the NP profession 50 years ago, told this news organization. “More NPs are starting their own practices, and in many cases, patients actually prefer to see an NP.”

As more NPs became more autonomous, the average payment that NPs incurred in professional liability lawsuits rose by 10.5% from 2017 to 2022, to $332,187, according to the Nurses Service Organization (NSO), a nursing malpractice insurer.

The number of malpractice judgments against autonomous NPs alone has also been rising. From 2012 to 2017, autonomous NPs’ share of all NP cases rose from 7% to 16.4%, the NSO reported.

The good news for physicians is that states’ removal of restrictions on NPs has reduced physicians’ liability to some extent. A 2017 study found that enacting less restrictive scope-of-practice laws for NPs decreased the number of payments made by physicians in NP cases by as much as 31%.

However, the top location for NP payouts remains the physician’s office, not the autonomous NP’s practice, according to the latter NSO report. Plaintiffs sue NPs’ and PAs’ supervising physicians on the basis of legal concepts, such as vicarious liability and respondeat superior. Even if the physician-employer never saw the patient, he or she can be held liable.

Court cases in which supervising physician was found liable

There are plenty of judgments against supervising or collaborating physicians when the NP or PA made the error. Typically, the doctor was faulted for paying little attention to the NP or PA he or she was supposed to supervise.

Dr. Sullivan points to a 2016 case in which a New York jury held a physician 40% liable for a $7 million judgment in a malpractice case involving a PA’s care of a patient in the emergency department. The case is Shajan v. South Nassau Community Hospital in New York.

“The patient presented with nontraumatic leg pain to his lower leg, was diagnosed by the PA with a muscle strain, and discharged without a physician evaluation,” Dr. Sullivan said. The next day, the patient visited an orthopedist who immediately diagnosed compartment syndrome, an emergent condition in which pressure builds up in an affected extremity, damaging the muscles and nerves. “The patient developed irreversible nerve damage and chronic regional pain syndrome,” he said.

A malpractice lawsuit named the PA and the emergency physician he was supposed to be reporting to. Even though the physician had never seen the patient, he had signed off on the PA’s note from a patient’s ED visit. “Testimony during the trial focused on hospital protocols that the supervising physician was supposed to take,” Dr. Sullivan said.

When doctors share fault, they frequently failed to follow the collaborative agreement with the NP or PA. In Collip v. Ratts, a 2015 Indiana case in which the patient died from a drug interaction, the doctor’s certified public accountant stated that the doctor was required to review at least 5% of the NP’s charts every week to evaluate her prescriptive practices.

The doctor admitted that he never reviewed the NP’s charts on a weekly basis. He did conduct some cursory reviews of some of the NP’s notes, and in them he noted concerns for her prescribing practices and suggested she attend a narcotics-prescribing seminar, but he did not follow up to make sure she had done this.

Sometimes the NP or PA who made the mistake may actually be dropped from the lawsuit, leaving the supervising physician fully liable. In these cases, courts reason that a fully engaged supervisor could have prevented the error. In the 2006 case of  Husak v. Siegal, the Florida Supreme Court dropped the NP from the case, ruling that the NP had provided the supervising doctor all the information he needed in order to tell her what to do for the patient.

The court noted the physician had failed to look at the chart, even though he was required to do so under his supervisory agreement with the NP. The doctor “could have made the correct diagnosis or referral had he been attentive,” the court said. Therefore, there was “no evidence of independent negligence” by the NP, even though she was the one who had made the incorrect diagnosis that harmed the patient.

When states require an autonomous NP to have a supervisory relationship with a doctor, the supervisor may be unavailable and may fail to designate a substitute. In Texas in January 2019, a 7-year-old girl died of pneumonia after being treated by an NP in an urgent care clinic. The NP had told the parents that the child could safely go home and only needed ibuprofen. The parents brought the girl back home, and she died 15 hours later. The Wattenbargers sued the NP, and the doctor’s supervision was a topic in the trial.

The supervising physician for the NP was out of the country at the time. He said that he had found a substitute, but the substitute doctor testified she had no idea she was designated to be the substitute, according to Niran Al-Agba, MD, a family physician in Silverdale, Wash., who has written on the Texas case. Dr. Al-Agba told this news organization the case appears to have been settled confidentially.
 

Different standards for expert witnesses

In many states, courts do not allow physicians to testify as expert witnesses in malpractice cases against NPs, arguing that nurses have a different set of standards than doctors have, Dr. Sullivan reported.

These states include Arkansas, Illinois, North Carolina, and New York, according to a report by SEAK Inc., an expert witness training program. The report said most other states allow physician experts in these cases, but they may still require that they have experience with the nursing standard of care.

Dr. Sullivan said some courts are whittling away at the ban on physician experts, and the ban may eventually disappear. He reported that in Oklahoma, which normally upholds the ban, a judge recently allowed a physician-expert to testify in a case involving the death of a 19-year-old woman, Alexus Ochoa, in an ED staffed by an NP. The judge reasoned that Ms. Ochoa’s parents assumed the ED was staffed by physicians and would adhere to medical standards.
 

Supervision pointers from a physician

Physicians who supervise NPs or PAs say it is important to keep track of their skills and help them sharpen their expertise. Their scope of practice and physicians’ supervisory responsibilities are included in the collaborative agreement.

Arthur Apolinario, MD, a family physician in Clinton, N.C., says his 10-physician practice, which employs six NPs and one PA, works under a collaborative agreement. “The agreement defines each person’s scope of practice. They can’t do certain procedures, such as surgery, and they need extra training before doing certain tasks alone, such as joint injection.

“You have to always figure that if there is a lawsuit against one of them, you as the supervising physician would be named,” said Dr. Apolinario, who is also president of the North Carolina Medical Society. “We try to avert mistakes by meeting regularly with our NPs and PAs and making sure they keep up to date.”
 

Collaborating with autonomous NPs

Even when NPs operate independently in states that have abolished supervision, physicians may still have some liability if they give NPs advice, Dr. Al-Agba said.

At her Washington state practice, Dr. Al-Agba shares an office with an autonomous NP. “We share overhead and a front desk, but we have separate patients,” Dr. Al-Agba said. “This arrangement works very well for both of us.”

The NP sometimes asks her for advice. When this occurs, Dr. Al-Agba said she always makes sure to see the patient first. “If you don’t actually see the patient, there could be a misunderstanding that could lead to an error,” she said.
 

Conclusion

Even though NPs now have autonomy in most states, supervising physicians may still be liable for NP malpractice by virtue of being their employers, and physicians in the remaining states are liable for NPs through state law and for PAs in virtually all the states. To determine the supervising physician’s fault, courts often study whether the physician has met the terms of the collaborative agreement.

Physicians can reduce collaborating NPs’ and PAs’ liability by properly training them, by verifying their scope of practice, by making themselves easily available for consultation, and by occasionally seeing their patients. If their NPs and PAs do commit malpractice, supervising physicians may be able to protect themselves from liability by adhering to all requirements of the collaborative agreement.

*Correction, 4/19/2023: An earlier version of this story misstated the name of the AAPA and the states that have ended physician supervision of PAs.

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

Court cases show that physicians continually underestimate their liability in supervising nurse practitioners (NPs) and physician assistants (PAs).

Even in states that have abolished requirements that NPs be physician-supervised, physicians may still be liable by virtue of employing the NP, according to William P. Sullivan, DO, an attorney and emergency physician in Frankfort, Ill.

Indeed, the vast majority of lawsuits against NPs and PAs name the supervising physician. According to a study of claims against NPs from 2011 to 2016, 82% of the cases also named the supervising physician.

Employed or contracted physicians assigned to supervise NPs or PAs are also affected, Dr. Sullivan said. “The employed physicians’ contract with a hospital or staffing company may require them to assist in the selection, supervision, and/or training of NPs or PAs,” he said. He added that supervisory duties may also be assigned through hospital bylaws.

“The physician is usually not paid anything extra for this work and may not be given extra time to perform it,” Dr. Sullivan said. But still, he said, that physician could be named in a lawsuit and wind up bearing some responsibility for an NP’s or PA’s mistake.

In addition to facing medical malpractice suits, Dr. Sullivan said, doctors are often sanctioned by state licensure boards for improperly supervising NPs and PAs. Licensure boards often require extensive protocols for supervision of NPs and PAs.
 

Yet more states are removing supervision requirements

With the addition of Kansas and New York in 2022 and California in 2023, 27 states no longer require supervision for all or most NPs. Sixteen of those states, including New York and California, have instituted progressive practice authority that requires temporary supervision of new NPs but then removes supervision after a period of 6 months to 4 years, depending on the state, for the rest of their career.

“When it comes to NP independence, the horse is already out of the barn,” Dr. Sullivan said. “It’s unlikely that states will repeal laws granting NPs independence, and in fact, more states are likely to pass them.”

*PAs, in contrast, are well behind NPs in achieving independence, but the American Academy of Physician Associates (AAPA) is calling to eliminate a mandated relationship with a specific physician. So far, Utah, North Dakota and Wyoming have ended physician supervision of PAs, while California and Hawaii have eliminated mandated chart review. Other states are considering eliminating physician supervision of PAs, according to the AAPA.

In states that have abolished oversight requirements for NPs, “liability can then shift to the NP when the NP is fully independent,” Cathy Klein, an advanced practice registered nurse who helped found the NP profession 50 years ago, told this news organization. “More NPs are starting their own practices, and in many cases, patients actually prefer to see an NP.”

As more NPs became more autonomous, the average payment that NPs incurred in professional liability lawsuits rose by 10.5% from 2017 to 2022, to $332,187, according to the Nurses Service Organization (NSO), a nursing malpractice insurer.

The number of malpractice judgments against autonomous NPs alone has also been rising. From 2012 to 2017, autonomous NPs’ share of all NP cases rose from 7% to 16.4%, the NSO reported.

The good news for physicians is that states’ removal of restrictions on NPs has reduced physicians’ liability to some extent. A 2017 study found that enacting less restrictive scope-of-practice laws for NPs decreased the number of payments made by physicians in NP cases by as much as 31%.

However, the top location for NP payouts remains the physician’s office, not the autonomous NP’s practice, according to the latter NSO report. Plaintiffs sue NPs’ and PAs’ supervising physicians on the basis of legal concepts, such as vicarious liability and respondeat superior. Even if the physician-employer never saw the patient, he or she can be held liable.

Court cases in which supervising physician was found liable

There are plenty of judgments against supervising or collaborating physicians when the NP or PA made the error. Typically, the doctor was faulted for paying little attention to the NP or PA he or she was supposed to supervise.

Dr. Sullivan points to a 2016 case in which a New York jury held a physician 40% liable for a $7 million judgment in a malpractice case involving a PA’s care of a patient in the emergency department. The case is Shajan v. South Nassau Community Hospital in New York.

“The patient presented with nontraumatic leg pain to his lower leg, was diagnosed by the PA with a muscle strain, and discharged without a physician evaluation,” Dr. Sullivan said. The next day, the patient visited an orthopedist who immediately diagnosed compartment syndrome, an emergent condition in which pressure builds up in an affected extremity, damaging the muscles and nerves. “The patient developed irreversible nerve damage and chronic regional pain syndrome,” he said.

A malpractice lawsuit named the PA and the emergency physician he was supposed to be reporting to. Even though the physician had never seen the patient, he had signed off on the PA’s note from a patient’s ED visit. “Testimony during the trial focused on hospital protocols that the supervising physician was supposed to take,” Dr. Sullivan said.

When doctors share fault, they frequently failed to follow the collaborative agreement with the NP or PA. In Collip v. Ratts, a 2015 Indiana case in which the patient died from a drug interaction, the doctor’s certified public accountant stated that the doctor was required to review at least 5% of the NP’s charts every week to evaluate her prescriptive practices.

The doctor admitted that he never reviewed the NP’s charts on a weekly basis. He did conduct some cursory reviews of some of the NP’s notes, and in them he noted concerns for her prescribing practices and suggested she attend a narcotics-prescribing seminar, but he did not follow up to make sure she had done this.

Sometimes the NP or PA who made the mistake may actually be dropped from the lawsuit, leaving the supervising physician fully liable. In these cases, courts reason that a fully engaged supervisor could have prevented the error. In the 2006 case of  Husak v. Siegal, the Florida Supreme Court dropped the NP from the case, ruling that the NP had provided the supervising doctor all the information he needed in order to tell her what to do for the patient.

The court noted the physician had failed to look at the chart, even though he was required to do so under his supervisory agreement with the NP. The doctor “could have made the correct diagnosis or referral had he been attentive,” the court said. Therefore, there was “no evidence of independent negligence” by the NP, even though she was the one who had made the incorrect diagnosis that harmed the patient.

When states require an autonomous NP to have a supervisory relationship with a doctor, the supervisor may be unavailable and may fail to designate a substitute. In Texas in January 2019, a 7-year-old girl died of pneumonia after being treated by an NP in an urgent care clinic. The NP had told the parents that the child could safely go home and only needed ibuprofen. The parents brought the girl back home, and she died 15 hours later. The Wattenbargers sued the NP, and the doctor’s supervision was a topic in the trial.

The supervising physician for the NP was out of the country at the time. He said that he had found a substitute, but the substitute doctor testified she had no idea she was designated to be the substitute, according to Niran Al-Agba, MD, a family physician in Silverdale, Wash., who has written on the Texas case. Dr. Al-Agba told this news organization the case appears to have been settled confidentially.
 

Different standards for expert witnesses

In many states, courts do not allow physicians to testify as expert witnesses in malpractice cases against NPs, arguing that nurses have a different set of standards than doctors have, Dr. Sullivan reported.

These states include Arkansas, Illinois, North Carolina, and New York, according to a report by SEAK Inc., an expert witness training program. The report said most other states allow physician experts in these cases, but they may still require that they have experience with the nursing standard of care.

Dr. Sullivan said some courts are whittling away at the ban on physician experts, and the ban may eventually disappear. He reported that in Oklahoma, which normally upholds the ban, a judge recently allowed a physician-expert to testify in a case involving the death of a 19-year-old woman, Alexus Ochoa, in an ED staffed by an NP. The judge reasoned that Ms. Ochoa’s parents assumed the ED was staffed by physicians and would adhere to medical standards.
 

Supervision pointers from a physician

Physicians who supervise NPs or PAs say it is important to keep track of their skills and help them sharpen their expertise. Their scope of practice and physicians’ supervisory responsibilities are included in the collaborative agreement.

Arthur Apolinario, MD, a family physician in Clinton, N.C., says his 10-physician practice, which employs six NPs and one PA, works under a collaborative agreement. “The agreement defines each person’s scope of practice. They can’t do certain procedures, such as surgery, and they need extra training before doing certain tasks alone, such as joint injection.

“You have to always figure that if there is a lawsuit against one of them, you as the supervising physician would be named,” said Dr. Apolinario, who is also president of the North Carolina Medical Society. “We try to avert mistakes by meeting regularly with our NPs and PAs and making sure they keep up to date.”
 

Collaborating with autonomous NPs

Even when NPs operate independently in states that have abolished supervision, physicians may still have some liability if they give NPs advice, Dr. Al-Agba said.

At her Washington state practice, Dr. Al-Agba shares an office with an autonomous NP. “We share overhead and a front desk, but we have separate patients,” Dr. Al-Agba said. “This arrangement works very well for both of us.”

The NP sometimes asks her for advice. When this occurs, Dr. Al-Agba said she always makes sure to see the patient first. “If you don’t actually see the patient, there could be a misunderstanding that could lead to an error,” she said.
 

Conclusion

Even though NPs now have autonomy in most states, supervising physicians may still be liable for NP malpractice by virtue of being their employers, and physicians in the remaining states are liable for NPs through state law and for PAs in virtually all the states. To determine the supervising physician’s fault, courts often study whether the physician has met the terms of the collaborative agreement.

Physicians can reduce collaborating NPs’ and PAs’ liability by properly training them, by verifying their scope of practice, by making themselves easily available for consultation, and by occasionally seeing their patients. If their NPs and PAs do commit malpractice, supervising physicians may be able to protect themselves from liability by adhering to all requirements of the collaborative agreement.

*Correction, 4/19/2023: An earlier version of this story misstated the name of the AAPA and the states that have ended physician supervision of PAs.

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

A whole new, tiny level of hangry

Ever been so hungry that everything just got on your nerves? Maybe you feel a little snappy right now? Like you’ll just lash out unless you get something to eat? Been there. And so have bacteria.

New research shows that some bacteria go into a full-on Hulk smash if they’re not getting the nutrients they need by releasing toxins into the body. Sounds like a bacterial temper tantrum.

Rosenthal et al.

Even though two cells may be genetically identical, they don’t always behave the same in a bacterial community. Some do their job and stay in line, but some evil twins rage out and make people sick by releasing toxins into the environment, Adam Rosenthal, PhD, of the University of North Carolina and his colleagues discovered.

To figure out why some cells were all business as usual while others were not, the investigators looked at Clostridium perfringens, a bacterium found in the intestines of humans and other vertebrates. When the C. perfringens cells were fed a little acetate to munch on, the hangry cells calmed down faster than a kid with a bag of fruit snacks, reducing toxin levels. Some cells even disappeared, falling in line with their model-citizen counterparts.

So what does this really mean? More research, duh. Now that we know nutrients play a role in toxicity, it may open the door to finding a way to fight against antibiotic resistance in humans and reduce antibiotic use in the food industry.

So think to yourself. Are you bothered for no reason? Getting a little testy with your friends and coworkers? Maybe you just haven’t eaten in a while. You’re literally not alone. Even a single-cell organism can behave based on its hunger levels.

Now go have a snack. Your bacteria are getting restless.
 

The very hangry iguana?

Imagine yourself on a warm, sunny tropical beach. You are enjoying a piece of cake as you take in the slow beat of the waves lapping against the shore. Life is as good as it could be.

Then you feel a presence nearby. Hostility. Hunger. A set of feral, covetous eyes in the nearby jungle. A reptilian beast stalks you, and its all-encompassing sweet tooth desires your cake.

Wait, hold on, what?

As an unfortunate 3-year-old on vacation in Costa Rica found out, there’s at least one iguana in the world out there with a taste for sugar (better than a taste for blood, we suppose).

Ulrike Mai/Pixabay

While out on the beach, the lizard darted out of nowhere, bit the girl on the back of the hand, and stole her cake. Still not the worst party guest ever. The child was taken to a local clinic, where the wound was cleaned and a 5-day antibiotic treatment (lizards carry salmonella) was provided. Things seemed fine, and the girl returned home without incident.

But of course, that’s not the end of the story. Five months later, the girl’s parents noticed a red bump at the wound site. Over the next 3 months, the surrounding skin grew red and painful. A trip to the hospital in California revealed that she had a ganglion cyst and a discharge of pus. Turns out our cake-obsessed lizard friend did give the little girl a gift: the first known human case of Mycobacterium marinum infection following an iguana bite on record.

M. marinum, which causes a disease similar to tuberculosis, typically infects fish but can infect humans if skin wounds are exposed to contaminated water. It’s also resistant to most antibiotics, which is why the first round didn’t clear up the infection. A second round of more-potent antibiotics seems to be working well.

So, to sum up, this poor child got bitten by a lizard, had her cake stolen, and contracted a rare illness in exchange. For a 3-year-old, that’s gotta be in the top-10 worst days ever. Unless, of course, we’re actually living in the Marvel universe (sorry, multiverse at this point). Then we’re totally going to see the emergence of the new superhero Iguana Girl in 15 years or so. Keep your eyes open.
 

No allergies? Let them give up cake

Allergy season is already here – starting earlier every year, it seems – and many people are not happy about it. So unhappy, actually, that there’s a list of things they would be willing to give up for a year to get rid of their of allergies, according to a survey conducted by OnePoll on behalf of Flonase.

nicoletaionescu/Getty Images

Nearly 40% of 2,000 respondents with allergies would go a year without eating cake or chocolate or playing video games in exchange for allergy-free status, the survey results show. Almost as many would forgo coffee (38%) or pizza (37%) for a year, while 36% would stay off social media and 31% would take a pay cut or give up their smartphones, the Independent reported.

More than half of the allergic Americans – 54%, to be exact – who were polled this past winter – Feb. 24 to March 1, to be exact – consider allergy symptoms to be the most frustrating part of the spring. Annoying things that were less frustrating to the group included mosquitoes (41%), filing tax returns (38%), and daylight savings time (37%).

The Trump arraignment circus, of course, occurred too late to make the list, as did the big “We’re going back to the office! No wait, we’re closing the office forever!” email extravaganza and emotional roller coaster. That second one, however, did not get nearly as much media coverage.

A whole new, tiny level of hangry

Ever been so hungry that everything just got on your nerves? Maybe you feel a little snappy right now? Like you’ll just lash out unless you get something to eat? Been there. And so have bacteria.

New research shows that some bacteria go into a full-on Hulk smash if they’re not getting the nutrients they need by releasing toxins into the body. Sounds like a bacterial temper tantrum.

Rosenthal et al.

Even though two cells may be genetically identical, they don’t always behave the same in a bacterial community. Some do their job and stay in line, but some evil twins rage out and make people sick by releasing toxins into the environment, Adam Rosenthal, PhD, of the University of North Carolina and his colleagues discovered.

To figure out why some cells were all business as usual while others were not, the investigators looked at Clostridium perfringens, a bacterium found in the intestines of humans and other vertebrates. When the C. perfringens cells were fed a little acetate to munch on, the hangry cells calmed down faster than a kid with a bag of fruit snacks, reducing toxin levels. Some cells even disappeared, falling in line with their model-citizen counterparts.

So what does this really mean? More research, duh. Now that we know nutrients play a role in toxicity, it may open the door to finding a way to fight against antibiotic resistance in humans and reduce antibiotic use in the food industry.

So think to yourself. Are you bothered for no reason? Getting a little testy with your friends and coworkers? Maybe you just haven’t eaten in a while. You’re literally not alone. Even a single-cell organism can behave based on its hunger levels.

Now go have a snack. Your bacteria are getting restless.
 

The very hangry iguana?

Imagine yourself on a warm, sunny tropical beach. You are enjoying a piece of cake as you take in the slow beat of the waves lapping against the shore. Life is as good as it could be.

Then you feel a presence nearby. Hostility. Hunger. A set of feral, covetous eyes in the nearby jungle. A reptilian beast stalks you, and its all-encompassing sweet tooth desires your cake.

Wait, hold on, what?

As an unfortunate 3-year-old on vacation in Costa Rica found out, there’s at least one iguana in the world out there with a taste for sugar (better than a taste for blood, we suppose).

Ulrike Mai/Pixabay

While out on the beach, the lizard darted out of nowhere, bit the girl on the back of the hand, and stole her cake. Still not the worst party guest ever. The child was taken to a local clinic, where the wound was cleaned and a 5-day antibiotic treatment (lizards carry salmonella) was provided. Things seemed fine, and the girl returned home without incident.

But of course, that’s not the end of the story. Five months later, the girl’s parents noticed a red bump at the wound site. Over the next 3 months, the surrounding skin grew red and painful. A trip to the hospital in California revealed that she had a ganglion cyst and a discharge of pus. Turns out our cake-obsessed lizard friend did give the little girl a gift: the first known human case of Mycobacterium marinum infection following an iguana bite on record.

M. marinum, which causes a disease similar to tuberculosis, typically infects fish but can infect humans if skin wounds are exposed to contaminated water. It’s also resistant to most antibiotics, which is why the first round didn’t clear up the infection. A second round of more-potent antibiotics seems to be working well.

So, to sum up, this poor child got bitten by a lizard, had her cake stolen, and contracted a rare illness in exchange. For a 3-year-old, that’s gotta be in the top-10 worst days ever. Unless, of course, we’re actually living in the Marvel universe (sorry, multiverse at this point). Then we’re totally going to see the emergence of the new superhero Iguana Girl in 15 years or so. Keep your eyes open.
 

No allergies? Let them give up cake

Allergy season is already here – starting earlier every year, it seems – and many people are not happy about it. So unhappy, actually, that there’s a list of things they would be willing to give up for a year to get rid of their of allergies, according to a survey conducted by OnePoll on behalf of Flonase.

nicoletaionescu/Getty Images

Nearly 40% of 2,000 respondents with allergies would go a year without eating cake or chocolate or playing video games in exchange for allergy-free status, the survey results show. Almost as many would forgo coffee (38%) or pizza (37%) for a year, while 36% would stay off social media and 31% would take a pay cut or give up their smartphones, the Independent reported.

More than half of the allergic Americans – 54%, to be exact – who were polled this past winter – Feb. 24 to March 1, to be exact – consider allergy symptoms to be the most frustrating part of the spring. Annoying things that were less frustrating to the group included mosquitoes (41%), filing tax returns (38%), and daylight savings time (37%).

The Trump arraignment circus, of course, occurred too late to make the list, as did the big “We’re going back to the office! No wait, we’re closing the office forever!” email extravaganza and emotional roller coaster. That second one, however, did not get nearly as much media coverage.

A whole new, tiny level of hangry

Ever been so hungry that everything just got on your nerves? Maybe you feel a little snappy right now? Like you’ll just lash out unless you get something to eat? Been there. And so have bacteria.

New research shows that some bacteria go into a full-on Hulk smash if they’re not getting the nutrients they need by releasing toxins into the body. Sounds like a bacterial temper tantrum.

Rosenthal et al.

Even though two cells may be genetically identical, they don’t always behave the same in a bacterial community. Some do their job and stay in line, but some evil twins rage out and make people sick by releasing toxins into the environment, Adam Rosenthal, PhD, of the University of North Carolina and his colleagues discovered.

To figure out why some cells were all business as usual while others were not, the investigators looked at Clostridium perfringens, a bacterium found in the intestines of humans and other vertebrates. When the C. perfringens cells were fed a little acetate to munch on, the hangry cells calmed down faster than a kid with a bag of fruit snacks, reducing toxin levels. Some cells even disappeared, falling in line with their model-citizen counterparts.

So what does this really mean? More research, duh. Now that we know nutrients play a role in toxicity, it may open the door to finding a way to fight against antibiotic resistance in humans and reduce antibiotic use in the food industry.

So think to yourself. Are you bothered for no reason? Getting a little testy with your friends and coworkers? Maybe you just haven’t eaten in a while. You’re literally not alone. Even a single-cell organism can behave based on its hunger levels.

Now go have a snack. Your bacteria are getting restless.
 

The very hangry iguana?

Imagine yourself on a warm, sunny tropical beach. You are enjoying a piece of cake as you take in the slow beat of the waves lapping against the shore. Life is as good as it could be.

Then you feel a presence nearby. Hostility. Hunger. A set of feral, covetous eyes in the nearby jungle. A reptilian beast stalks you, and its all-encompassing sweet tooth desires your cake.

Wait, hold on, what?

As an unfortunate 3-year-old on vacation in Costa Rica found out, there’s at least one iguana in the world out there with a taste for sugar (better than a taste for blood, we suppose).

Ulrike Mai/Pixabay

While out on the beach, the lizard darted out of nowhere, bit the girl on the back of the hand, and stole her cake. Still not the worst party guest ever. The child was taken to a local clinic, where the wound was cleaned and a 5-day antibiotic treatment (lizards carry salmonella) was provided. Things seemed fine, and the girl returned home without incident.

But of course, that’s not the end of the story. Five months later, the girl’s parents noticed a red bump at the wound site. Over the next 3 months, the surrounding skin grew red and painful. A trip to the hospital in California revealed that she had a ganglion cyst and a discharge of pus. Turns out our cake-obsessed lizard friend did give the little girl a gift: the first known human case of Mycobacterium marinum infection following an iguana bite on record.

M. marinum, which causes a disease similar to tuberculosis, typically infects fish but can infect humans if skin wounds are exposed to contaminated water. It’s also resistant to most antibiotics, which is why the first round didn’t clear up the infection. A second round of more-potent antibiotics seems to be working well.

So, to sum up, this poor child got bitten by a lizard, had her cake stolen, and contracted a rare illness in exchange. For a 3-year-old, that’s gotta be in the top-10 worst days ever. Unless, of course, we’re actually living in the Marvel universe (sorry, multiverse at this point). Then we’re totally going to see the emergence of the new superhero Iguana Girl in 15 years or so. Keep your eyes open.
 

No allergies? Let them give up cake

Allergy season is already here – starting earlier every year, it seems – and many people are not happy about it. So unhappy, actually, that there’s a list of things they would be willing to give up for a year to get rid of their of allergies, according to a survey conducted by OnePoll on behalf of Flonase.

nicoletaionescu/Getty Images

Nearly 40% of 2,000 respondents with allergies would go a year without eating cake or chocolate or playing video games in exchange for allergy-free status, the survey results show. Almost as many would forgo coffee (38%) or pizza (37%) for a year, while 36% would stay off social media and 31% would take a pay cut or give up their smartphones, the Independent reported.

More than half of the allergic Americans – 54%, to be exact – who were polled this past winter – Feb. 24 to March 1, to be exact – consider allergy symptoms to be the most frustrating part of the spring. Annoying things that were less frustrating to the group included mosquitoes (41%), filing tax returns (38%), and daylight savings time (37%).

The Trump arraignment circus, of course, occurred too late to make the list, as did the big “We’re going back to the office! No wait, we’re closing the office forever!” email extravaganza and emotional roller coaster. That second one, however, did not get nearly as much media coverage.

NEW ORLEANS – Demonstrated adherence to professional and ethical principles is one of the six core competencies for the dermatology residency curriculum set by the Accreditation Council for Graduate Medical Education, but results from a national survey of dermatology residency program directors suggest that ethics training is not a priority.

Of the 139 dermatology residency program or associate program directors surveyed in 2022, only 43% responded. Of these, 55% said that their program had no ethics curriculum. Among programs with an ethics curriculum, 75% were implemented in the past 10 years, and the most common settings for teaching ethics were formal didactics (32%) and ad hoc during clinical encounters (28%). Reported barriers to implementing and/or maintaining an ethics curriculum included a lack of time (30%), lack of faculty with expertise (24%), and lack of useful resources (20%).

“Clearly, medical ethics is needed more to be part of our dermatology residency curriculum,” one of the study authors, Jane M. Grant-Kels, MD, professor of dermatology, pathology, and pediatrics, and founding chair of dermatology at the University of Connecticut, Farmington, said during a plenary lecture at the annual meeting of the American Academy of Dermatology. “Why? Because even though we’re physicians, and some of us have big egos, we are just human beings. We have all the faults and frailties of other humans. What we do as doctors often has unintended consequences that impact patients and society at large.”

American Academy of Dermatology

Dr. Grant-Kels, one of the editors of the textbook “Dermatoethics”, said that, while she does not believe that physicians are intentionally unethical, “we stumble into bad behavior because we fool ourselves. We think that we are ethical. We think our colleagues are ethical, and we don’t view them with a clear, transparent eye. This is referred to as ethical fading or bounded ethicality.”

Similar to religion and good behavior, one can’t really teach someone to be ethical, she continued. “But you can teach people to think about ethics and to recognize an ethical dilemma when they’re in one,” she said. “Most articles that are available [pertain to] whether ethics can be taught or not, but there are very few resources available on how to actually teach ethics.”

That, she added, has been her goal for the last 2 decades: “How do I teach ethics without sounding like I’m more ethical than anybody else, and how do I make it relevant and fun? It’s a difficult challenge.”

Pillars of medical ethics

Dr. Grant-Kels defined ethics as a way of determining how individuals ought to act based on concepts of right and wrong. An ethical dilemma is when an individual faces two competing possibilities: either both justifiable or both unjustifiable, and you have to make a decision. The four pillars of medical ethics, she noted, are beneficence (the notion that the patient’s best interests come first); nonmaleficence (do no intentional harm); autonomy (the patient’s right to refuse or choose a treatment); and justice (fairness in how health care is distributed).

“Medical ethics are the moral principles by which physicians should conduct themselves,” she said. “There is normative ethics, which involves decisions about which moral norms or ethical arguments should we accept and why; and applied ethics, or applications of these norms to specific problems or cases. No ethics is better than bad ethics, and we can see that even in today’s world. The lack of ethics, or poor ethics, or the wrong ethics has terrible consequences.”

Ethics instruction

Dr. Grant-Kels provided a “top 10 list” of tips for incorporating ethics instruction into dermatology residency programs and clinical practices:

• Make room for ethics in your curriculum. “It’s not science, and it needs to be discussed and developed with faculty and residents,” she said.
• Focus on real situations that residents will experience. Discuss what you should do, what you might have done, and why.
• Share stories and be truthful. Include other faculty members, “because you need different perspectives,” she said.
• Go beyond what is right and wrong, and the rationale. “You have to talk about the impact, because decisions you make have unintended consequences for individual patients and for patient care in general,” Dr. Grant-Kels said.
• Practice, practice, practice. Make time for discussions involving ethics, “because it takes a lot of education to be able to identify ethical issues and process them,” she said. “The truth is, we can rationalize almost anything and convince ourselves that we made the right choice. That’s why we need to continue to practice good ethics.”
• Challenge the residents. “Decisions are not always straightforward,” she said. “Pressures push us and we start to justify small decisions and then bigger decisions. This is a very gray zone. What’s ethical for one person may not be ethical to another.”
• Encourage residents and colleagues to ask the right questions and give them confidence to make the right decisions. “We have to work in an environment of ethics,” Dr. Grant-Kels said. “Many of us are role models, and we are not always behaving the way we should be. As role models, we need to be aware of that.”
• Expose residents to a variety of issues. Ethics vary depending on the situation, the people involved, and the information presented.
• Ethics cannot just come up in an ethics class. “We need to foster a culture of ethics,” she said. “If things go wrong and unethical behavior is noted, it needs to be brought to the floor and discussed.”
• Discuss the misguided pursuit of happiness and ethical decision-making. In the opinion of Dr. Grant-Kels, people can behave badly when they’re pursuing something like a career advancement, a new house, or an expensive object like a car or a boat. “They think that if they get that job or get that promotion or if they buy that big house or they buy that sports car, they’re going to be really happy,” she said.

“That’s called impact bias, which causes focalism, where you focus on that one thing, like ‘I’m going to make a lot of money’ or ‘I’m going to buy that big house on the mountain.’ The truth is, buying that car doesn’t make you happy. Buying that big house doesn’t make you happy. We need to combat focalism with professionalism, which means conducting oneself with responsibility, integrity, accountability, and excellence. Practicing ethical medicine is not a luxury; it’s a requirement. We should all try for aspirational ethics.”

Dr. Grant-Kels reported having no relevant financial disclosures.

NEW ORLEANS – Demonstrated adherence to professional and ethical principles is one of the six core competencies for the dermatology residency curriculum set by the Accreditation Council for Graduate Medical Education, but results from a national survey of dermatology residency program directors suggest that ethics training is not a priority.

Of the 139 dermatology residency program or associate program directors surveyed in 2022, only 43% responded. Of these, 55% said that their program had no ethics curriculum. Among programs with an ethics curriculum, 75% were implemented in the past 10 years, and the most common settings for teaching ethics were formal didactics (32%) and ad hoc during clinical encounters (28%). Reported barriers to implementing and/or maintaining an ethics curriculum included a lack of time (30%), lack of faculty with expertise (24%), and lack of useful resources (20%).

“Clearly, medical ethics is needed more to be part of our dermatology residency curriculum,” one of the study authors, Jane M. Grant-Kels, MD, professor of dermatology, pathology, and pediatrics, and founding chair of dermatology at the University of Connecticut, Farmington, said during a plenary lecture at the annual meeting of the American Academy of Dermatology. “Why? Because even though we’re physicians, and some of us have big egos, we are just human beings. We have all the faults and frailties of other humans. What we do as doctors often has unintended consequences that impact patients and society at large.”

American Academy of Dermatology

Dr. Grant-Kels, one of the editors of the textbook “Dermatoethics”, said that, while she does not believe that physicians are intentionally unethical, “we stumble into bad behavior because we fool ourselves. We think that we are ethical. We think our colleagues are ethical, and we don’t view them with a clear, transparent eye. This is referred to as ethical fading or bounded ethicality.”

Similar to religion and good behavior, one can’t really teach someone to be ethical, she continued. “But you can teach people to think about ethics and to recognize an ethical dilemma when they’re in one,” she said. “Most articles that are available [pertain to] whether ethics can be taught or not, but there are very few resources available on how to actually teach ethics.”

That, she added, has been her goal for the last 2 decades: “How do I teach ethics without sounding like I’m more ethical than anybody else, and how do I make it relevant and fun? It’s a difficult challenge.”

Pillars of medical ethics

Dr. Grant-Kels defined ethics as a way of determining how individuals ought to act based on concepts of right and wrong. An ethical dilemma is when an individual faces two competing possibilities: either both justifiable or both unjustifiable, and you have to make a decision. The four pillars of medical ethics, she noted, are beneficence (the notion that the patient’s best interests come first); nonmaleficence (do no intentional harm); autonomy (the patient’s right to refuse or choose a treatment); and justice (fairness in how health care is distributed).

“Medical ethics are the moral principles by which physicians should conduct themselves,” she said. “There is normative ethics, which involves decisions about which moral norms or ethical arguments should we accept and why; and applied ethics, or applications of these norms to specific problems or cases. No ethics is better than bad ethics, and we can see that even in today’s world. The lack of ethics, or poor ethics, or the wrong ethics has terrible consequences.”

Ethics instruction

Dr. Grant-Kels provided a “top 10 list” of tips for incorporating ethics instruction into dermatology residency programs and clinical practices:

• Make room for ethics in your curriculum. “It’s not science, and it needs to be discussed and developed with faculty and residents,” she said.
• Focus on real situations that residents will experience. Discuss what you should do, what you might have done, and why.
• Share stories and be truthful. Include other faculty members, “because you need different perspectives,” she said.
• Go beyond what is right and wrong, and the rationale. “You have to talk about the impact, because decisions you make have unintended consequences for individual patients and for patient care in general,” Dr. Grant-Kels said.
• Practice, practice, practice. Make time for discussions involving ethics, “because it takes a lot of education to be able to identify ethical issues and process them,” she said. “The truth is, we can rationalize almost anything and convince ourselves that we made the right choice. That’s why we need to continue to practice good ethics.”
• Challenge the residents. “Decisions are not always straightforward,” she said. “Pressures push us and we start to justify small decisions and then bigger decisions. This is a very gray zone. What’s ethical for one person may not be ethical to another.”
• Encourage residents and colleagues to ask the right questions and give them confidence to make the right decisions. “We have to work in an environment of ethics,” Dr. Grant-Kels said. “Many of us are role models, and we are not always behaving the way we should be. As role models, we need to be aware of that.”
• Expose residents to a variety of issues. Ethics vary depending on the situation, the people involved, and the information presented.
• Ethics cannot just come up in an ethics class. “We need to foster a culture of ethics,” she said. “If things go wrong and unethical behavior is noted, it needs to be brought to the floor and discussed.”
• Discuss the misguided pursuit of happiness and ethical decision-making. In the opinion of Dr. Grant-Kels, people can behave badly when they’re pursuing something like a career advancement, a new house, or an expensive object like a car or a boat. “They think that if they get that job or get that promotion or if they buy that big house or they buy that sports car, they’re going to be really happy,” she said.

“That’s called impact bias, which causes focalism, where you focus on that one thing, like ‘I’m going to make a lot of money’ or ‘I’m going to buy that big house on the mountain.’ The truth is, buying that car doesn’t make you happy. Buying that big house doesn’t make you happy. We need to combat focalism with professionalism, which means conducting oneself with responsibility, integrity, accountability, and excellence. Practicing ethical medicine is not a luxury; it’s a requirement. We should all try for aspirational ethics.”

Dr. Grant-Kels reported having no relevant financial disclosures.

NEW ORLEANS – Demonstrated adherence to professional and ethical principles is one of the six core competencies for the dermatology residency curriculum set by the Accreditation Council for Graduate Medical Education, but results from a national survey of dermatology residency program directors suggest that ethics training is not a priority.

Of the 139 dermatology residency program or associate program directors surveyed in 2022, only 43% responded. Of these, 55% said that their program had no ethics curriculum. Among programs with an ethics curriculum, 75% were implemented in the past 10 years, and the most common settings for teaching ethics were formal didactics (32%) and ad hoc during clinical encounters (28%). Reported barriers to implementing and/or maintaining an ethics curriculum included a lack of time (30%), lack of faculty with expertise (24%), and lack of useful resources (20%).

“Clearly, medical ethics is needed more to be part of our dermatology residency curriculum,” one of the study authors, Jane M. Grant-Kels, MD, professor of dermatology, pathology, and pediatrics, and founding chair of dermatology at the University of Connecticut, Farmington, said during a plenary lecture at the annual meeting of the American Academy of Dermatology. “Why? Because even though we’re physicians, and some of us have big egos, we are just human beings. We have all the faults and frailties of other humans. What we do as doctors often has unintended consequences that impact patients and society at large.”

American Academy of Dermatology

Dr. Grant-Kels, one of the editors of the textbook “Dermatoethics”, said that, while she does not believe that physicians are intentionally unethical, “we stumble into bad behavior because we fool ourselves. We think that we are ethical. We think our colleagues are ethical, and we don’t view them with a clear, transparent eye. This is referred to as ethical fading or bounded ethicality.”

Similar to religion and good behavior, one can’t really teach someone to be ethical, she continued. “But you can teach people to think about ethics and to recognize an ethical dilemma when they’re in one,” she said. “Most articles that are available [pertain to] whether ethics can be taught or not, but there are very few resources available on how to actually teach ethics.”

That, she added, has been her goal for the last 2 decades: “How do I teach ethics without sounding like I’m more ethical than anybody else, and how do I make it relevant and fun? It’s a difficult challenge.”

Pillars of medical ethics

Dr. Grant-Kels defined ethics as a way of determining how individuals ought to act based on concepts of right and wrong. An ethical dilemma is when an individual faces two competing possibilities: either both justifiable or both unjustifiable, and you have to make a decision. The four pillars of medical ethics, she noted, are beneficence (the notion that the patient’s best interests come first); nonmaleficence (do no intentional harm); autonomy (the patient’s right to refuse or choose a treatment); and justice (fairness in how health care is distributed).

“Medical ethics are the moral principles by which physicians should conduct themselves,” she said. “There is normative ethics, which involves decisions about which moral norms or ethical arguments should we accept and why; and applied ethics, or applications of these norms to specific problems or cases. No ethics is better than bad ethics, and we can see that even in today’s world. The lack of ethics, or poor ethics, or the wrong ethics has terrible consequences.”

Ethics instruction

Dr. Grant-Kels provided a “top 10 list” of tips for incorporating ethics instruction into dermatology residency programs and clinical practices:

• Make room for ethics in your curriculum. “It’s not science, and it needs to be discussed and developed with faculty and residents,” she said.
• Focus on real situations that residents will experience. Discuss what you should do, what you might have done, and why.
• Share stories and be truthful. Include other faculty members, “because you need different perspectives,” she said.
• Go beyond what is right and wrong, and the rationale. “You have to talk about the impact, because decisions you make have unintended consequences for individual patients and for patient care in general,” Dr. Grant-Kels said.
• Practice, practice, practice. Make time for discussions involving ethics, “because it takes a lot of education to be able to identify ethical issues and process them,” she said. “The truth is, we can rationalize almost anything and convince ourselves that we made the right choice. That’s why we need to continue to practice good ethics.”
• Challenge the residents. “Decisions are not always straightforward,” she said. “Pressures push us and we start to justify small decisions and then bigger decisions. This is a very gray zone. What’s ethical for one person may not be ethical to another.”
• Encourage residents and colleagues to ask the right questions and give them confidence to make the right decisions. “We have to work in an environment of ethics,” Dr. Grant-Kels said. “Many of us are role models, and we are not always behaving the way we should be. As role models, we need to be aware of that.”
• Expose residents to a variety of issues. Ethics vary depending on the situation, the people involved, and the information presented.
• Ethics cannot just come up in an ethics class. “We need to foster a culture of ethics,” she said. “If things go wrong and unethical behavior is noted, it needs to be brought to the floor and discussed.”
• Discuss the misguided pursuit of happiness and ethical decision-making. In the opinion of Dr. Grant-Kels, people can behave badly when they’re pursuing something like a career advancement, a new house, or an expensive object like a car or a boat. “They think that if they get that job or get that promotion or if they buy that big house or they buy that sports car, they’re going to be really happy,” she said.

“That’s called impact bias, which causes focalism, where you focus on that one thing, like ‘I’m going to make a lot of money’ or ‘I’m going to buy that big house on the mountain.’ The truth is, buying that car doesn’t make you happy. Buying that big house doesn’t make you happy. We need to combat focalism with professionalism, which means conducting oneself with responsibility, integrity, accountability, and excellence. Practicing ethical medicine is not a luxury; it’s a requirement. We should all try for aspirational ethics.”

Dr. Grant-Kels reported having no relevant financial disclosures.

THE COMPARISON

A Melasma on the face of a Hispanic woman, with hyperpigmentation on the cheeks, bridge of the nose, and upper lip.

B Melasma on the face of a Malaysian woman, with hyperpigmentation on the upper cheeks and bridge of the nose.

C Melasma on the face of an African woman, with hyperpigmentation on the upper cheeks and lateral to the eyes.

Photographs courtesy of Richard P. Usatine, MD.

Melasma (also known as chloasma) is a pigmentary disorder that causes chronic symmetric hyperpigmentation on the face. In patients with darker skin tones, centrofacial areas are affected.¹ Increased deposition of melanin distributed in the dermis leads to dermal melanosis. Newer research suggests that mast cell and keratinocyte interactions, altered gene regulation, neovascularization, and disruptions in the basement membrane cause melasma.² Patients present with epidermal or dermal melasma or a combination of both (mixed melasma).³ Wood lamp examination is helpful to distinguish between epidermal and dermal melasma. Dermal and mixed melasma can be difficult to treat and require multimodal treatments.

Epidemiology

Melasma commonly affects women aged 20 to 40 years,⁴ with a female to male ratio of 9:1.⁵ Potential triggers of melasma include hormones (eg, pregnancy, oral contraceptives, hormone replacement therapy) and exposure to UV light.^2,5 Melasma occurs in patients of all racial and ethnic backgrounds; however, the prevalence is higher in patients with darker skin tones.²

Key clinical features in people with darker skin tones

Melasma commonly manifests as symmetrically distributed, reticulated (lacy), dark brown to grayish brown patches on the cheeks, nose, forehead, upper lip, and chin in patients with darker skin tones.⁵ The pigment can be tan brown in patients with lighter skin tones. Given that postinflammatory hyperpigmentation and other pigmentary disorders can cause a similar appearance, a biopsy sometimes is needed to confirm the diagnosis, but melasma is diagnosed via physical examination in most patients. Melasma can be misdiagnosed as postinflammatory hyperpigmentation, solar lentigines, exogenous ochronosis, and Hori nevus.⁵

Worth noting

Prevention

• Daily sunscreen use is critical to prevent worsening of melasma. Sunscreen may not appear cosmetically elegant on darker skin tones, which creates a barrier to its use.⁶ Protection from both sunlight and visible light is necessary. Visible light, including light from light bulbs and device-emitted blue light, can worsen melasma. Iron oxides in tinted sunscreen offer protection from visible light.

• Physicians can recommend sunscreens that are more transparent or tinted for a better cosmetic match.

• Severe flares of melasma can occur with sun exposure despite good control with medications and laser modalities.

Treatment

• First-line therapies include topical hydroquinone 2% to 4%, tretinoin, azelaic acid, kojic acid, or ascorbic acid (vitamin C). A popular topical compound is a steroid, tretinoin, and hydroquinone.^1,5 Over-the-counter hydroquinone has been removed from the market due to safety concerns; however, it is still first line in the treatment of melasma. If hydroquinone is prescribed, treatment intervals of 6 to 8 weeks followed by a hydroquinone-free period is advised to reduce the risk for exogenous ochronosis (a paradoxical darkening of the skin).

• Chemical peels are second-line treatments that are effective for melasma. Improvement in epidermal melasma has been shown with chemical peels containing Jessner solution, salicylic acid, or α-hydroxy acid. Patients with dermal and mixed melasma have seen improvement with trichloroacetic acid 25% to 35% with or without Jessner solution.¹

• Cysteamine is a topical treatment created from the degradation of coenzyme A. It disrupts the synthesis of melanin to create a more even skin tone. It may be recommended in combination with sunscreen as a first-line or second-line topical therapy.

• Oral tranexamic acid is a third-line treatment that is an analogue for lysine. It decreases prostaglandin production, which leads to a lower number of tyrosine precursors available for the creation of melanin. Tranexamic acid has been shown to lighten the appearance of melasma.⁷ The most common and dangerous adverse effect of tranexamic acid is blood clots and this treatment should be avoided in those on combination (estrogen and progestin) contraceptives or those with a personal or family history of clotting disorders.⁸

• Fourth-line treatments such as lasers (performed by dermatologists) can destroy the deposition of pigment while avoiding destruction of epidermal keratinocytes.^1,9,10 They also are commonly employed in refractive melasma. The most common lasers are nonablative fractionated lasers and low-fluence Q-switched lasers. The Q-switched Nd:YAG and picosecond lasers are safe for treating melasma in darker skin tones. Ablative fractionated lasers such as CO₂ lasers and erbium:YAG lasers also have been used in the treatment of melasma; however, there is still an extremely high risk for postinflammatory dyspigmentation 1 to 2 months after the procedure.¹⁰

• Although there is still a risk for rebound hyperpigmentation after laser treatment, use of topical hydroquinone pretreatment may help decrease postoperative hyperpigmentation.^1,5 Patients who are treated with the incorrect laser or overtreated may develop postinflammatory hyperpigmentation, rebound hyperpigmentation, or hypopigmentation.

Health disparity highlight

Melasma, most common in patients with skin of color, is a common chronic pigmentation disorder that is cosmetically and psychologically burdensome,¹¹ leading to decreased quality of life, emotional functioning, and selfesteem.¹² Clinicians should counsel patients and work closely on long-term management. The treatment options for melasma are considered cosmetic and may be cost prohibitive for many to cover out-of-pocket. Topical treatments have been found to be the most cost-effective.¹³ Some compounding pharmacies and drug discount programs provide more affordable treatment pricing; however, some patients are still unable to afford these options.

THE COMPARISON

A Melasma on the face of a Hispanic woman, with hyperpigmentation on the cheeks, bridge of the nose, and upper lip.

B Melasma on the face of a Malaysian woman, with hyperpigmentation on the upper cheeks and bridge of the nose.

C Melasma on the face of an African woman, with hyperpigmentation on the upper cheeks and lateral to the eyes.

Photographs courtesy of Richard P. Usatine, MD.

Melasma (also known as chloasma) is a pigmentary disorder that causes chronic symmetric hyperpigmentation on the face. In patients with darker skin tones, centrofacial areas are affected.¹ Increased deposition of melanin distributed in the dermis leads to dermal melanosis. Newer research suggests that mast cell and keratinocyte interactions, altered gene regulation, neovascularization, and disruptions in the basement membrane cause melasma.² Patients present with epidermal or dermal melasma or a combination of both (mixed melasma).³ Wood lamp examination is helpful to distinguish between epidermal and dermal melasma. Dermal and mixed melasma can be difficult to treat and require multimodal treatments.

Epidemiology

Melasma commonly affects women aged 20 to 40 years,⁴ with a female to male ratio of 9:1.⁵ Potential triggers of melasma include hormones (eg, pregnancy, oral contraceptives, hormone replacement therapy) and exposure to UV light.^2,5 Melasma occurs in patients of all racial and ethnic backgrounds; however, the prevalence is higher in patients with darker skin tones.²

Key clinical features in people with darker skin tones

Melasma commonly manifests as symmetrically distributed, reticulated (lacy), dark brown to grayish brown patches on the cheeks, nose, forehead, upper lip, and chin in patients with darker skin tones.⁵ The pigment can be tan brown in patients with lighter skin tones. Given that postinflammatory hyperpigmentation and other pigmentary disorders can cause a similar appearance, a biopsy sometimes is needed to confirm the diagnosis, but melasma is diagnosed via physical examination in most patients. Melasma can be misdiagnosed as postinflammatory hyperpigmentation, solar lentigines, exogenous ochronosis, and Hori nevus.⁵

Worth noting

Prevention

• Daily sunscreen use is critical to prevent worsening of melasma. Sunscreen may not appear cosmetically elegant on darker skin tones, which creates a barrier to its use.⁶ Protection from both sunlight and visible light is necessary. Visible light, including light from light bulbs and device-emitted blue light, can worsen melasma. Iron oxides in tinted sunscreen offer protection from visible light.

• Physicians can recommend sunscreens that are more transparent or tinted for a better cosmetic match.

• Severe flares of melasma can occur with sun exposure despite good control with medications and laser modalities.

Treatment

• First-line therapies include topical hydroquinone 2% to 4%, tretinoin, azelaic acid, kojic acid, or ascorbic acid (vitamin C). A popular topical compound is a steroid, tretinoin, and hydroquinone.^1,5 Over-the-counter hydroquinone has been removed from the market due to safety concerns; however, it is still first line in the treatment of melasma. If hydroquinone is prescribed, treatment intervals of 6 to 8 weeks followed by a hydroquinone-free period is advised to reduce the risk for exogenous ochronosis (a paradoxical darkening of the skin).

• Chemical peels are second-line treatments that are effective for melasma. Improvement in epidermal melasma has been shown with chemical peels containing Jessner solution, salicylic acid, or α-hydroxy acid. Patients with dermal and mixed melasma have seen improvement with trichloroacetic acid 25% to 35% with or without Jessner solution.¹

• Cysteamine is a topical treatment created from the degradation of coenzyme A. It disrupts the synthesis of melanin to create a more even skin tone. It may be recommended in combination with sunscreen as a first-line or second-line topical therapy.

• Oral tranexamic acid is a third-line treatment that is an analogue for lysine. It decreases prostaglandin production, which leads to a lower number of tyrosine precursors available for the creation of melanin. Tranexamic acid has been shown to lighten the appearance of melasma.⁷ The most common and dangerous adverse effect of tranexamic acid is blood clots and this treatment should be avoided in those on combination (estrogen and progestin) contraceptives or those with a personal or family history of clotting disorders.⁸

• Fourth-line treatments such as lasers (performed by dermatologists) can destroy the deposition of pigment while avoiding destruction of epidermal keratinocytes.^1,9,10 They also are commonly employed in refractive melasma. The most common lasers are nonablative fractionated lasers and low-fluence Q-switched lasers. The Q-switched Nd:YAG and picosecond lasers are safe for treating melasma in darker skin tones. Ablative fractionated lasers such as CO₂ lasers and erbium:YAG lasers also have been used in the treatment of melasma; however, there is still an extremely high risk for postinflammatory dyspigmentation 1 to 2 months after the procedure.¹⁰

• Although there is still a risk for rebound hyperpigmentation after laser treatment, use of topical hydroquinone pretreatment may help decrease postoperative hyperpigmentation.^1,5 Patients who are treated with the incorrect laser or overtreated may develop postinflammatory hyperpigmentation, rebound hyperpigmentation, or hypopigmentation.

Health disparity highlight

Melasma, most common in patients with skin of color, is a common chronic pigmentation disorder that is cosmetically and psychologically burdensome,¹¹ leading to decreased quality of life, emotional functioning, and selfesteem.¹² Clinicians should counsel patients and work closely on long-term management. The treatment options for melasma are considered cosmetic and may be cost prohibitive for many to cover out-of-pocket. Topical treatments have been found to be the most cost-effective.¹³ Some compounding pharmacies and drug discount programs provide more affordable treatment pricing; however, some patients are still unable to afford these options.

THE COMPARISON

A Melasma on the face of a Hispanic woman, with hyperpigmentation on the cheeks, bridge of the nose, and upper lip.

B Melasma on the face of a Malaysian woman, with hyperpigmentation on the upper cheeks and bridge of the nose.

C Melasma on the face of an African woman, with hyperpigmentation on the upper cheeks and lateral to the eyes.

Photographs courtesy of Richard P. Usatine, MD.

Melasma (also known as chloasma) is a pigmentary disorder that causes chronic symmetric hyperpigmentation on the face. In patients with darker skin tones, centrofacial areas are affected.¹ Increased deposition of melanin distributed in the dermis leads to dermal melanosis. Newer research suggests that mast cell and keratinocyte interactions, altered gene regulation, neovascularization, and disruptions in the basement membrane cause melasma.² Patients present with epidermal or dermal melasma or a combination of both (mixed melasma).³ Wood lamp examination is helpful to distinguish between epidermal and dermal melasma. Dermal and mixed melasma can be difficult to treat and require multimodal treatments.

Epidemiology

Melasma commonly affects women aged 20 to 40 years,⁴ with a female to male ratio of 9:1.⁵ Potential triggers of melasma include hormones (eg, pregnancy, oral contraceptives, hormone replacement therapy) and exposure to UV light.^2,5 Melasma occurs in patients of all racial and ethnic backgrounds; however, the prevalence is higher in patients with darker skin tones.²

Key clinical features in people with darker skin tones

Melasma commonly manifests as symmetrically distributed, reticulated (lacy), dark brown to grayish brown patches on the cheeks, nose, forehead, upper lip, and chin in patients with darker skin tones.⁵ The pigment can be tan brown in patients with lighter skin tones. Given that postinflammatory hyperpigmentation and other pigmentary disorders can cause a similar appearance, a biopsy sometimes is needed to confirm the diagnosis, but melasma is diagnosed via physical examination in most patients. Melasma can be misdiagnosed as postinflammatory hyperpigmentation, solar lentigines, exogenous ochronosis, and Hori nevus.⁵

Worth noting

Prevention

• Daily sunscreen use is critical to prevent worsening of melasma. Sunscreen may not appear cosmetically elegant on darker skin tones, which creates a barrier to its use.⁶ Protection from both sunlight and visible light is necessary. Visible light, including light from light bulbs and device-emitted blue light, can worsen melasma. Iron oxides in tinted sunscreen offer protection from visible light.

• Physicians can recommend sunscreens that are more transparent or tinted for a better cosmetic match.

• Severe flares of melasma can occur with sun exposure despite good control with medications and laser modalities.

Treatment

• First-line therapies include topical hydroquinone 2% to 4%, tretinoin, azelaic acid, kojic acid, or ascorbic acid (vitamin C). A popular topical compound is a steroid, tretinoin, and hydroquinone.^1,5 Over-the-counter hydroquinone has been removed from the market due to safety concerns; however, it is still first line in the treatment of melasma. If hydroquinone is prescribed, treatment intervals of 6 to 8 weeks followed by a hydroquinone-free period is advised to reduce the risk for exogenous ochronosis (a paradoxical darkening of the skin).

• Chemical peels are second-line treatments that are effective for melasma. Improvement in epidermal melasma has been shown with chemical peels containing Jessner solution, salicylic acid, or α-hydroxy acid. Patients with dermal and mixed melasma have seen improvement with trichloroacetic acid 25% to 35% with or without Jessner solution.¹

• Cysteamine is a topical treatment created from the degradation of coenzyme A. It disrupts the synthesis of melanin to create a more even skin tone. It may be recommended in combination with sunscreen as a first-line or second-line topical therapy.

• Oral tranexamic acid is a third-line treatment that is an analogue for lysine. It decreases prostaglandin production, which leads to a lower number of tyrosine precursors available for the creation of melanin. Tranexamic acid has been shown to lighten the appearance of melasma.⁷ The most common and dangerous adverse effect of tranexamic acid is blood clots and this treatment should be avoided in those on combination (estrogen and progestin) contraceptives or those with a personal or family history of clotting disorders.⁸

• Fourth-line treatments such as lasers (performed by dermatologists) can destroy the deposition of pigment while avoiding destruction of epidermal keratinocytes.^1,9,10 They also are commonly employed in refractive melasma. The most common lasers are nonablative fractionated lasers and low-fluence Q-switched lasers. The Q-switched Nd:YAG and picosecond lasers are safe for treating melasma in darker skin tones. Ablative fractionated lasers such as CO₂ lasers and erbium:YAG lasers also have been used in the treatment of melasma; however, there is still an extremely high risk for postinflammatory dyspigmentation 1 to 2 months after the procedure.¹⁰

• Although there is still a risk for rebound hyperpigmentation after laser treatment, use of topical hydroquinone pretreatment may help decrease postoperative hyperpigmentation.^1,5 Patients who are treated with the incorrect laser or overtreated may develop postinflammatory hyperpigmentation, rebound hyperpigmentation, or hypopigmentation.

Health disparity highlight

Melasma, most common in patients with skin of color, is a common chronic pigmentation disorder that is cosmetically and psychologically burdensome,¹¹ leading to decreased quality of life, emotional functioning, and selfesteem.¹² Clinicians should counsel patients and work closely on long-term management. The treatment options for melasma are considered cosmetic and may be cost prohibitive for many to cover out-of-pocket. Topical treatments have been found to be the most cost-effective.¹³ Some compounding pharmacies and drug discount programs provide more affordable treatment pricing; however, some patients are still unable to afford these options.

The Diagnosis: Lichen Planus Pemphigoides

Lichen planus pemphigoides (LPP) is a rare acquired autoimmune blistering disorder with an estimated worldwide prevalence of approximately 1 in 1,000,000 individuals.¹ It often manifests with overlapping features of both LP and bullous pemphigoid (BP). The condition usually presents in the fifth decade of life and has a slight female predominance.² Although primarily idiopathic, it has been associated with certain medications and treatments, such as angiotensin-converting enzyme inhibitors, programmed cell death protein 1 inhibitors, programmed cell death ligand 1 inhibitors, labetalol, narrowband UVB, and psoralen plus UVA.^3,4

Patients initially present with lesions of classic lichen planus (LP) with pink-purple, flat-topped, pruritic, polygonal papules and plaques.⁵ After weeks to months, tense vesicles and bullae usually develop on the sites of LP as well as on uninvolved skin. One study found a mean lag time of about 8.3 months for blistering to present after LP,⁵ but concurrent presentations of both have been reported.¹ In addition, oral mucosal involvement has been seen in 36% of cases. The most commonly affected sites are the extremities; however, involvement can be widespread.²

The pathogenesis of LPP currently is unknown. It has been proposed that in LP, injury of basal keratinocytes exposes hidden basement membrane and hemidesmosome antigens including BP180, a 180 kDa transmembrane protein of the basement membrane zone (BMZ),⁶ which triggers an immune response where T cells recognize the extracellular portion of BP180 and antibodies are formed against the likely autoantigen.1 One study has suggested that the autoantigen in LPP is the MCW-4 epitope within the C-terminal end of the NC16A domain of BP180.⁷

Histopathology of LPP reveals characteristics of both LP as well as BP. Typical features of LP on hematoxylin and eosin (H&E) staining include lichenoid lymphocytic interface dermatitis, sawtooth rete ridges, wedge-shaped hypergranulosis, and colloid bodies, as demonstrated from the biopsy of our patient’s gluteal cleft lesion (quiz image 1), while the predominant feature of BP on H&E staining includes a subepidermal bulla with eosinophils.² Typically, direct immunofluorescence (DIF) shows linear deposits of IgG and/or C3 along the BMZ. Indirect immunofluorescence (IIF) often reveals IgG against the roof of the BMZ in a human split-skin substrate.¹ Antibodies against BP180 or uncommonly BP230 often are detected on enzyme-linked immunosorbent assay (ELISA). For our patient, IIF and ELISA tests were positive. Given the clinical presentation with recurrent oral and gluteal cleft erosions, histologic findings, and the results of our patient’s immunological testing, the diagnosis of LPP was made.

Topical steroids often are used to treat localized disease of LPP.8 Oral prednisone also may be given for widespread or unresponsive disease.⁹ Other treatments include azathioprine, mycophenolate mofetil, hydroxychloroquine, dapsone, tetracycline in combination with nicotinamide, acitretin, ustekinumab, baricitinib, and rituximab with intravenous immunoglobulin.^3,8,10-12 Any potential medication culprits should be discontinued.⁹ Patients with oral involvement may require a soft diet to avoid further mucosal insult.¹⁰ Additionally, providers should consider dentistry, ophthalmology, and/or otolaryngology referrals depending on disease severity.

Bullous pemphigoid, the most common autoimmune blistering disease, has an estimated incidence of 10 to 43 per million individuals per year.² Classically, it presents with tense bullae on the skin of the lower abdomen, thighs, groin, forearms, and axillae. Circulating antibodies against 2 BMZ proteins—BP180 and BP230—are important factors in BP pathogenesis.² Diagnosis of BP is based on clinical features, histologic findings, and immunological studies including DIF, IIF, and ELISA. An eosinophil-rich subepidermal split typically is seen on H&E staining (Figure 1).

Direct immunofluorescence displays linear IgG and/ or C3 staining at the BMZ. Indirect immunofluorescence on a human salt-split skin substrate commonly shows linear BMZ deposition on the roof of the blister.² Indirect immunofluorescence for IgG deposition on monkey esophagus substrate shows linear BMZ deposition. Antibodies against the NC16A domain of BP180 (NC16A-BP180) are dominant, but BP230 antibodies against BP230 also are detected with ELISA.² Further studies have indicated that the NC16A epitopes of BP180 that are targeted in BP are MCW-0-3,² different from the autoantigen MCW-4 that is targeted in LPP.⁷

Paraneoplastic pemphigus (PNP) is another diagnosis to consider. Patients with PNP initially present with oral findings—most commonly chronic, erosive, and painful mucositis—followed by cutaneous involvement, which varies from the development of bullae to the formation of plaques similar to those of LP.¹³ The latter, in combination with oral erosions, may appear clinically similar to LPP. The results of DIF in conjugation with IIF and ELISA may help to further differentiate these disorders. Direct immunofluorescence in PNP typically reveals positive intercellular and/or BMZ IgG and C3, while DIF in LPP reveals depositions along the BMZ alone. Indirect immunofluorescence performed on rat bladder epithelium is particularly useful, as binding of IgG to rat bladder epithelium is characteristic of PNP and not seen in other disorders.¹⁴ Lastly, patients with PNP may develop IgG antibodies to various antigens such as desmoplakin I, desmoplakin II, envoplakin, periplakin, BP230, desmoglein 1, and desmoglein 3, which would not be expected in LPP patients.¹⁵ Hematoxylin and eosin staining differs from LPP, primarily with the location of the blister being intraepidermal. Acantholysis with hemorrhagic bullae can be seen (Figure 2).

Classic LP is an inflammatory disorder that mainly affects adults, with an estimated incidence of less than 1%.¹⁶ The classic form presents with purple, flat-topped, pruritic, polygonal papules and plaques of varying size that often are characterized by Wickham striae. Lichen planus possesses a broad spectrum of subtypes involving different locations, though skin lesions usually are localized to the extremities. Despite an unknown etiology, activated T cells and T helper type 1 cytokines are considered key in keratinocyte injury. Compact orthokeratosis, wedge-shaped hypergranulosis, focal dyskeratosis, and colloid bodies typically are found on H&E staining, along with a dense bandlike lymphohistiocytic infiltrate at the dermoepidermal junction (DEJ)(Figure 3). Direct immunofluorescence typically shows a shaggy band of fibrinogen along the DEJ in addition to colloid bodies that stain with various autoantibodies including IgM, IgG, IgA, and C3.¹⁶

Bullous LP is a rare variant of LP that commonly develops on the oral mucosa and the legs, with blisters confined on pre-existing LP lesions.⁹ The pathogenesis is related to an epidermal inflammatory infiltrate that leads to basal layer destruction followed by dermal-epidermal separations that cause blistering.¹⁷ Bullous LP does not have positive DIF, IIF, or ELISA because the pathophysiology does not involve autoantibody production. Histopathology typically displays an extensive inflammatory infiltrate and degeneration of the basal keratinocytes, resulting in large dermal-epidermal separations called Max-Joseph spaces (Figure 4).¹⁷ Colloid bodies are prominent in bullous LP but rarely are seen in LPP; eosinophils also are much more prominent in LPP compared to bullous LP.¹⁸ Unlike in LPP, DIF usually is negative in bullous LP, though lichenoid lesions may exhibit globular deposition of IgM, IgG, and IgA in the colloid bodies of the lower epidermis and/or papillary dermis. Similar to LP, DIF of the biopsy specimen shows linear or shaggy deposits of fibrinogen at the DEJ.¹⁷

The Diagnosis: Lichen Planus Pemphigoides

Lichen planus pemphigoides (LPP) is a rare acquired autoimmune blistering disorder with an estimated worldwide prevalence of approximately 1 in 1,000,000 individuals.¹ It often manifests with overlapping features of both LP and bullous pemphigoid (BP). The condition usually presents in the fifth decade of life and has a slight female predominance.² Although primarily idiopathic, it has been associated with certain medications and treatments, such as angiotensin-converting enzyme inhibitors, programmed cell death protein 1 inhibitors, programmed cell death ligand 1 inhibitors, labetalol, narrowband UVB, and psoralen plus UVA.^3,4

Patients initially present with lesions of classic lichen planus (LP) with pink-purple, flat-topped, pruritic, polygonal papules and plaques.⁵ After weeks to months, tense vesicles and bullae usually develop on the sites of LP as well as on uninvolved skin. One study found a mean lag time of about 8.3 months for blistering to present after LP,⁵ but concurrent presentations of both have been reported.¹ In addition, oral mucosal involvement has been seen in 36% of cases. The most commonly affected sites are the extremities; however, involvement can be widespread.²

The pathogenesis of LPP currently is unknown. It has been proposed that in LP, injury of basal keratinocytes exposes hidden basement membrane and hemidesmosome antigens including BP180, a 180 kDa transmembrane protein of the basement membrane zone (BMZ),⁶ which triggers an immune response where T cells recognize the extracellular portion of BP180 and antibodies are formed against the likely autoantigen.1 One study has suggested that the autoantigen in LPP is the MCW-4 epitope within the C-terminal end of the NC16A domain of BP180.⁷

Histopathology of LPP reveals characteristics of both LP as well as BP. Typical features of LP on hematoxylin and eosin (H&E) staining include lichenoid lymphocytic interface dermatitis, sawtooth rete ridges, wedge-shaped hypergranulosis, and colloid bodies, as demonstrated from the biopsy of our patient’s gluteal cleft lesion (quiz image 1), while the predominant feature of BP on H&E staining includes a subepidermal bulla with eosinophils.² Typically, direct immunofluorescence (DIF) shows linear deposits of IgG and/or C3 along the BMZ. Indirect immunofluorescence (IIF) often reveals IgG against the roof of the BMZ in a human split-skin substrate.¹ Antibodies against BP180 or uncommonly BP230 often are detected on enzyme-linked immunosorbent assay (ELISA). For our patient, IIF and ELISA tests were positive. Given the clinical presentation with recurrent oral and gluteal cleft erosions, histologic findings, and the results of our patient’s immunological testing, the diagnosis of LPP was made.

Topical steroids often are used to treat localized disease of LPP.8 Oral prednisone also may be given for widespread or unresponsive disease.⁹ Other treatments include azathioprine, mycophenolate mofetil, hydroxychloroquine, dapsone, tetracycline in combination with nicotinamide, acitretin, ustekinumab, baricitinib, and rituximab with intravenous immunoglobulin.^3,8,10-12 Any potential medication culprits should be discontinued.⁹ Patients with oral involvement may require a soft diet to avoid further mucosal insult.¹⁰ Additionally, providers should consider dentistry, ophthalmology, and/or otolaryngology referrals depending on disease severity.

Bullous pemphigoid, the most common autoimmune blistering disease, has an estimated incidence of 10 to 43 per million individuals per year.² Classically, it presents with tense bullae on the skin of the lower abdomen, thighs, groin, forearms, and axillae. Circulating antibodies against 2 BMZ proteins—BP180 and BP230—are important factors in BP pathogenesis.² Diagnosis of BP is based on clinical features, histologic findings, and immunological studies including DIF, IIF, and ELISA. An eosinophil-rich subepidermal split typically is seen on H&E staining (Figure 1).

Direct immunofluorescence displays linear IgG and/ or C3 staining at the BMZ. Indirect immunofluorescence on a human salt-split skin substrate commonly shows linear BMZ deposition on the roof of the blister.² Indirect immunofluorescence for IgG deposition on monkey esophagus substrate shows linear BMZ deposition. Antibodies against the NC16A domain of BP180 (NC16A-BP180) are dominant, but BP230 antibodies against BP230 also are detected with ELISA.² Further studies have indicated that the NC16A epitopes of BP180 that are targeted in BP are MCW-0-3,² different from the autoantigen MCW-4 that is targeted in LPP.⁷

Paraneoplastic pemphigus (PNP) is another diagnosis to consider. Patients with PNP initially present with oral findings—most commonly chronic, erosive, and painful mucositis—followed by cutaneous involvement, which varies from the development of bullae to the formation of plaques similar to those of LP.¹³ The latter, in combination with oral erosions, may appear clinically similar to LPP. The results of DIF in conjugation with IIF and ELISA may help to further differentiate these disorders. Direct immunofluorescence in PNP typically reveals positive intercellular and/or BMZ IgG and C3, while DIF in LPP reveals depositions along the BMZ alone. Indirect immunofluorescence performed on rat bladder epithelium is particularly useful, as binding of IgG to rat bladder epithelium is characteristic of PNP and not seen in other disorders.¹⁴ Lastly, patients with PNP may develop IgG antibodies to various antigens such as desmoplakin I, desmoplakin II, envoplakin, periplakin, BP230, desmoglein 1, and desmoglein 3, which would not be expected in LPP patients.¹⁵ Hematoxylin and eosin staining differs from LPP, primarily with the location of the blister being intraepidermal. Acantholysis with hemorrhagic bullae can be seen (Figure 2).

Classic LP is an inflammatory disorder that mainly affects adults, with an estimated incidence of less than 1%.¹⁶ The classic form presents with purple, flat-topped, pruritic, polygonal papules and plaques of varying size that often are characterized by Wickham striae. Lichen planus possesses a broad spectrum of subtypes involving different locations, though skin lesions usually are localized to the extremities. Despite an unknown etiology, activated T cells and T helper type 1 cytokines are considered key in keratinocyte injury. Compact orthokeratosis, wedge-shaped hypergranulosis, focal dyskeratosis, and colloid bodies typically are found on H&E staining, along with a dense bandlike lymphohistiocytic infiltrate at the dermoepidermal junction (DEJ)(Figure 3). Direct immunofluorescence typically shows a shaggy band of fibrinogen along the DEJ in addition to colloid bodies that stain with various autoantibodies including IgM, IgG, IgA, and C3.¹⁶

Bullous LP is a rare variant of LP that commonly develops on the oral mucosa and the legs, with blisters confined on pre-existing LP lesions.⁹ The pathogenesis is related to an epidermal inflammatory infiltrate that leads to basal layer destruction followed by dermal-epidermal separations that cause blistering.¹⁷ Bullous LP does not have positive DIF, IIF, or ELISA because the pathophysiology does not involve autoantibody production. Histopathology typically displays an extensive inflammatory infiltrate and degeneration of the basal keratinocytes, resulting in large dermal-epidermal separations called Max-Joseph spaces (Figure 4).¹⁷ Colloid bodies are prominent in bullous LP but rarely are seen in LPP; eosinophils also are much more prominent in LPP compared to bullous LP.¹⁸ Unlike in LPP, DIF usually is negative in bullous LP, though lichenoid lesions may exhibit globular deposition of IgM, IgG, and IgA in the colloid bodies of the lower epidermis and/or papillary dermis. Similar to LP, DIF of the biopsy specimen shows linear or shaggy deposits of fibrinogen at the DEJ.¹⁷

The Diagnosis: Lichen Planus Pemphigoides

Lichen planus pemphigoides (LPP) is a rare acquired autoimmune blistering disorder with an estimated worldwide prevalence of approximately 1 in 1,000,000 individuals.¹ It often manifests with overlapping features of both LP and bullous pemphigoid (BP). The condition usually presents in the fifth decade of life and has a slight female predominance.² Although primarily idiopathic, it has been associated with certain medications and treatments, such as angiotensin-converting enzyme inhibitors, programmed cell death protein 1 inhibitors, programmed cell death ligand 1 inhibitors, labetalol, narrowband UVB, and psoralen plus UVA.^3,4

Patients initially present with lesions of classic lichen planus (LP) with pink-purple, flat-topped, pruritic, polygonal papules and plaques.⁵ After weeks to months, tense vesicles and bullae usually develop on the sites of LP as well as on uninvolved skin. One study found a mean lag time of about 8.3 months for blistering to present after LP,⁵ but concurrent presentations of both have been reported.¹ In addition, oral mucosal involvement has been seen in 36% of cases. The most commonly affected sites are the extremities; however, involvement can be widespread.²

The pathogenesis of LPP currently is unknown. It has been proposed that in LP, injury of basal keratinocytes exposes hidden basement membrane and hemidesmosome antigens including BP180, a 180 kDa transmembrane protein of the basement membrane zone (BMZ),⁶ which triggers an immune response where T cells recognize the extracellular portion of BP180 and antibodies are formed against the likely autoantigen.1 One study has suggested that the autoantigen in LPP is the MCW-4 epitope within the C-terminal end of the NC16A domain of BP180.⁷

Histopathology of LPP reveals characteristics of both LP as well as BP. Typical features of LP on hematoxylin and eosin (H&E) staining include lichenoid lymphocytic interface dermatitis, sawtooth rete ridges, wedge-shaped hypergranulosis, and colloid bodies, as demonstrated from the biopsy of our patient’s gluteal cleft lesion (quiz image 1), while the predominant feature of BP on H&E staining includes a subepidermal bulla with eosinophils.² Typically, direct immunofluorescence (DIF) shows linear deposits of IgG and/or C3 along the BMZ. Indirect immunofluorescence (IIF) often reveals IgG against the roof of the BMZ in a human split-skin substrate.¹ Antibodies against BP180 or uncommonly BP230 often are detected on enzyme-linked immunosorbent assay (ELISA). For our patient, IIF and ELISA tests were positive. Given the clinical presentation with recurrent oral and gluteal cleft erosions, histologic findings, and the results of our patient’s immunological testing, the diagnosis of LPP was made.

Topical steroids often are used to treat localized disease of LPP.8 Oral prednisone also may be given for widespread or unresponsive disease.⁹ Other treatments include azathioprine, mycophenolate mofetil, hydroxychloroquine, dapsone, tetracycline in combination with nicotinamide, acitretin, ustekinumab, baricitinib, and rituximab with intravenous immunoglobulin.^3,8,10-12 Any potential medication culprits should be discontinued.⁹ Patients with oral involvement may require a soft diet to avoid further mucosal insult.¹⁰ Additionally, providers should consider dentistry, ophthalmology, and/or otolaryngology referrals depending on disease severity.

Bullous pemphigoid, the most common autoimmune blistering disease, has an estimated incidence of 10 to 43 per million individuals per year.² Classically, it presents with tense bullae on the skin of the lower abdomen, thighs, groin, forearms, and axillae. Circulating antibodies against 2 BMZ proteins—BP180 and BP230—are important factors in BP pathogenesis.² Diagnosis of BP is based on clinical features, histologic findings, and immunological studies including DIF, IIF, and ELISA. An eosinophil-rich subepidermal split typically is seen on H&E staining (Figure 1).

Direct immunofluorescence displays linear IgG and/ or C3 staining at the BMZ. Indirect immunofluorescence on a human salt-split skin substrate commonly shows linear BMZ deposition on the roof of the blister.² Indirect immunofluorescence for IgG deposition on monkey esophagus substrate shows linear BMZ deposition. Antibodies against the NC16A domain of BP180 (NC16A-BP180) are dominant, but BP230 antibodies against BP230 also are detected with ELISA.² Further studies have indicated that the NC16A epitopes of BP180 that are targeted in BP are MCW-0-3,² different from the autoantigen MCW-4 that is targeted in LPP.⁷

Paraneoplastic pemphigus (PNP) is another diagnosis to consider. Patients with PNP initially present with oral findings—most commonly chronic, erosive, and painful mucositis—followed by cutaneous involvement, which varies from the development of bullae to the formation of plaques similar to those of LP.¹³ The latter, in combination with oral erosions, may appear clinically similar to LPP. The results of DIF in conjugation with IIF and ELISA may help to further differentiate these disorders. Direct immunofluorescence in PNP typically reveals positive intercellular and/or BMZ IgG and C3, while DIF in LPP reveals depositions along the BMZ alone. Indirect immunofluorescence performed on rat bladder epithelium is particularly useful, as binding of IgG to rat bladder epithelium is characteristic of PNP and not seen in other disorders.¹⁴ Lastly, patients with PNP may develop IgG antibodies to various antigens such as desmoplakin I, desmoplakin II, envoplakin, periplakin, BP230, desmoglein 1, and desmoglein 3, which would not be expected in LPP patients.¹⁵ Hematoxylin and eosin staining differs from LPP, primarily with the location of the blister being intraepidermal. Acantholysis with hemorrhagic bullae can be seen (Figure 2).

Classic LP is an inflammatory disorder that mainly affects adults, with an estimated incidence of less than 1%.¹⁶ The classic form presents with purple, flat-topped, pruritic, polygonal papules and plaques of varying size that often are characterized by Wickham striae. Lichen planus possesses a broad spectrum of subtypes involving different locations, though skin lesions usually are localized to the extremities. Despite an unknown etiology, activated T cells and T helper type 1 cytokines are considered key in keratinocyte injury. Compact orthokeratosis, wedge-shaped hypergranulosis, focal dyskeratosis, and colloid bodies typically are found on H&E staining, along with a dense bandlike lymphohistiocytic infiltrate at the dermoepidermal junction (DEJ)(Figure 3). Direct immunofluorescence typically shows a shaggy band of fibrinogen along the DEJ in addition to colloid bodies that stain with various autoantibodies including IgM, IgG, IgA, and C3.¹⁶

Bullous LP is a rare variant of LP that commonly develops on the oral mucosa and the legs, with blisters confined on pre-existing LP lesions.⁹ The pathogenesis is related to an epidermal inflammatory infiltrate that leads to basal layer destruction followed by dermal-epidermal separations that cause blistering.¹⁷ Bullous LP does not have positive DIF, IIF, or ELISA because the pathophysiology does not involve autoantibody production. Histopathology typically displays an extensive inflammatory infiltrate and degeneration of the basal keratinocytes, resulting in large dermal-epidermal separations called Max-Joseph spaces (Figure 4).¹⁷ Colloid bodies are prominent in bullous LP but rarely are seen in LPP; eosinophils also are much more prominent in LPP compared to bullous LP.¹⁸ Unlike in LPP, DIF usually is negative in bullous LP, though lichenoid lesions may exhibit globular deposition of IgM, IgG, and IgA in the colloid bodies of the lower epidermis and/or papillary dermis. Similar to LP, DIF of the biopsy specimen shows linear or shaggy deposits of fibrinogen at the DEJ.¹⁷

Frontal fibrosing alopecia (FFA) is a lymphocytic cicatricial alopecia that primarily affects postmenopausal women. Considered a subtype of lichen planopilaris (LPP), FFA is histologically identical but presents as symmetric frontotemporal hairline recession rather than the multifocal distribution typical of LPP (Figure 1). Patients also may experience symptoms such as itching, facial papules, and eyebrow loss. As a progressive and scarring alopecia, early management of FFA is necessary to prevent permanent hair loss; however, there still are no clear guidelines regarding the efficacy of different treatment options for FFA due to a lack of randomized controlled studies in the literature. Patients with skin of color (SOC) also may have varying responses to treatment, further complicating the establishment of any treatment algorithm. Furthermore, symptoms, clinical findings, and demographics of FFA have been observed to vary across different ethnicities, especially among Black individuals. We conducted a systematic review of the literature on FFA in Black patients, with an analysis of demographics, clinical findings, concomitant skin conditions, treatments given, and treatment responses.

Methods

A PubMed search of articles indexed for MEDLINE was conducted of studies investigating FFA in patients with SOC from January 1, 2000, through November 30, 2020, using the terms frontal fibrosing alopecia, ethnicity, African, Black, Asian, Indian, Hispanic, and Latino. Articles were included if they were available in English and discussed treatment and clinical outcomes of FFA in Black individuals. The reference lists of included studies also were reviewed. Articles were assessed for quality of evidence using a 4-point scale (1=well-designed randomized controlled trials; 2=controlled trials with limitations or well-designed cohort or case-control studies; 3=case series with or without intervention; 4=case reports). Variables related to study type, patient demographics, treatments, and clinical outcomes were recorded.

Results

Of the 69 search results, 8 studies—2 retrospective cohort studies, 3 case series, and 3 case reports—describing 51 Black individuals with FFA were included in our review (eTable). Of these, 49 (96.1%) were female and 2 (3.9%) were male. Of the 45 females with data available for menopausal status, 24 (53.3%) were premenopausal and 21 (46.7%) were postmenopausal; data were not available for 4 females. Patients identified as African or African American in 27 (52.9%) cases, South African in 19 (37.3%), Black in 3 (5.9%), Indian in 1 (2.0%), and Afro-Caribbean in 1 (2.0%). The average age of FFA onset was 43.8 years in females (raw data available in 24 patients) and 35 years in males (raw data available in 2 patients). A family history of hair loss was reported in 15.7% (8/51) of patients.

Involved areas of hair loss included the frontotemporal hairline (51/51 [100%]), eyebrows (32/51 [62.7%]), limbs (4/51 [7.8%]), occiput (4/51 [7.8%]), facial hair (2/51 [3.9%]), vertex scalp (1/51 [2.0%]), and eyelashes (1/51 [2.0%]). Patchy alopecia suggestive of LPP was reported in 2 (3.9%) patients.

Patients frequently presented with scalp pruritus (26/51 [51.0%]), perifollicular papules or pustules (9/51 [17.6%]), and perifollicular hyperpigmentation (9/51 [17.6%]). Other associated symptoms included perifollicular erythema (6/51 [11.8%]), scalp pain (5/51 [9.8%]), hyperkeratosis or flaking (3/51 [5.9%]), and facial papules (2/51 [3.9%]). Loss of follicular ostia, prominent follicular ostia, and the lonely hair sign (Figure 2) was described in 21 (41.2%), 5 (9.8%), and 15 (29.4%) of patients, respectively. Hairstyles that involve scalp traction (19/51 [37.3%]) and/or chemicals (28/51 [54.9%]), such as hair dye or chemical relaxers, commonly were reported in patients prior to the onset of FFA.

The most commonly reported dermatologic comorbidities included traction alopecia (17/51 [33.3%]), followed by lichen planus pigmentosus (LLPigm)(7/51 [13.7%]), LPP (2/51 [3.9%]), psoriasis (1/51 [2.0%]), and morphea (1/51 [2.0%]). Reported comorbid diseases included Sjögren syndrome (2/51 [3.9%]), hypothyroidism (2/51 [3.9%]), HIV (1/51 [2.0%]), and diabetes mellitus (1/51 [2.0%]).

Of available reports (n=32), the most common histologic findings included perifollicular fibrosis (23/32 [71.9%]), lichenoid lymphocytic inflammation (22/23 [95.7%]) primarily affecting the isthmus and infundibular areas of the follicles, and decreased follicular density (21/23 [91.3%]).

The average time interval from treatment initiation to treatment assessment in available reports (n=25) was 1.8 years (range, 0.5–2 years). Response to treatment included regrowth of hair in 5.9% (3/51) of patients, FFA stabilization in 39.2% (20/51), FFA progression in 51.0% (26/51), and not reported in 3.9% (2/51). Combination therapy was used in 84.3% (43/51) of patients, while monotherapy was used in 11.8% (6/51), and 3.9% (2/51) did not have any treatment reported. Response to treatment was highly variable among patients, as were the combinations of therapeutic agents used (Table). Regrowth of hair was rare, occurring in only 2 (100%) patients treated with oral prednisone plus hydroxychloroquine (HCQ) or chloroquine (CHQ), and in 1 (50.0%) patient treated with topical corticosteroids plus antifungal shampoo, while there was no response in the other patient treated with this combination.

Improvement in hair loss, defined as having at least slowed progression of FFA, was observed in 100% (2/2) of patients who had oral steroids as part of their treatment regimen, followed by 5-alpha-reductase inhibitors (5-ARIs)(finasteride and dutasteride; 62.5% [5/8]), intralesional steroids (57.1% [8/14]), HCQ/CHQ (42.9% [15/35]), topical steroids (41.5% [17/41]), antifungal shampoo (40.0% [2/5]), topical/oral minoxidil (36.0% [9/25]), and tacrolimus (33.3% [7/21]).

Comment

Frontal fibrosing alopecia is a progressive scarring alopecia and a clinical variant of LPP. First described in 1994 by Kossard,¹ it initially was thought to be a disease of postmenopausal White women. Although still most prevalent in White individuals, there has been a growing number of reports describing FFA in patients with SOC, including Black individuals.¹⁰ Despite the increasing number of cases over the years, studies on the treatment of FFA remain sparse. Without expert guidelines, treatments usually are chosen based on clinician preferences. Few observational studies on these treatment modalities and their clinical outcomes exist, and the cohorts largely are composed of White patients.^10-12 However, Black individuals may respond differently to these treatments, just as they have been shown to exhibit unique features of FFA.³

Demographics of Patients With FFA—Consistent with our findings, prior studies have found that Black patients are more likely to be younger and premenopausal at FFA onset than their White counterparts.^13-15 Among the Black individuals included in our review, the majority were premenopausal (53%) with an average age of FFA onset of 46.7 years. Conversely, only 5% of 60 White females with FFA reported in a retrospective review were premenopausal and had an older mean age of FFA onset of 64 years,¹ substantiating prior reports.

Clinical Findings in Patients With FFA—The clinical findings observed in our cohort were consistent with what has previously been described in Black patients, including loss of follicular ostia (41.2%), lonely hair sign (29.4%), perifollicular erythema (11.8%), perifollicular papules (17.6%), and hyperkeratosis or flaking (5.9%). In comparing these findings with a review of 932 patients, 86% of whom were White, the observed frequencies of follicular ostia loss (38.3%) and lonely hair sign (26.7%) were similar; however, perifollicular erythema (44.2%), and hyperkeratosis (44.4%) were more prevalent in this group, while perifollicular papules (6.2%) were less common compared to our Black cohort.¹⁶ An explanation for this discrepancy in perifollicular erythema may be the increased skin pigmentation diminishing the appearance of erythema in Black individuals. Our cohort of Black individuals noted the presence of follicular hyperpigmentation (17.6%) and a high prevalence of scalp pruritus (51.0%), which appear to be more common in Black patients.^3,17 Although it is unclear why these differences in FFA presentation exist, it may be helpful for clinicians to be aware of these unique features when examining Black patients with suspected FFA.

Concomitant Cutaneous Disorders—A notable proportion of our cohort also had concomitant traction alopecia, which presents with frontotemporal alopecia, similar to FFA, making the diagnosis more challenging; however, the presence of perifollicular hyperpigmentation and facial hyperpigmentation in FFA may aid in differentiating these 2 entities.³ Other concomitant conditions noted in our review included androgenic alopecia, Sjögren syndrome, psoriasis, hypothyroidism, morphea, and HIV, suggesting a potential interplay between autoimmune, genetic, hormonal, and environmental components in the etiology of FFA. In fact, a recent study found that a persistent inflammatory response, loss of immune privilege, and a genetic susceptibility are some of the key processes in the pathogenesis of FFA.¹⁸ Although the authors speculated that there may be other triggers in initiating the onset of FFA, such as steroid hormones, sun exposure, and topical allergens, more evidence and controlled studies are needed

Additionally, concomitant LPPigm occurred in 13.7% of our FFA cohort, which appears to be more common in patients with darker skin types.^5,19-21 Lichen planus pigmentosus is a rare variant of LPP, and previous reports suggest that it may be associated with FFA.⁵ Similar to FFA, the pathogenesis of LPPigm also is unclear, and its treatment may be just as difficult.²² Because LPPigm may occur before, during, or after onset of FFA,²³ it may be helpful for clinicians to search for the signs of LPPigm in patients with darker skin types patients presenting with hair loss both as a diagnostic clue and so that treatment may be tailored to both conditions.

Response to Treatment—Similar to the varying clinical pictures, the response to treatment also can vary between patients of different ethnicities. For Black patients, treatment outcomes did not seem as successful as they did for other patients with SOC described in the literature. A retrospective cohort of 58 Asian individuals with FFA found that up to 90% had improvement or stabilization of FFA after treatment,²³ while only 45.1% (23/51) of the Black patients included in our study had improvement or stabilization. One reason may be that a greater proportion of Black patients are premenopausal at FFA onset (53%) compared to what is reported in Asian patients (28%),²³ and women who are premenopausal at FFA onset often face more severe disease.¹⁵ Although there may be additional explanations for these differences in treatment outcomes between ethnic groups, further investigation is needed.

All patients included in our study received either monotherapy or combination therapy of topical/intralesional/oral steroids, HCQ or CHQ, 5-ARIs, topical/oral minoxidil, antifungal shampoo, and/or a calcineurin inhibitor; however, most patients (51.0%) did not see a response to treatment, while only 45.1% showed slowed or halted progression of FFA. Hair regrowth was rare, occurring in only 3 (5.9%) patients; 2 of them were the only patients treated with oral prednisone, making for a potentially promising therapeutic for Black patients that should be further investigated in larger controlled cohort studies. In a prior study, intramuscular steroids (40 mg every 3 weeks) plus topical minoxidil were unsuccessful in slowing the progression of FFA in 3 postmenopausal women,²⁴ which may be explained by the racial differences in the response to FFA treatments and perhaps also menopausal status. Although not included in any of the regimens in our review, isotretinoin was shown to be effective in an ethnically unspecified group of patients (n=16) and also may be efficacious in Black individuals.²⁵ Although FFA may stabilize with time,²⁶ this was not observed in any of the patients included in our study; however, we only included patients who were treated, making it impossible to discern whether resolution was idiopathic or due to treatment.

Future Research—Research on treatments for FFA is lacking, especially in patients with SOC. Although we observed that there may be differences in the treatment response among Black individuals compared to other patients with SOC, additional studies are needed to delineate these racial differences, which can help guide management. More randomized controlled trials evaluating the various treatment regimens also are required to establish treatment guidelines. Frontal fibrosing alopecia likely is underdiagnosed in Black individuals, contributing to the lack of research in this group. Darker skin can obscure some of the clinical and dermoscopic features that are more visible in fair skin. Furthermore, it may be challenging to distinguish clinical features of FFA in the setting of concomitant traction alopecia, which is more common in Black patients.²⁷ Frontal fibrosing alopecia presenting in Black women also is less likely to be biopsied, contributing to the tendency to miss FFA in favor of traction or androgenic alopecia, which often are assumed to be more common in this population.^2,27 Therefore, histologic evaluation through biopsy is paramount in securing an accurate diagnosis for Black patients with frontotemporal alopecia.

Study Limitations—The studies included in our review were limited by a lack of control comparison groups, especially among the retrospective cohort studies. Additionally, some of the studies included cases refractory to prior treatment modalities, possibly leading to a selection bias of more severe cases that were not representative of FFA in the general population. Thus, further studies involving larger populations of those with SOC are needed to fully evaluate the clinical utility of the current treatment modalities in this group.

Frontal fibrosing alopecia (FFA) is a lymphocytic cicatricial alopecia that primarily affects postmenopausal women. Considered a subtype of lichen planopilaris (LPP), FFA is histologically identical but presents as symmetric frontotemporal hairline recession rather than the multifocal distribution typical of LPP (Figure 1). Patients also may experience symptoms such as itching, facial papules, and eyebrow loss. As a progressive and scarring alopecia, early management of FFA is necessary to prevent permanent hair loss; however, there still are no clear guidelines regarding the efficacy of different treatment options for FFA due to a lack of randomized controlled studies in the literature. Patients with skin of color (SOC) also may have varying responses to treatment, further complicating the establishment of any treatment algorithm. Furthermore, symptoms, clinical findings, and demographics of FFA have been observed to vary across different ethnicities, especially among Black individuals. We conducted a systematic review of the literature on FFA in Black patients, with an analysis of demographics, clinical findings, concomitant skin conditions, treatments given, and treatment responses.

Methods

A PubMed search of articles indexed for MEDLINE was conducted of studies investigating FFA in patients with SOC from January 1, 2000, through November 30, 2020, using the terms frontal fibrosing alopecia, ethnicity, African, Black, Asian, Indian, Hispanic, and Latino. Articles were included if they were available in English and discussed treatment and clinical outcomes of FFA in Black individuals. The reference lists of included studies also were reviewed. Articles were assessed for quality of evidence using a 4-point scale (1=well-designed randomized controlled trials; 2=controlled trials with limitations or well-designed cohort or case-control studies; 3=case series with or without intervention; 4=case reports). Variables related to study type, patient demographics, treatments, and clinical outcomes were recorded.

Results

Of the 69 search results, 8 studies—2 retrospective cohort studies, 3 case series, and 3 case reports—describing 51 Black individuals with FFA were included in our review (eTable). Of these, 49 (96.1%) were female and 2 (3.9%) were male. Of the 45 females with data available for menopausal status, 24 (53.3%) were premenopausal and 21 (46.7%) were postmenopausal; data were not available for 4 females. Patients identified as African or African American in 27 (52.9%) cases, South African in 19 (37.3%), Black in 3 (5.9%), Indian in 1 (2.0%), and Afro-Caribbean in 1 (2.0%). The average age of FFA onset was 43.8 years in females (raw data available in 24 patients) and 35 years in males (raw data available in 2 patients). A family history of hair loss was reported in 15.7% (8/51) of patients.

Involved areas of hair loss included the frontotemporal hairline (51/51 [100%]), eyebrows (32/51 [62.7%]), limbs (4/51 [7.8%]), occiput (4/51 [7.8%]), facial hair (2/51 [3.9%]), vertex scalp (1/51 [2.0%]), and eyelashes (1/51 [2.0%]). Patchy alopecia suggestive of LPP was reported in 2 (3.9%) patients.

Patients frequently presented with scalp pruritus (26/51 [51.0%]), perifollicular papules or pustules (9/51 [17.6%]), and perifollicular hyperpigmentation (9/51 [17.6%]). Other associated symptoms included perifollicular erythema (6/51 [11.8%]), scalp pain (5/51 [9.8%]), hyperkeratosis or flaking (3/51 [5.9%]), and facial papules (2/51 [3.9%]). Loss of follicular ostia, prominent follicular ostia, and the lonely hair sign (Figure 2) was described in 21 (41.2%), 5 (9.8%), and 15 (29.4%) of patients, respectively. Hairstyles that involve scalp traction (19/51 [37.3%]) and/or chemicals (28/51 [54.9%]), such as hair dye or chemical relaxers, commonly were reported in patients prior to the onset of FFA.

The most commonly reported dermatologic comorbidities included traction alopecia (17/51 [33.3%]), followed by lichen planus pigmentosus (LLPigm)(7/51 [13.7%]), LPP (2/51 [3.9%]), psoriasis (1/51 [2.0%]), and morphea (1/51 [2.0%]). Reported comorbid diseases included Sjögren syndrome (2/51 [3.9%]), hypothyroidism (2/51 [3.9%]), HIV (1/51 [2.0%]), and diabetes mellitus (1/51 [2.0%]).

Of available reports (n=32), the most common histologic findings included perifollicular fibrosis (23/32 [71.9%]), lichenoid lymphocytic inflammation (22/23 [95.7%]) primarily affecting the isthmus and infundibular areas of the follicles, and decreased follicular density (21/23 [91.3%]).

The average time interval from treatment initiation to treatment assessment in available reports (n=25) was 1.8 years (range, 0.5–2 years). Response to treatment included regrowth of hair in 5.9% (3/51) of patients, FFA stabilization in 39.2% (20/51), FFA progression in 51.0% (26/51), and not reported in 3.9% (2/51). Combination therapy was used in 84.3% (43/51) of patients, while monotherapy was used in 11.8% (6/51), and 3.9% (2/51) did not have any treatment reported. Response to treatment was highly variable among patients, as were the combinations of therapeutic agents used (Table). Regrowth of hair was rare, occurring in only 2 (100%) patients treated with oral prednisone plus hydroxychloroquine (HCQ) or chloroquine (CHQ), and in 1 (50.0%) patient treated with topical corticosteroids plus antifungal shampoo, while there was no response in the other patient treated with this combination.

Improvement in hair loss, defined as having at least slowed progression of FFA, was observed in 100% (2/2) of patients who had oral steroids as part of their treatment regimen, followed by 5-alpha-reductase inhibitors (5-ARIs)(finasteride and dutasteride; 62.5% [5/8]), intralesional steroids (57.1% [8/14]), HCQ/CHQ (42.9% [15/35]), topical steroids (41.5% [17/41]), antifungal shampoo (40.0% [2/5]), topical/oral minoxidil (36.0% [9/25]), and tacrolimus (33.3% [7/21]).

Comment

Frontal fibrosing alopecia is a progressive scarring alopecia and a clinical variant of LPP. First described in 1994 by Kossard,¹ it initially was thought to be a disease of postmenopausal White women. Although still most prevalent in White individuals, there has been a growing number of reports describing FFA in patients with SOC, including Black individuals.¹⁰ Despite the increasing number of cases over the years, studies on the treatment of FFA remain sparse. Without expert guidelines, treatments usually are chosen based on clinician preferences. Few observational studies on these treatment modalities and their clinical outcomes exist, and the cohorts largely are composed of White patients.^10-12 However, Black individuals may respond differently to these treatments, just as they have been shown to exhibit unique features of FFA.³

Demographics of Patients With FFA—Consistent with our findings, prior studies have found that Black patients are more likely to be younger and premenopausal at FFA onset than their White counterparts.^13-15 Among the Black individuals included in our review, the majority were premenopausal (53%) with an average age of FFA onset of 46.7 years. Conversely, only 5% of 60 White females with FFA reported in a retrospective review were premenopausal and had an older mean age of FFA onset of 64 years,¹ substantiating prior reports.

Clinical Findings in Patients With FFA—The clinical findings observed in our cohort were consistent with what has previously been described in Black patients, including loss of follicular ostia (41.2%), lonely hair sign (29.4%), perifollicular erythema (11.8%), perifollicular papules (17.6%), and hyperkeratosis or flaking (5.9%). In comparing these findings with a review of 932 patients, 86% of whom were White, the observed frequencies of follicular ostia loss (38.3%) and lonely hair sign (26.7%) were similar; however, perifollicular erythema (44.2%), and hyperkeratosis (44.4%) were more prevalent in this group, while perifollicular papules (6.2%) were less common compared to our Black cohort.¹⁶ An explanation for this discrepancy in perifollicular erythema may be the increased skin pigmentation diminishing the appearance of erythema in Black individuals. Our cohort of Black individuals noted the presence of follicular hyperpigmentation (17.6%) and a high prevalence of scalp pruritus (51.0%), which appear to be more common in Black patients.^3,17 Although it is unclear why these differences in FFA presentation exist, it may be helpful for clinicians to be aware of these unique features when examining Black patients with suspected FFA.

Concomitant Cutaneous Disorders—A notable proportion of our cohort also had concomitant traction alopecia, which presents with frontotemporal alopecia, similar to FFA, making the diagnosis more challenging; however, the presence of perifollicular hyperpigmentation and facial hyperpigmentation in FFA may aid in differentiating these 2 entities.³ Other concomitant conditions noted in our review included androgenic alopecia, Sjögren syndrome, psoriasis, hypothyroidism, morphea, and HIV, suggesting a potential interplay between autoimmune, genetic, hormonal, and environmental components in the etiology of FFA. In fact, a recent study found that a persistent inflammatory response, loss of immune privilege, and a genetic susceptibility are some of the key processes in the pathogenesis of FFA.¹⁸ Although the authors speculated that there may be other triggers in initiating the onset of FFA, such as steroid hormones, sun exposure, and topical allergens, more evidence and controlled studies are needed

Additionally, concomitant LPPigm occurred in 13.7% of our FFA cohort, which appears to be more common in patients with darker skin types.^5,19-21 Lichen planus pigmentosus is a rare variant of LPP, and previous reports suggest that it may be associated with FFA.⁵ Similar to FFA, the pathogenesis of LPPigm also is unclear, and its treatment may be just as difficult.²² Because LPPigm may occur before, during, or after onset of FFA,²³ it may be helpful for clinicians to search for the signs of LPPigm in patients with darker skin types patients presenting with hair loss both as a diagnostic clue and so that treatment may be tailored to both conditions.

Response to Treatment—Similar to the varying clinical pictures, the response to treatment also can vary between patients of different ethnicities. For Black patients, treatment outcomes did not seem as successful as they did for other patients with SOC described in the literature. A retrospective cohort of 58 Asian individuals with FFA found that up to 90% had improvement or stabilization of FFA after treatment,²³ while only 45.1% (23/51) of the Black patients included in our study had improvement or stabilization. One reason may be that a greater proportion of Black patients are premenopausal at FFA onset (53%) compared to what is reported in Asian patients (28%),²³ and women who are premenopausal at FFA onset often face more severe disease.¹⁵ Although there may be additional explanations for these differences in treatment outcomes between ethnic groups, further investigation is needed.

All patients included in our study received either monotherapy or combination therapy of topical/intralesional/oral steroids, HCQ or CHQ, 5-ARIs, topical/oral minoxidil, antifungal shampoo, and/or a calcineurin inhibitor; however, most patients (51.0%) did not see a response to treatment, while only 45.1% showed slowed or halted progression of FFA. Hair regrowth was rare, occurring in only 3 (5.9%) patients; 2 of them were the only patients treated with oral prednisone, making for a potentially promising therapeutic for Black patients that should be further investigated in larger controlled cohort studies. In a prior study, intramuscular steroids (40 mg every 3 weeks) plus topical minoxidil were unsuccessful in slowing the progression of FFA in 3 postmenopausal women,²⁴ which may be explained by the racial differences in the response to FFA treatments and perhaps also menopausal status. Although not included in any of the regimens in our review, isotretinoin was shown to be effective in an ethnically unspecified group of patients (n=16) and also may be efficacious in Black individuals.²⁵ Although FFA may stabilize with time,²⁶ this was not observed in any of the patients included in our study; however, we only included patients who were treated, making it impossible to discern whether resolution was idiopathic or due to treatment.

Future Research—Research on treatments for FFA is lacking, especially in patients with SOC. Although we observed that there may be differences in the treatment response among Black individuals compared to other patients with SOC, additional studies are needed to delineate these racial differences, which can help guide management. More randomized controlled trials evaluating the various treatment regimens also are required to establish treatment guidelines. Frontal fibrosing alopecia likely is underdiagnosed in Black individuals, contributing to the lack of research in this group. Darker skin can obscure some of the clinical and dermoscopic features that are more visible in fair skin. Furthermore, it may be challenging to distinguish clinical features of FFA in the setting of concomitant traction alopecia, which is more common in Black patients.²⁷ Frontal fibrosing alopecia presenting in Black women also is less likely to be biopsied, contributing to the tendency to miss FFA in favor of traction or androgenic alopecia, which often are assumed to be more common in this population.^2,27 Therefore, histologic evaluation through biopsy is paramount in securing an accurate diagnosis for Black patients with frontotemporal alopecia.

Study Limitations—The studies included in our review were limited by a lack of control comparison groups, especially among the retrospective cohort studies. Additionally, some of the studies included cases refractory to prior treatment modalities, possibly leading to a selection bias of more severe cases that were not representative of FFA in the general population. Thus, further studies involving larger populations of those with SOC are needed to fully evaluate the clinical utility of the current treatment modalities in this group.

Frontal fibrosing alopecia (FFA) is a lymphocytic cicatricial alopecia that primarily affects postmenopausal women. Considered a subtype of lichen planopilaris (LPP), FFA is histologically identical but presents as symmetric frontotemporal hairline recession rather than the multifocal distribution typical of LPP (Figure 1). Patients also may experience symptoms such as itching, facial papules, and eyebrow loss. As a progressive and scarring alopecia, early management of FFA is necessary to prevent permanent hair loss; however, there still are no clear guidelines regarding the efficacy of different treatment options for FFA due to a lack of randomized controlled studies in the literature. Patients with skin of color (SOC) also may have varying responses to treatment, further complicating the establishment of any treatment algorithm. Furthermore, symptoms, clinical findings, and demographics of FFA have been observed to vary across different ethnicities, especially among Black individuals. We conducted a systematic review of the literature on FFA in Black patients, with an analysis of demographics, clinical findings, concomitant skin conditions, treatments given, and treatment responses.

Methods

A PubMed search of articles indexed for MEDLINE was conducted of studies investigating FFA in patients with SOC from January 1, 2000, through November 30, 2020, using the terms frontal fibrosing alopecia, ethnicity, African, Black, Asian, Indian, Hispanic, and Latino. Articles were included if they were available in English and discussed treatment and clinical outcomes of FFA in Black individuals. The reference lists of included studies also were reviewed. Articles were assessed for quality of evidence using a 4-point scale (1=well-designed randomized controlled trials; 2=controlled trials with limitations or well-designed cohort or case-control studies; 3=case series with or without intervention; 4=case reports). Variables related to study type, patient demographics, treatments, and clinical outcomes were recorded.

Results

Of the 69 search results, 8 studies—2 retrospective cohort studies, 3 case series, and 3 case reports—describing 51 Black individuals with FFA were included in our review (eTable). Of these, 49 (96.1%) were female and 2 (3.9%) were male. Of the 45 females with data available for menopausal status, 24 (53.3%) were premenopausal and 21 (46.7%) were postmenopausal; data were not available for 4 females. Patients identified as African or African American in 27 (52.9%) cases, South African in 19 (37.3%), Black in 3 (5.9%), Indian in 1 (2.0%), and Afro-Caribbean in 1 (2.0%). The average age of FFA onset was 43.8 years in females (raw data available in 24 patients) and 35 years in males (raw data available in 2 patients). A family history of hair loss was reported in 15.7% (8/51) of patients.

Involved areas of hair loss included the frontotemporal hairline (51/51 [100%]), eyebrows (32/51 [62.7%]), limbs (4/51 [7.8%]), occiput (4/51 [7.8%]), facial hair (2/51 [3.9%]), vertex scalp (1/51 [2.0%]), and eyelashes (1/51 [2.0%]). Patchy alopecia suggestive of LPP was reported in 2 (3.9%) patients.

Patients frequently presented with scalp pruritus (26/51 [51.0%]), perifollicular papules or pustules (9/51 [17.6%]), and perifollicular hyperpigmentation (9/51 [17.6%]). Other associated symptoms included perifollicular erythema (6/51 [11.8%]), scalp pain (5/51 [9.8%]), hyperkeratosis or flaking (3/51 [5.9%]), and facial papules (2/51 [3.9%]). Loss of follicular ostia, prominent follicular ostia, and the lonely hair sign (Figure 2) was described in 21 (41.2%), 5 (9.8%), and 15 (29.4%) of patients, respectively. Hairstyles that involve scalp traction (19/51 [37.3%]) and/or chemicals (28/51 [54.9%]), such as hair dye or chemical relaxers, commonly were reported in patients prior to the onset of FFA.

The most commonly reported dermatologic comorbidities included traction alopecia (17/51 [33.3%]), followed by lichen planus pigmentosus (LLPigm)(7/51 [13.7%]), LPP (2/51 [3.9%]), psoriasis (1/51 [2.0%]), and morphea (1/51 [2.0%]). Reported comorbid diseases included Sjögren syndrome (2/51 [3.9%]), hypothyroidism (2/51 [3.9%]), HIV (1/51 [2.0%]), and diabetes mellitus (1/51 [2.0%]).

Of available reports (n=32), the most common histologic findings included perifollicular fibrosis (23/32 [71.9%]), lichenoid lymphocytic inflammation (22/23 [95.7%]) primarily affecting the isthmus and infundibular areas of the follicles, and decreased follicular density (21/23 [91.3%]).

The average time interval from treatment initiation to treatment assessment in available reports (n=25) was 1.8 years (range, 0.5–2 years). Response to treatment included regrowth of hair in 5.9% (3/51) of patients, FFA stabilization in 39.2% (20/51), FFA progression in 51.0% (26/51), and not reported in 3.9% (2/51). Combination therapy was used in 84.3% (43/51) of patients, while monotherapy was used in 11.8% (6/51), and 3.9% (2/51) did not have any treatment reported. Response to treatment was highly variable among patients, as were the combinations of therapeutic agents used (Table). Regrowth of hair was rare, occurring in only 2 (100%) patients treated with oral prednisone plus hydroxychloroquine (HCQ) or chloroquine (CHQ), and in 1 (50.0%) patient treated with topical corticosteroids plus antifungal shampoo, while there was no response in the other patient treated with this combination.

Improvement in hair loss, defined as having at least slowed progression of FFA, was observed in 100% (2/2) of patients who had oral steroids as part of their treatment regimen, followed by 5-alpha-reductase inhibitors (5-ARIs)(finasteride and dutasteride; 62.5% [5/8]), intralesional steroids (57.1% [8/14]), HCQ/CHQ (42.9% [15/35]), topical steroids (41.5% [17/41]), antifungal shampoo (40.0% [2/5]), topical/oral minoxidil (36.0% [9/25]), and tacrolimus (33.3% [7/21]).

Comment

Frontal fibrosing alopecia is a progressive scarring alopecia and a clinical variant of LPP. First described in 1994 by Kossard,¹ it initially was thought to be a disease of postmenopausal White women. Although still most prevalent in White individuals, there has been a growing number of reports describing FFA in patients with SOC, including Black individuals.¹⁰ Despite the increasing number of cases over the years, studies on the treatment of FFA remain sparse. Without expert guidelines, treatments usually are chosen based on clinician preferences. Few observational studies on these treatment modalities and their clinical outcomes exist, and the cohorts largely are composed of White patients.^10-12 However, Black individuals may respond differently to these treatments, just as they have been shown to exhibit unique features of FFA.³

Demographics of Patients With FFA—Consistent with our findings, prior studies have found that Black patients are more likely to be younger and premenopausal at FFA onset than their White counterparts.^13-15 Among the Black individuals included in our review, the majority were premenopausal (53%) with an average age of FFA onset of 46.7 years. Conversely, only 5% of 60 White females with FFA reported in a retrospective review were premenopausal and had an older mean age of FFA onset of 64 years,¹ substantiating prior reports.

Clinical Findings in Patients With FFA—The clinical findings observed in our cohort were consistent with what has previously been described in Black patients, including loss of follicular ostia (41.2%), lonely hair sign (29.4%), perifollicular erythema (11.8%), perifollicular papules (17.6%), and hyperkeratosis or flaking (5.9%). In comparing these findings with a review of 932 patients, 86% of whom were White, the observed frequencies of follicular ostia loss (38.3%) and lonely hair sign (26.7%) were similar; however, perifollicular erythema (44.2%), and hyperkeratosis (44.4%) were more prevalent in this group, while perifollicular papules (6.2%) were less common compared to our Black cohort.¹⁶ An explanation for this discrepancy in perifollicular erythema may be the increased skin pigmentation diminishing the appearance of erythema in Black individuals. Our cohort of Black individuals noted the presence of follicular hyperpigmentation (17.6%) and a high prevalence of scalp pruritus (51.0%), which appear to be more common in Black patients.^3,17 Although it is unclear why these differences in FFA presentation exist, it may be helpful for clinicians to be aware of these unique features when examining Black patients with suspected FFA.

Concomitant Cutaneous Disorders—A notable proportion of our cohort also had concomitant traction alopecia, which presents with frontotemporal alopecia, similar to FFA, making the diagnosis more challenging; however, the presence of perifollicular hyperpigmentation and facial hyperpigmentation in FFA may aid in differentiating these 2 entities.³ Other concomitant conditions noted in our review included androgenic alopecia, Sjögren syndrome, psoriasis, hypothyroidism, morphea, and HIV, suggesting a potential interplay between autoimmune, genetic, hormonal, and environmental components in the etiology of FFA. In fact, a recent study found that a persistent inflammatory response, loss of immune privilege, and a genetic susceptibility are some of the key processes in the pathogenesis of FFA.¹⁸ Although the authors speculated that there may be other triggers in initiating the onset of FFA, such as steroid hormones, sun exposure, and topical allergens, more evidence and controlled studies are needed

Additionally, concomitant LPPigm occurred in 13.7% of our FFA cohort, which appears to be more common in patients with darker skin types.^5,19-21 Lichen planus pigmentosus is a rare variant of LPP, and previous reports suggest that it may be associated with FFA.⁵ Similar to FFA, the pathogenesis of LPPigm also is unclear, and its treatment may be just as difficult.²² Because LPPigm may occur before, during, or after onset of FFA,²³ it may be helpful for clinicians to search for the signs of LPPigm in patients with darker skin types patients presenting with hair loss both as a diagnostic clue and so that treatment may be tailored to both conditions.

Response to Treatment—Similar to the varying clinical pictures, the response to treatment also can vary between patients of different ethnicities. For Black patients, treatment outcomes did not seem as successful as they did for other patients with SOC described in the literature. A retrospective cohort of 58 Asian individuals with FFA found that up to 90% had improvement or stabilization of FFA after treatment,²³ while only 45.1% (23/51) of the Black patients included in our study had improvement or stabilization. One reason may be that a greater proportion of Black patients are premenopausal at FFA onset (53%) compared to what is reported in Asian patients (28%),²³ and women who are premenopausal at FFA onset often face more severe disease.¹⁵ Although there may be additional explanations for these differences in treatment outcomes between ethnic groups, further investigation is needed.

All patients included in our study received either monotherapy or combination therapy of topical/intralesional/oral steroids, HCQ or CHQ, 5-ARIs, topical/oral minoxidil, antifungal shampoo, and/or a calcineurin inhibitor; however, most patients (51.0%) did not see a response to treatment, while only 45.1% showed slowed or halted progression of FFA. Hair regrowth was rare, occurring in only 3 (5.9%) patients; 2 of them were the only patients treated with oral prednisone, making for a potentially promising therapeutic for Black patients that should be further investigated in larger controlled cohort studies. In a prior study, intramuscular steroids (40 mg every 3 weeks) plus topical minoxidil were unsuccessful in slowing the progression of FFA in 3 postmenopausal women,²⁴ which may be explained by the racial differences in the response to FFA treatments and perhaps also menopausal status. Although not included in any of the regimens in our review, isotretinoin was shown to be effective in an ethnically unspecified group of patients (n=16) and also may be efficacious in Black individuals.²⁵ Although FFA may stabilize with time,²⁶ this was not observed in any of the patients included in our study; however, we only included patients who were treated, making it impossible to discern whether resolution was idiopathic or due to treatment.

Future Research—Research on treatments for FFA is lacking, especially in patients with SOC. Although we observed that there may be differences in the treatment response among Black individuals compared to other patients with SOC, additional studies are needed to delineate these racial differences, which can help guide management. More randomized controlled trials evaluating the various treatment regimens also are required to establish treatment guidelines. Frontal fibrosing alopecia likely is underdiagnosed in Black individuals, contributing to the lack of research in this group. Darker skin can obscure some of the clinical and dermoscopic features that are more visible in fair skin. Furthermore, it may be challenging to distinguish clinical features of FFA in the setting of concomitant traction alopecia, which is more common in Black patients.²⁷ Frontal fibrosing alopecia presenting in Black women also is less likely to be biopsied, contributing to the tendency to miss FFA in favor of traction or androgenic alopecia, which often are assumed to be more common in this population.^2,27 Therefore, histologic evaluation through biopsy is paramount in securing an accurate diagnosis for Black patients with frontotemporal alopecia.

Study Limitations—The studies included in our review were limited by a lack of control comparison groups, especially among the retrospective cohort studies. Additionally, some of the studies included cases refractory to prior treatment modalities, possibly leading to a selection bias of more severe cases that were not representative of FFA in the general population. Thus, further studies involving larger populations of those with SOC are needed to fully evaluate the clinical utility of the current treatment modalities in this group.

NEW ORLEANS – The sociodemographic characteristics of Black and Hispanic children with systemic lupus erythematosus (SLE) appear to play a strong role in influencing the severity of disease in these patients, according to two studies presented at the Pediatric Rheumatology Symposium.

One study showed an association between multiple determinants of health and disease severity among children seen in a large Texas city, and a separate descriptive cross-sectional cohort study of predominantly Black children at two centers in Mississippi and Alabama reinforced the finding of greater severity of disease and social hardships among this racial group.

The findings from both studies supplement existing evidence that the prevalence of childhood-onset SLE is greater among Black and Hispanic children.

“Several demographic and social determinants of health parameters influenced disease severity at levels that reached statistical significance, including insurance status, race/ethnicity, referral source, PCP [primary care provider] availability, primary language, and transportation needs,” Emily Beil, MD, a pediatric rheumatologist at Texas Children’s Hospital in Houston, told attendees at the conference, which was sponsored by the American College of Rheumatology. Her team’s goal, she said, was to “better understand our patient population and social disparities that contribute to disease severity.”

Dr. Beil and her colleagues conducted a retrospective review of 136 children who had been diagnosed with childhood-onset SLE between January 2018 and May 2022 at Texas Children’s Hospital. Only children who were younger than 18 years at the time of diagnosis at Texas Children’s were included. The analysis considered demographics, clinical characteristics, insurance status, social work consultation, access to a primary care provider, transportation needs, primary language, and other parameters related to social determinants of health.

The average age of the patients was 13 years, and most were girls (82%). Just over half were Hispanic (53%), and just over a quarter were Black (26%). Half had Medicaid or participated in the Children’s Health Insurance Program (CHIP), and 1 in 10 were uninsured (10%). Half the diagnoses were made during an inpatient admission; 36% were made on the floor, and 14% were made in the intensive care unit (ICU).

The average Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score was 12.5, and 48.5% of patients had severe disease, indicated by a score of at least 12. Only two in three children were documented as having a primary care physician (66%), and 32% preferred a language other than English. Most of the children (80%) had a social work consult.

Black and biracial children had higher SLEDAI scores at presentation. Non-Hispanic White children were less likely to have a social work consult, compared with other racial/ethnic groups (P = .01 for both). Central nervous system involvement was most prevalent among Black patients (P = .004). Cyclophosphamide was used most often for Black and biracial patients.

Uninsured patients were most likely to be diagnosed on an inpatient floor. The highest proportion of ICU admissions was among patients insured by Medicaid (P = .034). Average SLEDAI scores were highest among uninsured patients, followed by Medicaid patients. More than half of the patients who did not have insurance lacked access to a regular primary care provider, compared with 12% of Medicaid patients and 7% of privately insured patients (P = .001). All the uninsured patients had transportation needs, which was a significantly higher rate than among those with Medicaid (13%) or private insurance (15%) (P = .001). The highest percentage of social work consults was among patients who were insured by Medicaid or were without insurance (P = .001).
 

Salient demographics and clinical features

In the second presentation, Anita Dhanrajani, MD, assistant professor of pediatrics at the University of Mississippi Medical Center in Jackson, began by noting that Alabama and Mississippi are ranked in the top 10 states for the highest poverty rate: Mississippi is No. 1, and Alabama is No. 7. Further, 40% of children in Mississippi and 29% of children in Alabama are of African American ancestry, she said.

“So, we know that this population that we’re dealing with has several high-risk factors that can lead them to have poor outcomes, and yet, we haven’t really ever characterized their clinical features or their social demographic features,” Dr. Dhanrajani told attendees. “My hope is that with this very miniscule first step, we’re able to move towards solutions to decrease health care disparities in this population.”

She presented findings regarding the first of three aims in the study, which was to describe the baseline clinical, demographic, and socioeconomic profiles of childhood lupus patients at the two centers. The two other aims were to examine genetic factors potentially linked to poor outcomes in the cohort and to assess the mental health status of the population.

The study relied on a retrospective chart review for the 17 patients at the University of Mississippi Medical Center and on Childhood Arthritis and Rheumatology Research Alliance registry data for the 19 patients at the University of Alabama at Birmingham. Most of the patients (86%) were female, Black (78%), and insured by Medicaid (64%). The average age at diagnosis was 13 years. Most (83%) also lived in a ZIP code that met the criteria for a medium-high or high Social Vulnerability Index. The children had to travel an average 75 miles to see a rheumatologist, compared with the national average of 43 miles.

At diagnosis, their average Systemic Lupus International Collaborating Clinics (SLICC) score was 8.8, their average American College of Rheumatology score was 5.2, and their average SLEDAI score was 12.1 – the latter was substantially higher than the average 3.1 score in a multiethnic Canadian cohort (the 1000 Canadian Faces of Lupus Study) with 10% Black children (P < .00001). The SLEDAI score dropped to 6.8 at 6 months and to 4 at 1 year. Nearly half (47%) had a SLICC Damage Index (SDI) greater than 0, and one-third had an SDI of 2 or greater, compared with 16% and 7%, respectively, reported in other recent studies (P < .0001 for both).

“These disparities are very difficult to investigate in terms of causal relationships and [are] likely to be very modifiable,” Coziana Ciurtin, MD, PhD, associate professor of rheumatology at University College London, told this news organization. “I think the socioeconomic status, the level of education, poverty, [type of] medical insurance, and probably genetic variants are all underpinning the presentation, damage, or disease activity being very high, and also organ involvement,” such as the greater CNS involvement seen in non-White patients.

Being mindful of these risk profiles can help doctors in asking about patients’ support at home and their families’ education, beliefs, and cultural practices, Dr. Ciurtin added. “Helping them to engage and be involved in decision-making is probably the most important” aspect of learning this information about families, she said.

Collecting this information should not be the sole responsibility of the physician, added Eve Smith, PhD, MBCHB, an academic clinical lecturer at the University of Liverpool, England, who attended the presentations. Dr. Smith noted a discussion in a work group during the previous day of the conference concerning questionnaires for screening patients regarding the need for social services and for identifying areas in which patients and their families were having difficulties.

“Obviously, if you’re going to do that, you have to have access to someone who can actually help to deal with that. Some hospitals have patient navigators that can help, for example, with a food security issue to highlight resources within the community, so it’s not all on the doctor,” Dr. Smith said. “To really make a difference in this area, it can’t just be down to the doctor. There needs to be social care, there needs to be community-based interventions and things to do about it. Doctors can help identify these patients, or maybe somebody in the [medical] team can help with that, but there needs to be an intervention. Otherwise, you’re left with this problem without a solution that you can’t do anything about.”

The researchers did not note any external funding for either study. Dr. Beil, Dr. Dhanrajani, Dr. Smith, and Dr. Ciurtin reported no relevant financial relationships.

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

NEW ORLEANS – The sociodemographic characteristics of Black and Hispanic children with systemic lupus erythematosus (SLE) appear to play a strong role in influencing the severity of disease in these patients, according to two studies presented at the Pediatric Rheumatology Symposium.

One study showed an association between multiple determinants of health and disease severity among children seen in a large Texas city, and a separate descriptive cross-sectional cohort study of predominantly Black children at two centers in Mississippi and Alabama reinforced the finding of greater severity of disease and social hardships among this racial group.

The findings from both studies supplement existing evidence that the prevalence of childhood-onset SLE is greater among Black and Hispanic children.

“Several demographic and social determinants of health parameters influenced disease severity at levels that reached statistical significance, including insurance status, race/ethnicity, referral source, PCP [primary care provider] availability, primary language, and transportation needs,” Emily Beil, MD, a pediatric rheumatologist at Texas Children’s Hospital in Houston, told attendees at the conference, which was sponsored by the American College of Rheumatology. Her team’s goal, she said, was to “better understand our patient population and social disparities that contribute to disease severity.”

Dr. Beil and her colleagues conducted a retrospective review of 136 children who had been diagnosed with childhood-onset SLE between January 2018 and May 2022 at Texas Children’s Hospital. Only children who were younger than 18 years at the time of diagnosis at Texas Children’s were included. The analysis considered demographics, clinical characteristics, insurance status, social work consultation, access to a primary care provider, transportation needs, primary language, and other parameters related to social determinants of health.

The average age of the patients was 13 years, and most were girls (82%). Just over half were Hispanic (53%), and just over a quarter were Black (26%). Half had Medicaid or participated in the Children’s Health Insurance Program (CHIP), and 1 in 10 were uninsured (10%). Half the diagnoses were made during an inpatient admission; 36% were made on the floor, and 14% were made in the intensive care unit (ICU).

The average Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score was 12.5, and 48.5% of patients had severe disease, indicated by a score of at least 12. Only two in three children were documented as having a primary care physician (66%), and 32% preferred a language other than English. Most of the children (80%) had a social work consult.

Black and biracial children had higher SLEDAI scores at presentation. Non-Hispanic White children were less likely to have a social work consult, compared with other racial/ethnic groups (P = .01 for both). Central nervous system involvement was most prevalent among Black patients (P = .004). Cyclophosphamide was used most often for Black and biracial patients.

Uninsured patients were most likely to be diagnosed on an inpatient floor. The highest proportion of ICU admissions was among patients insured by Medicaid (P = .034). Average SLEDAI scores were highest among uninsured patients, followed by Medicaid patients. More than half of the patients who did not have insurance lacked access to a regular primary care provider, compared with 12% of Medicaid patients and 7% of privately insured patients (P = .001). All the uninsured patients had transportation needs, which was a significantly higher rate than among those with Medicaid (13%) or private insurance (15%) (P = .001). The highest percentage of social work consults was among patients who were insured by Medicaid or were without insurance (P = .001).
 

Salient demographics and clinical features

In the second presentation, Anita Dhanrajani, MD, assistant professor of pediatrics at the University of Mississippi Medical Center in Jackson, began by noting that Alabama and Mississippi are ranked in the top 10 states for the highest poverty rate: Mississippi is No. 1, and Alabama is No. 7. Further, 40% of children in Mississippi and 29% of children in Alabama are of African American ancestry, she said.

“So, we know that this population that we’re dealing with has several high-risk factors that can lead them to have poor outcomes, and yet, we haven’t really ever characterized their clinical features or their social demographic features,” Dr. Dhanrajani told attendees. “My hope is that with this very miniscule first step, we’re able to move towards solutions to decrease health care disparities in this population.”

She presented findings regarding the first of three aims in the study, which was to describe the baseline clinical, demographic, and socioeconomic profiles of childhood lupus patients at the two centers. The two other aims were to examine genetic factors potentially linked to poor outcomes in the cohort and to assess the mental health status of the population.

The study relied on a retrospective chart review for the 17 patients at the University of Mississippi Medical Center and on Childhood Arthritis and Rheumatology Research Alliance registry data for the 19 patients at the University of Alabama at Birmingham. Most of the patients (86%) were female, Black (78%), and insured by Medicaid (64%). The average age at diagnosis was 13 years. Most (83%) also lived in a ZIP code that met the criteria for a medium-high or high Social Vulnerability Index. The children had to travel an average 75 miles to see a rheumatologist, compared with the national average of 43 miles.

At diagnosis, their average Systemic Lupus International Collaborating Clinics (SLICC) score was 8.8, their average American College of Rheumatology score was 5.2, and their average SLEDAI score was 12.1 – the latter was substantially higher than the average 3.1 score in a multiethnic Canadian cohort (the 1000 Canadian Faces of Lupus Study) with 10% Black children (P < .00001). The SLEDAI score dropped to 6.8 at 6 months and to 4 at 1 year. Nearly half (47%) had a SLICC Damage Index (SDI) greater than 0, and one-third had an SDI of 2 or greater, compared with 16% and 7%, respectively, reported in other recent studies (P < .0001 for both).

“These disparities are very difficult to investigate in terms of causal relationships and [are] likely to be very modifiable,” Coziana Ciurtin, MD, PhD, associate professor of rheumatology at University College London, told this news organization. “I think the socioeconomic status, the level of education, poverty, [type of] medical insurance, and probably genetic variants are all underpinning the presentation, damage, or disease activity being very high, and also organ involvement,” such as the greater CNS involvement seen in non-White patients.

Being mindful of these risk profiles can help doctors in asking about patients’ support at home and their families’ education, beliefs, and cultural practices, Dr. Ciurtin added. “Helping them to engage and be involved in decision-making is probably the most important” aspect of learning this information about families, she said.

Collecting this information should not be the sole responsibility of the physician, added Eve Smith, PhD, MBCHB, an academic clinical lecturer at the University of Liverpool, England, who attended the presentations. Dr. Smith noted a discussion in a work group during the previous day of the conference concerning questionnaires for screening patients regarding the need for social services and for identifying areas in which patients and their families were having difficulties.

“Obviously, if you’re going to do that, you have to have access to someone who can actually help to deal with that. Some hospitals have patient navigators that can help, for example, with a food security issue to highlight resources within the community, so it’s not all on the doctor,” Dr. Smith said. “To really make a difference in this area, it can’t just be down to the doctor. There needs to be social care, there needs to be community-based interventions and things to do about it. Doctors can help identify these patients, or maybe somebody in the [medical] team can help with that, but there needs to be an intervention. Otherwise, you’re left with this problem without a solution that you can’t do anything about.”

The researchers did not note any external funding for either study. Dr. Beil, Dr. Dhanrajani, Dr. Smith, and Dr. Ciurtin reported no relevant financial relationships.

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

NEW ORLEANS – The sociodemographic characteristics of Black and Hispanic children with systemic lupus erythematosus (SLE) appear to play a strong role in influencing the severity of disease in these patients, according to two studies presented at the Pediatric Rheumatology Symposium.

One study showed an association between multiple determinants of health and disease severity among children seen in a large Texas city, and a separate descriptive cross-sectional cohort study of predominantly Black children at two centers in Mississippi and Alabama reinforced the finding of greater severity of disease and social hardships among this racial group.

The findings from both studies supplement existing evidence that the prevalence of childhood-onset SLE is greater among Black and Hispanic children.

“Several demographic and social determinants of health parameters influenced disease severity at levels that reached statistical significance, including insurance status, race/ethnicity, referral source, PCP [primary care provider] availability, primary language, and transportation needs,” Emily Beil, MD, a pediatric rheumatologist at Texas Children’s Hospital in Houston, told attendees at the conference, which was sponsored by the American College of Rheumatology. Her team’s goal, she said, was to “better understand our patient population and social disparities that contribute to disease severity.”

Dr. Beil and her colleagues conducted a retrospective review of 136 children who had been diagnosed with childhood-onset SLE between January 2018 and May 2022 at Texas Children’s Hospital. Only children who were younger than 18 years at the time of diagnosis at Texas Children’s were included. The analysis considered demographics, clinical characteristics, insurance status, social work consultation, access to a primary care provider, transportation needs, primary language, and other parameters related to social determinants of health.

The average age of the patients was 13 years, and most were girls (82%). Just over half were Hispanic (53%), and just over a quarter were Black (26%). Half had Medicaid or participated in the Children’s Health Insurance Program (CHIP), and 1 in 10 were uninsured (10%). Half the diagnoses were made during an inpatient admission; 36% were made on the floor, and 14% were made in the intensive care unit (ICU).

The average Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score was 12.5, and 48.5% of patients had severe disease, indicated by a score of at least 12. Only two in three children were documented as having a primary care physician (66%), and 32% preferred a language other than English. Most of the children (80%) had a social work consult.

Black and biracial children had higher SLEDAI scores at presentation. Non-Hispanic White children were less likely to have a social work consult, compared with other racial/ethnic groups (P = .01 for both). Central nervous system involvement was most prevalent among Black patients (P = .004). Cyclophosphamide was used most often for Black and biracial patients.

Uninsured patients were most likely to be diagnosed on an inpatient floor. The highest proportion of ICU admissions was among patients insured by Medicaid (P = .034). Average SLEDAI scores were highest among uninsured patients, followed by Medicaid patients. More than half of the patients who did not have insurance lacked access to a regular primary care provider, compared with 12% of Medicaid patients and 7% of privately insured patients (P = .001). All the uninsured patients had transportation needs, which was a significantly higher rate than among those with Medicaid (13%) or private insurance (15%) (P = .001). The highest percentage of social work consults was among patients who were insured by Medicaid or were without insurance (P = .001).
 

Salient demographics and clinical features

In the second presentation, Anita Dhanrajani, MD, assistant professor of pediatrics at the University of Mississippi Medical Center in Jackson, began by noting that Alabama and Mississippi are ranked in the top 10 states for the highest poverty rate: Mississippi is No. 1, and Alabama is No. 7. Further, 40% of children in Mississippi and 29% of children in Alabama are of African American ancestry, she said.

“So, we know that this population that we’re dealing with has several high-risk factors that can lead them to have poor outcomes, and yet, we haven’t really ever characterized their clinical features or their social demographic features,” Dr. Dhanrajani told attendees. “My hope is that with this very miniscule first step, we’re able to move towards solutions to decrease health care disparities in this population.”

She presented findings regarding the first of three aims in the study, which was to describe the baseline clinical, demographic, and socioeconomic profiles of childhood lupus patients at the two centers. The two other aims were to examine genetic factors potentially linked to poor outcomes in the cohort and to assess the mental health status of the population.

The study relied on a retrospective chart review for the 17 patients at the University of Mississippi Medical Center and on Childhood Arthritis and Rheumatology Research Alliance registry data for the 19 patients at the University of Alabama at Birmingham. Most of the patients (86%) were female, Black (78%), and insured by Medicaid (64%). The average age at diagnosis was 13 years. Most (83%) also lived in a ZIP code that met the criteria for a medium-high or high Social Vulnerability Index. The children had to travel an average 75 miles to see a rheumatologist, compared with the national average of 43 miles.

At diagnosis, their average Systemic Lupus International Collaborating Clinics (SLICC) score was 8.8, their average American College of Rheumatology score was 5.2, and their average SLEDAI score was 12.1 – the latter was substantially higher than the average 3.1 score in a multiethnic Canadian cohort (the 1000 Canadian Faces of Lupus Study) with 10% Black children (P < .00001). The SLEDAI score dropped to 6.8 at 6 months and to 4 at 1 year. Nearly half (47%) had a SLICC Damage Index (SDI) greater than 0, and one-third had an SDI of 2 or greater, compared with 16% and 7%, respectively, reported in other recent studies (P < .0001 for both).

“These disparities are very difficult to investigate in terms of causal relationships and [are] likely to be very modifiable,” Coziana Ciurtin, MD, PhD, associate professor of rheumatology at University College London, told this news organization. “I think the socioeconomic status, the level of education, poverty, [type of] medical insurance, and probably genetic variants are all underpinning the presentation, damage, or disease activity being very high, and also organ involvement,” such as the greater CNS involvement seen in non-White patients.

Being mindful of these risk profiles can help doctors in asking about patients’ support at home and their families’ education, beliefs, and cultural practices, Dr. Ciurtin added. “Helping them to engage and be involved in decision-making is probably the most important” aspect of learning this information about families, she said.

Collecting this information should not be the sole responsibility of the physician, added Eve Smith, PhD, MBCHB, an academic clinical lecturer at the University of Liverpool, England, who attended the presentations. Dr. Smith noted a discussion in a work group during the previous day of the conference concerning questionnaires for screening patients regarding the need for social services and for identifying areas in which patients and their families were having difficulties.

“Obviously, if you’re going to do that, you have to have access to someone who can actually help to deal with that. Some hospitals have patient navigators that can help, for example, with a food security issue to highlight resources within the community, so it’s not all on the doctor,” Dr. Smith said. “To really make a difference in this area, it can’t just be down to the doctor. There needs to be social care, there needs to be community-based interventions and things to do about it. Doctors can help identify these patients, or maybe somebody in the [medical] team can help with that, but there needs to be an intervention. Otherwise, you’re left with this problem without a solution that you can’t do anything about.”

The researchers did not note any external funding for either study. Dr. Beil, Dr. Dhanrajani, Dr. Smith, and Dr. Ciurtin reported no relevant financial relationships.

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

Laundry detergent, a cleaning agent ubiquitous in the modern household, often is suspected as a cause of allergic contact dermatitis (ACD). In one North American study, 10.7% of 738 patients undergoing patch testing believed that laundry detergent was a contributing factor, whereas their referring physicians had the same concern less often (in 2.3% of cases).¹Likewise, in a 1992 survey of western US households, more than 20% of 3841 respondents reported skin or health problems attributed to a textile and/or laundry product.² The suspicion of laundry detergent as a causative agent of ACD is perpetuated across popular wellness and beauty websites.^3,4 Does the evidence support this degree of suspicion? Or, similar to the well-meaning parent who misguidedly fixates on foods as the cause of their child’s atopic dermatitis and believes elimination diets are the solution,⁵ could a similar desire for control in the face of the unpredictability of eczema drive consumers and health care providers alike to blame laundry detergent—a familiar and modifiable cause?

We provide a summary of the evidence for the potential allergenicity of laundry detergent, including common allergens present in laundry detergent, the role of machine washing, and the differential diagnosis for laundry detergent–associated ACD.

Allergenic Ingredients in Laundry Detergent

Potential allergens present in laundry detergent include fragrances, preservatives, surfactants, emulsifiers, bleaches, brighteners, enzymes, and dyes.^6-8 In an analysis of allergens present in laundry detergents available in the United States, fragrances and preservatives were most common (eTable).^7,8 Contact allergy to fragrances occurs in approximately 3.5% of the general population⁹ and is detected in as many as 9.2% of patients referred for patch testing in North America.¹⁰ Preservatives commonly found in laundry detergent include isothiazolinones, such as methylchloroisothiazolinone (MCI)/methylisothiazolinone (MI), MI alone, and benzisothiazolinone (BIT). Methylisothiazolinone has gained attention for causing an ACD epidemic beginning in the early 2000s and peaking in Europe between 2013 and 2014 and decreasing thereafter due to consumer personal care product regulatory changes enacted in the European Union.¹¹ In contrast, rates of MI allergy in North America have continued to increase (reaching as high as 15% of patch tested patients in 2017-2018) due to a lack of similar regulation.^10,12 More recently, the prevalence of positive patch tests to BIT has been rising, though it often is difficult to ascertain relevant sources of exposure, and some cases could represent cross-reactions to MCI/MI.^10,13

Other allergens that may be present in laundry detergent include surfactants and propylene glycol. Alkyl glucosides such as decyl glucoside and lauryl glucoside are considered gentle surfactants and often are included in products marketed as safe for sensitive skin,¹⁴ such as “free and gentle” detergents.⁸ However, they actually may pose an increased risk for sensitization in patients with atopic dermatitis.¹⁴ In addition to being allergenic, surfactants and emulsifiers are known irritants.^6,15 Although pathologically distinct, ACD and irritant contact dermatitis can be indistinguishable on clinical presentation.

How Commonly Does Laundry Detergent Cause ACD?

The mere presence of a contact allergen in laundry detergent does not necessarily imply that it is likely to cause ACD. To do so, the chemical in question must exceed the exposure thresholds for primary sensitization (ie, induction of contact allergy) and/or elicitation (ie, development of ACD in sensitized individuals). These depend on a complex interplay of product- and patient-specific factors, among them the concentration of the chemical in the detergent, the method of use, and the amount of detergent residue remaining on clothing after washing.

In the 1990s, the North American Contact Dermatitis Group (NACDG) attempted to determine the prevalence of ACD caused by laundry detergent.¹ Among 738 patients patch tested to aqueous dilutions of granular and liquid laundry detergents, only 5 (0.7%) had a possible allergic patch test reaction. It was unclear what the culprit allergens in the detergents may have been; only 1 of the patients also tested positive to fragrance. Two patients underwent further testing to additional detergent dilutions, and the results called into question whether their initial reactions had truly been allergic (positive) or were actually irritant (negative). The investigators concluded that the prevalence of laundry detergent–associated ACD in this large group of patients was at most 0.7%, and possibly lower.¹

Importantly, patch testing to laundry detergents should not be undertaken in routine clinical practice. Laundry detergents should never be tested “as is” (ie, undiluted) on the skin; they are inherently irritating and have a high likelihood of producing misleading false-positive reactions. Careful dilutions and testing of control subjects are necessary if patch testing with these products is to be appropriately conducted.

The extremely low prevalence of laundry detergent–associated ACD reported by the NACDG was determined prior to the start of the worldwide MI allergy epidemic, raising the possibility that laundry detergents containing isothiazolinones may be associated with ACD. There is no consensus about the minimum level at which isothiazolinones pose no risk to consumers,^16-19 but the US Expert Panel for Cosmetic Ingredient Safety declared that MI is “safe for use in rinse-off cosmetic products at concentrations up to 100 ppm and safe in leave-on cosmetic products when they are formulated to be nonsensitizing.”^18,19 Although ingredient lists do not always reveal when isothiazolinones are present, analyses of commercially available laundry detergents have shown MI concentrations ranging from undetectable to 65.7 ppm.^20-23

Published reports suggest that MCI/MI in laundry detergent can elicit ACD in sensitized individuals. In one case, a 7-year-old girl with chronic truncal dermatitis (atopic history unspecified) was patch tested, revealing a strongly positive reaction to MCI/MI.²⁴ Her laundry detergent was the only personal product found to contain MI. The dermatitis completely resolved after switching detergents and flared after wearing a jacket that had been washed in the implicated detergent, further supporting the relevance of the positive patch test. The investigators suspected initial sensitization to MI from wet wipes used earlier in childhood.²⁴ In another case involving occupational exposure, a 39-year-old nonatopic factory worker was responsible for directly adding MI to laundry detergent.²⁵ Although he wore disposable work gloves, he developed severe hand dermatitis, eczematous pretibial patches, and generalized pruritus. Patch testing revealed positive reactions to MCI/MI and MI, and he experienced improvement when reassigned to different work duties. It was hypothesized that the leg dermatitis and generalized pruritus may have been related to exposure to small concentrations of MI in work clothes washed with an MI-containing detergent.²⁵ Notably, this patient’s level of exposure was much greater than that encountered by individuals in day-to-day life outside of specialized occupational settings.

Regarding other isothiazolinones, a toxicologic study estimated that BIT in laundry detergent would be unlikely to induce sensitization, even at the maximal acceptable concentration, as recommended by preservative manufacturers, and accounting for undiluted detergent spilling directly onto the skin.²⁶Nonetheless, a single European center recently reported that almost half of the 38 patients with positive patch tests to BIT had a potentially relevant exposure attributed to household cleaning products, including laundry detergent.¹³ This emphasizes the need for further examination of sources of exposure to this increasingly common positive patch test allergen.

Does Machine Washing Impact Allergen Concentrations?

Two recent investigations have suggested that machine washing reduces concentrations of isothiazolinones to levels that are likely below clinical relevance. In the first study, 3 fabrics—cotton, polyester, cotton-polyester—were machine washed and line dried.²⁷ A standard detergent was used with MI added at different concentrations: less than 1 ppm, 100 ppm, and 1000 ppm. This process was either performed once or 10 times. Following laundering and line drying, MI was undetectable in all fabrics regardless of MI concentration or number of times washed (detection limit, 0.5 ppm).²⁷ In the second study, 4 fabrics—cotton, wool, polyester, linen—were washed with standard laundry detergent in 1 of 4 ways: handwashing (positive control), standard machine washing, standard machine washing with fabric softener, and standard machine washing with a double rinse.²⁸ After laundering and line drying, concentrations of MI, MCI, and BIT were low or undetectable regardless of fabric type or method of laundering. The highest levels detected were in handwashed garments at a maximum of 0.5 ppm of MI. The study authors postulated that chemical concentrations near these maximum residual levels may pose a risk for eliciting ACD in highly sensitized individuals. Therefore, handwashing can be considered a much higher risk activity for isothiazolinone ACD compared with machine washing.²⁸

It is intriguing that machine washing appears to reduce isothiazolinones to low concentrations that may have limited likelihood of causing ACD. Similar findings have been reported regarding fragrances. A quantitative risk assessment performed on 24 of 26 fragrance allergens regulated by the European Union determined that the amount of fragrance deposited on the skin from laundered garments would be less than the threshold for causing sensitization.²⁹ Although this risk assessment was unable to address the threshold of elicitation, another study conducted in Europe investigated whether fragrance residues present on fabric, such as those deposited from laundry detergent, are present at high enough concentrations to elicit ACD in previously sensitized individuals.³⁰ When 36 individuals were patch tested with increasing concentrations of a fragrance to which they were already sensitized, only 2 (5.6%) had a weakly positive reaction and then only to the highest concentration, which was estimated to be 20-fold higher than the level of skin exposure after normal laundering. No patient reacted at lower concentrations.³⁰

Although machine washing may decrease isothiazolinone and/or fragrance concentrations in laundry detergent to below clinically relevant levels, these findings should not necessarily be extrapolated to all chemicals in laundry detergent. Indeed, a prior study observed that after washing cotton cloths in a detergent solution for 10 minutes, detergent residue was present at concentrations ranging from 139 to 2820 ppm and required a subsequent 20 to 22 washes in water to become undetectable.³¹ Another study produced a mathematical model of the residual concentration of sodium dodecyl sulphate (SDS), a surfactant and known irritant, in laundered clothing.³² It was estimated that after machine washing, the residual concentration of SDS on clothes would be too low to cause irritation; however, as the clothes dry (ie, as moisture evaporates but solutes remain), the concentration of SDS on the fabric’s surface would increase to potentially irritating levels. The extensive drying that is possible with electric dryers may further enhance this solute-concentrating effect.

Differential Diagnosis of Laundry Detergent ACD

The propensity for laundry detergent to cause ACD is a question that is nowhere near settled, but the prevalence of allergy likely is far less common than is generally suspected. In our experience, many patients presenting for patch testing have already made the change to “free and clear” detergents without noticeable improvement in their dermatitis, which could possibly relate to the ongoing presence of contact allergens in these “gentle” formulations.⁷ However, to avoid anchoring bias, more frequent causes of dermatitis should be included in the differential diagnosis. Textile ACD presents beneath clothing with accentuation at areas of closest contact with the skin, classically involving the axillary rim but sparing the vault. The most frequently implicated allergens in textile ACD are disperse dyes and less commonly textile resins.^33,34 Between 2017 and 2018, 2.3% of 4882 patients patch tested by the NACDG reacted positively to disperse dye mix.¹⁰ There is evidence to suggest that the actual prevalence of disperse dye allergy might be higher due to inadequacy of screening allergens on baseline patch test series.³⁵ Additional diagnoses that should be distinguished from presumed detergent contact dermatitis include atopic dermatitis and cutaneous T-cell lymphoma.

Final Interpretation

Although many patients and physicians consider laundry detergent to be a major cause of ACD, there is limited high-quality evidence to support this belief. Contact allergy to laundry detergent is probably much less common than is widely supposed. Although laundry detergents can contain common allergens such as fragrances and preservatives, evidence suggests that they are likely reduced to below clinically relevant levels during routine machine washing; however, we cannot assume that we are in the “free and clear,” as uncertainty remains about the impact of these low concentrationson individuals with strong contact allergy, and large studies of patch testing to modern detergents have yet to be carried out.

Laundry detergent, a cleaning agent ubiquitous in the modern household, often is suspected as a cause of allergic contact dermatitis (ACD). In one North American study, 10.7% of 738 patients undergoing patch testing believed that laundry detergent was a contributing factor, whereas their referring physicians had the same concern less often (in 2.3% of cases).¹Likewise, in a 1992 survey of western US households, more than 20% of 3841 respondents reported skin or health problems attributed to a textile and/or laundry product.² The suspicion of laundry detergent as a causative agent of ACD is perpetuated across popular wellness and beauty websites.^3,4 Does the evidence support this degree of suspicion? Or, similar to the well-meaning parent who misguidedly fixates on foods as the cause of their child’s atopic dermatitis and believes elimination diets are the solution,⁵ could a similar desire for control in the face of the unpredictability of eczema drive consumers and health care providers alike to blame laundry detergent—a familiar and modifiable cause?

We provide a summary of the evidence for the potential allergenicity of laundry detergent, including common allergens present in laundry detergent, the role of machine washing, and the differential diagnosis for laundry detergent–associated ACD.

Allergenic Ingredients in Laundry Detergent

Potential allergens present in laundry detergent include fragrances, preservatives, surfactants, emulsifiers, bleaches, brighteners, enzymes, and dyes.^6-8 In an analysis of allergens present in laundry detergents available in the United States, fragrances and preservatives were most common (eTable).^7,8 Contact allergy to fragrances occurs in approximately 3.5% of the general population⁹ and is detected in as many as 9.2% of patients referred for patch testing in North America.¹⁰ Preservatives commonly found in laundry detergent include isothiazolinones, such as methylchloroisothiazolinone (MCI)/methylisothiazolinone (MI), MI alone, and benzisothiazolinone (BIT). Methylisothiazolinone has gained attention for causing an ACD epidemic beginning in the early 2000s and peaking in Europe between 2013 and 2014 and decreasing thereafter due to consumer personal care product regulatory changes enacted in the European Union.¹¹ In contrast, rates of MI allergy in North America have continued to increase (reaching as high as 15% of patch tested patients in 2017-2018) due to a lack of similar regulation.^10,12 More recently, the prevalence of positive patch tests to BIT has been rising, though it often is difficult to ascertain relevant sources of exposure, and some cases could represent cross-reactions to MCI/MI.^10,13

Other allergens that may be present in laundry detergent include surfactants and propylene glycol. Alkyl glucosides such as decyl glucoside and lauryl glucoside are considered gentle surfactants and often are included in products marketed as safe for sensitive skin,¹⁴ such as “free and gentle” detergents.⁸ However, they actually may pose an increased risk for sensitization in patients with atopic dermatitis.¹⁴ In addition to being allergenic, surfactants and emulsifiers are known irritants.^6,15 Although pathologically distinct, ACD and irritant contact dermatitis can be indistinguishable on clinical presentation.

How Commonly Does Laundry Detergent Cause ACD?

The mere presence of a contact allergen in laundry detergent does not necessarily imply that it is likely to cause ACD. To do so, the chemical in question must exceed the exposure thresholds for primary sensitization (ie, induction of contact allergy) and/or elicitation (ie, development of ACD in sensitized individuals). These depend on a complex interplay of product- and patient-specific factors, among them the concentration of the chemical in the detergent, the method of use, and the amount of detergent residue remaining on clothing after washing.

In the 1990s, the North American Contact Dermatitis Group (NACDG) attempted to determine the prevalence of ACD caused by laundry detergent.¹ Among 738 patients patch tested to aqueous dilutions of granular and liquid laundry detergents, only 5 (0.7%) had a possible allergic patch test reaction. It was unclear what the culprit allergens in the detergents may have been; only 1 of the patients also tested positive to fragrance. Two patients underwent further testing to additional detergent dilutions, and the results called into question whether their initial reactions had truly been allergic (positive) or were actually irritant (negative). The investigators concluded that the prevalence of laundry detergent–associated ACD in this large group of patients was at most 0.7%, and possibly lower.¹

Importantly, patch testing to laundry detergents should not be undertaken in routine clinical practice. Laundry detergents should never be tested “as is” (ie, undiluted) on the skin; they are inherently irritating and have a high likelihood of producing misleading false-positive reactions. Careful dilutions and testing of control subjects are necessary if patch testing with these products is to be appropriately conducted.

The extremely low prevalence of laundry detergent–associated ACD reported by the NACDG was determined prior to the start of the worldwide MI allergy epidemic, raising the possibility that laundry detergents containing isothiazolinones may be associated with ACD. There is no consensus about the minimum level at which isothiazolinones pose no risk to consumers,^16-19 but the US Expert Panel for Cosmetic Ingredient Safety declared that MI is “safe for use in rinse-off cosmetic products at concentrations up to 100 ppm and safe in leave-on cosmetic products when they are formulated to be nonsensitizing.”^18,19 Although ingredient lists do not always reveal when isothiazolinones are present, analyses of commercially available laundry detergents have shown MI concentrations ranging from undetectable to 65.7 ppm.^20-23

Published reports suggest that MCI/MI in laundry detergent can elicit ACD in sensitized individuals. In one case, a 7-year-old girl with chronic truncal dermatitis (atopic history unspecified) was patch tested, revealing a strongly positive reaction to MCI/MI.²⁴ Her laundry detergent was the only personal product found to contain MI. The dermatitis completely resolved after switching detergents and flared after wearing a jacket that had been washed in the implicated detergent, further supporting the relevance of the positive patch test. The investigators suspected initial sensitization to MI from wet wipes used earlier in childhood.²⁴ In another case involving occupational exposure, a 39-year-old nonatopic factory worker was responsible for directly adding MI to laundry detergent.²⁵ Although he wore disposable work gloves, he developed severe hand dermatitis, eczematous pretibial patches, and generalized pruritus. Patch testing revealed positive reactions to MCI/MI and MI, and he experienced improvement when reassigned to different work duties. It was hypothesized that the leg dermatitis and generalized pruritus may have been related to exposure to small concentrations of MI in work clothes washed with an MI-containing detergent.²⁵ Notably, this patient’s level of exposure was much greater than that encountered by individuals in day-to-day life outside of specialized occupational settings.

Regarding other isothiazolinones, a toxicologic study estimated that BIT in laundry detergent would be unlikely to induce sensitization, even at the maximal acceptable concentration, as recommended by preservative manufacturers, and accounting for undiluted detergent spilling directly onto the skin.²⁶Nonetheless, a single European center recently reported that almost half of the 38 patients with positive patch tests to BIT had a potentially relevant exposure attributed to household cleaning products, including laundry detergent.¹³ This emphasizes the need for further examination of sources of exposure to this increasingly common positive patch test allergen.

Does Machine Washing Impact Allergen Concentrations?

Two recent investigations have suggested that machine washing reduces concentrations of isothiazolinones to levels that are likely below clinical relevance. In the first study, 3 fabrics—cotton, polyester, cotton-polyester—were machine washed and line dried.²⁷ A standard detergent was used with MI added at different concentrations: less than 1 ppm, 100 ppm, and 1000 ppm. This process was either performed once or 10 times. Following laundering and line drying, MI was undetectable in all fabrics regardless of MI concentration or number of times washed (detection limit, 0.5 ppm).²⁷ In the second study, 4 fabrics—cotton, wool, polyester, linen—were washed with standard laundry detergent in 1 of 4 ways: handwashing (positive control), standard machine washing, standard machine washing with fabric softener, and standard machine washing with a double rinse.²⁸ After laundering and line drying, concentrations of MI, MCI, and BIT were low or undetectable regardless of fabric type or method of laundering. The highest levels detected were in handwashed garments at a maximum of 0.5 ppm of MI. The study authors postulated that chemical concentrations near these maximum residual levels may pose a risk for eliciting ACD in highly sensitized individuals. Therefore, handwashing can be considered a much higher risk activity for isothiazolinone ACD compared with machine washing.²⁸

It is intriguing that machine washing appears to reduce isothiazolinones to low concentrations that may have limited likelihood of causing ACD. Similar findings have been reported regarding fragrances. A quantitative risk assessment performed on 24 of 26 fragrance allergens regulated by the European Union determined that the amount of fragrance deposited on the skin from laundered garments would be less than the threshold for causing sensitization.²⁹ Although this risk assessment was unable to address the threshold of elicitation, another study conducted in Europe investigated whether fragrance residues present on fabric, such as those deposited from laundry detergent, are present at high enough concentrations to elicit ACD in previously sensitized individuals.³⁰ When 36 individuals were patch tested with increasing concentrations of a fragrance to which they were already sensitized, only 2 (5.6%) had a weakly positive reaction and then only to the highest concentration, which was estimated to be 20-fold higher than the level of skin exposure after normal laundering. No patient reacted at lower concentrations.³⁰

Although machine washing may decrease isothiazolinone and/or fragrance concentrations in laundry detergent to below clinically relevant levels, these findings should not necessarily be extrapolated to all chemicals in laundry detergent. Indeed, a prior study observed that after washing cotton cloths in a detergent solution for 10 minutes, detergent residue was present at concentrations ranging from 139 to 2820 ppm and required a subsequent 20 to 22 washes in water to become undetectable.³¹ Another study produced a mathematical model of the residual concentration of sodium dodecyl sulphate (SDS), a surfactant and known irritant, in laundered clothing.³² It was estimated that after machine washing, the residual concentration of SDS on clothes would be too low to cause irritation; however, as the clothes dry (ie, as moisture evaporates but solutes remain), the concentration of SDS on the fabric’s surface would increase to potentially irritating levels. The extensive drying that is possible with electric dryers may further enhance this solute-concentrating effect.

Differential Diagnosis of Laundry Detergent ACD

The propensity for laundry detergent to cause ACD is a question that is nowhere near settled, but the prevalence of allergy likely is far less common than is generally suspected. In our experience, many patients presenting for patch testing have already made the change to “free and clear” detergents without noticeable improvement in their dermatitis, which could possibly relate to the ongoing presence of contact allergens in these “gentle” formulations.⁷ However, to avoid anchoring bias, more frequent causes of dermatitis should be included in the differential diagnosis. Textile ACD presents beneath clothing with accentuation at areas of closest contact with the skin, classically involving the axillary rim but sparing the vault. The most frequently implicated allergens in textile ACD are disperse dyes and less commonly textile resins.^33,34 Between 2017 and 2018, 2.3% of 4882 patients patch tested by the NACDG reacted positively to disperse dye mix.¹⁰ There is evidence to suggest that the actual prevalence of disperse dye allergy might be higher due to inadequacy of screening allergens on baseline patch test series.³⁵ Additional diagnoses that should be distinguished from presumed detergent contact dermatitis include atopic dermatitis and cutaneous T-cell lymphoma.

Final Interpretation

Although many patients and physicians consider laundry detergent to be a major cause of ACD, there is limited high-quality evidence to support this belief. Contact allergy to laundry detergent is probably much less common than is widely supposed. Although laundry detergents can contain common allergens such as fragrances and preservatives, evidence suggests that they are likely reduced to below clinically relevant levels during routine machine washing; however, we cannot assume that we are in the “free and clear,” as uncertainty remains about the impact of these low concentrationson individuals with strong contact allergy, and large studies of patch testing to modern detergents have yet to be carried out.

Laundry detergent, a cleaning agent ubiquitous in the modern household, often is suspected as a cause of allergic contact dermatitis (ACD). In one North American study, 10.7% of 738 patients undergoing patch testing believed that laundry detergent was a contributing factor, whereas their referring physicians had the same concern less often (in 2.3% of cases).¹Likewise, in a 1992 survey of western US households, more than 20% of 3841 respondents reported skin or health problems attributed to a textile and/or laundry product.² The suspicion of laundry detergent as a causative agent of ACD is perpetuated across popular wellness and beauty websites.^3,4 Does the evidence support this degree of suspicion? Or, similar to the well-meaning parent who misguidedly fixates on foods as the cause of their child’s atopic dermatitis and believes elimination diets are the solution,⁵ could a similar desire for control in the face of the unpredictability of eczema drive consumers and health care providers alike to blame laundry detergent—a familiar and modifiable cause?

We provide a summary of the evidence for the potential allergenicity of laundry detergent, including common allergens present in laundry detergent, the role of machine washing, and the differential diagnosis for laundry detergent–associated ACD.

Allergenic Ingredients in Laundry Detergent

Potential allergens present in laundry detergent include fragrances, preservatives, surfactants, emulsifiers, bleaches, brighteners, enzymes, and dyes.^6-8 In an analysis of allergens present in laundry detergents available in the United States, fragrances and preservatives were most common (eTable).^7,8 Contact allergy to fragrances occurs in approximately 3.5% of the general population⁹ and is detected in as many as 9.2% of patients referred for patch testing in North America.¹⁰ Preservatives commonly found in laundry detergent include isothiazolinones, such as methylchloroisothiazolinone (MCI)/methylisothiazolinone (MI), MI alone, and benzisothiazolinone (BIT). Methylisothiazolinone has gained attention for causing an ACD epidemic beginning in the early 2000s and peaking in Europe between 2013 and 2014 and decreasing thereafter due to consumer personal care product regulatory changes enacted in the European Union.¹¹ In contrast, rates of MI allergy in North America have continued to increase (reaching as high as 15% of patch tested patients in 2017-2018) due to a lack of similar regulation.^10,12 More recently, the prevalence of positive patch tests to BIT has been rising, though it often is difficult to ascertain relevant sources of exposure, and some cases could represent cross-reactions to MCI/MI.^10,13

Other allergens that may be present in laundry detergent include surfactants and propylene glycol. Alkyl glucosides such as decyl glucoside and lauryl glucoside are considered gentle surfactants and often are included in products marketed as safe for sensitive skin,¹⁴ such as “free and gentle” detergents.⁸ However, they actually may pose an increased risk for sensitization in patients with atopic dermatitis.¹⁴ In addition to being allergenic, surfactants and emulsifiers are known irritants.^6,15 Although pathologically distinct, ACD and irritant contact dermatitis can be indistinguishable on clinical presentation.

How Commonly Does Laundry Detergent Cause ACD?

The mere presence of a contact allergen in laundry detergent does not necessarily imply that it is likely to cause ACD. To do so, the chemical in question must exceed the exposure thresholds for primary sensitization (ie, induction of contact allergy) and/or elicitation (ie, development of ACD in sensitized individuals). These depend on a complex interplay of product- and patient-specific factors, among them the concentration of the chemical in the detergent, the method of use, and the amount of detergent residue remaining on clothing after washing.

In the 1990s, the North American Contact Dermatitis Group (NACDG) attempted to determine the prevalence of ACD caused by laundry detergent.¹ Among 738 patients patch tested to aqueous dilutions of granular and liquid laundry detergents, only 5 (0.7%) had a possible allergic patch test reaction. It was unclear what the culprit allergens in the detergents may have been; only 1 of the patients also tested positive to fragrance. Two patients underwent further testing to additional detergent dilutions, and the results called into question whether their initial reactions had truly been allergic (positive) or were actually irritant (negative). The investigators concluded that the prevalence of laundry detergent–associated ACD in this large group of patients was at most 0.7%, and possibly lower.¹

Importantly, patch testing to laundry detergents should not be undertaken in routine clinical practice. Laundry detergents should never be tested “as is” (ie, undiluted) on the skin; they are inherently irritating and have a high likelihood of producing misleading false-positive reactions. Careful dilutions and testing of control subjects are necessary if patch testing with these products is to be appropriately conducted.

The extremely low prevalence of laundry detergent–associated ACD reported by the NACDG was determined prior to the start of the worldwide MI allergy epidemic, raising the possibility that laundry detergents containing isothiazolinones may be associated with ACD. There is no consensus about the minimum level at which isothiazolinones pose no risk to consumers,^16-19 but the US Expert Panel for Cosmetic Ingredient Safety declared that MI is “safe for use in rinse-off cosmetic products at concentrations up to 100 ppm and safe in leave-on cosmetic products when they are formulated to be nonsensitizing.”^18,19 Although ingredient lists do not always reveal when isothiazolinones are present, analyses of commercially available laundry detergents have shown MI concentrations ranging from undetectable to 65.7 ppm.^20-23

Published reports suggest that MCI/MI in laundry detergent can elicit ACD in sensitized individuals. In one case, a 7-year-old girl with chronic truncal dermatitis (atopic history unspecified) was patch tested, revealing a strongly positive reaction to MCI/MI.²⁴ Her laundry detergent was the only personal product found to contain MI. The dermatitis completely resolved after switching detergents and flared after wearing a jacket that had been washed in the implicated detergent, further supporting the relevance of the positive patch test. The investigators suspected initial sensitization to MI from wet wipes used earlier in childhood.²⁴ In another case involving occupational exposure, a 39-year-old nonatopic factory worker was responsible for directly adding MI to laundry detergent.²⁵ Although he wore disposable work gloves, he developed severe hand dermatitis, eczematous pretibial patches, and generalized pruritus. Patch testing revealed positive reactions to MCI/MI and MI, and he experienced improvement when reassigned to different work duties. It was hypothesized that the leg dermatitis and generalized pruritus may have been related to exposure to small concentrations of MI in work clothes washed with an MI-containing detergent.²⁵ Notably, this patient’s level of exposure was much greater than that encountered by individuals in day-to-day life outside of specialized occupational settings.

Regarding other isothiazolinones, a toxicologic study estimated that BIT in laundry detergent would be unlikely to induce sensitization, even at the maximal acceptable concentration, as recommended by preservative manufacturers, and accounting for undiluted detergent spilling directly onto the skin.²⁶Nonetheless, a single European center recently reported that almost half of the 38 patients with positive patch tests to BIT had a potentially relevant exposure attributed to household cleaning products, including laundry detergent.¹³ This emphasizes the need for further examination of sources of exposure to this increasingly common positive patch test allergen.

Does Machine Washing Impact Allergen Concentrations?

Two recent investigations have suggested that machine washing reduces concentrations of isothiazolinones to levels that are likely below clinical relevance. In the first study, 3 fabrics—cotton, polyester, cotton-polyester—were machine washed and line dried.²⁷ A standard detergent was used with MI added at different concentrations: less than 1 ppm, 100 ppm, and 1000 ppm. This process was either performed once or 10 times. Following laundering and line drying, MI was undetectable in all fabrics regardless of MI concentration or number of times washed (detection limit, 0.5 ppm).²⁷ In the second study, 4 fabrics—cotton, wool, polyester, linen—were washed with standard laundry detergent in 1 of 4 ways: handwashing (positive control), standard machine washing, standard machine washing with fabric softener, and standard machine washing with a double rinse.²⁸ After laundering and line drying, concentrations of MI, MCI, and BIT were low or undetectable regardless of fabric type or method of laundering. The highest levels detected were in handwashed garments at a maximum of 0.5 ppm of MI. The study authors postulated that chemical concentrations near these maximum residual levels may pose a risk for eliciting ACD in highly sensitized individuals. Therefore, handwashing can be considered a much higher risk activity for isothiazolinone ACD compared with machine washing.²⁸

It is intriguing that machine washing appears to reduce isothiazolinones to low concentrations that may have limited likelihood of causing ACD. Similar findings have been reported regarding fragrances. A quantitative risk assessment performed on 24 of 26 fragrance allergens regulated by the European Union determined that the amount of fragrance deposited on the skin from laundered garments would be less than the threshold for causing sensitization.²⁹ Although this risk assessment was unable to address the threshold of elicitation, another study conducted in Europe investigated whether fragrance residues present on fabric, such as those deposited from laundry detergent, are present at high enough concentrations to elicit ACD in previously sensitized individuals.³⁰ When 36 individuals were patch tested with increasing concentrations of a fragrance to which they were already sensitized, only 2 (5.6%) had a weakly positive reaction and then only to the highest concentration, which was estimated to be 20-fold higher than the level of skin exposure after normal laundering. No patient reacted at lower concentrations.³⁰

Although machine washing may decrease isothiazolinone and/or fragrance concentrations in laundry detergent to below clinically relevant levels, these findings should not necessarily be extrapolated to all chemicals in laundry detergent. Indeed, a prior study observed that after washing cotton cloths in a detergent solution for 10 minutes, detergent residue was present at concentrations ranging from 139 to 2820 ppm and required a subsequent 20 to 22 washes in water to become undetectable.³¹ Another study produced a mathematical model of the residual concentration of sodium dodecyl sulphate (SDS), a surfactant and known irritant, in laundered clothing.³² It was estimated that after machine washing, the residual concentration of SDS on clothes would be too low to cause irritation; however, as the clothes dry (ie, as moisture evaporates but solutes remain), the concentration of SDS on the fabric’s surface would increase to potentially irritating levels. The extensive drying that is possible with electric dryers may further enhance this solute-concentrating effect.

Differential Diagnosis of Laundry Detergent ACD

The propensity for laundry detergent to cause ACD is a question that is nowhere near settled, but the prevalence of allergy likely is far less common than is generally suspected. In our experience, many patients presenting for patch testing have already made the change to “free and clear” detergents without noticeable improvement in their dermatitis, which could possibly relate to the ongoing presence of contact allergens in these “gentle” formulations.⁷ However, to avoid anchoring bias, more frequent causes of dermatitis should be included in the differential diagnosis. Textile ACD presents beneath clothing with accentuation at areas of closest contact with the skin, classically involving the axillary rim but sparing the vault. The most frequently implicated allergens in textile ACD are disperse dyes and less commonly textile resins.^33,34 Between 2017 and 2018, 2.3% of 4882 patients patch tested by the NACDG reacted positively to disperse dye mix.¹⁰ There is evidence to suggest that the actual prevalence of disperse dye allergy might be higher due to inadequacy of screening allergens on baseline patch test series.³⁵ Additional diagnoses that should be distinguished from presumed detergent contact dermatitis include atopic dermatitis and cutaneous T-cell lymphoma.

Final Interpretation

Although many patients and physicians consider laundry detergent to be a major cause of ACD, there is limited high-quality evidence to support this belief. Contact allergy to laundry detergent is probably much less common than is widely supposed. Although laundry detergents can contain common allergens such as fragrances and preservatives, evidence suggests that they are likely reduced to below clinically relevant levels during routine machine washing; however, we cannot assume that we are in the “free and clear,” as uncertainty remains about the impact of these low concentrationson individuals with strong contact allergy, and large studies of patch testing to modern detergents have yet to be carried out.

The 2022 mpox (monkeypox) virus outbreak represents the latest example of how infectious diseases with previously limited reach can spread in a globalized society. More than 86,000 cases have been reported worldwide, with more than 30,000 cases in the United States as of March 15, 2023.¹ Herein, we summarize the key features of mpox infection for the dermatologist.

Mpox Transmission

The mpox virus is a double-stranded DNA virus of the Orthopoxvirus genus and Poxviridae family.^2,3 There are 2 types of the mpox virus: clade I (formerly the Congo Basin clade) and clade II (formerly the West African clade). Clade I causes more severe disease (10% mortality rate), while clade II is associated with lower mortality (1%–3%) and has been split into subclades of IIa (exhibits zoonotic transmission) and IIb (exhibits human-to-human spread).^3,4 The current outbreak is caused by clade IIb, and patients typically have no travel history to classic endemic regions.^5,6

In endemic countries, mpox transmission is zoonotic from small forest animals. In nonendemic countries, sporadic cases rarely have been reported, including a cluster in the United States in 2003 related to pet prairie dogs. In stark contrast, human-to-human transmission is occurring in the current epidemic mainly via intimate skin-to-skin contact and possibly via sexual fluids, meeting the criteria for a sexually transmitted infection. However, nonsexual transmission does still occur, though it is less common.⁷ Many of the reported cases so far are in young to middle-aged men who have sex with men (MSM).^2,8 However, it is crucial to understand that mpox is not exclusive to the MSM population; the virus has been transmitted to heterosexual males, females, children, and even household pets of infected individuals.^2,9,10 Labeling mpox as exclusive to the MSM community is both inaccurate and inappropriately stigmatizing.

Cutaneous Presentation and Diagnosis of Mpox

Mpox has an incubation time of approximately 9 days (range, 7–21 days), after which affected persons develop macular lesions that evolve over 2 to 4 weeks into papules, vesicles, and deep-seated pustules before crusting over and resolving with possible residual scarring.^{2,3,5,9,11,12} Palmoplantar involvement is a key feature.¹¹ Although in some cases there will be multiple lesions with centrifugal progression, the lesions also may be few in number, with some patients presenting with a single lesion in the anogenital region or on the face, hand, or foot (Figure).^6,9 Systemic symptoms such as prodromal fever, lymphadenopathy, and headache are common but not universal.^9,13 Potential complications include penile edema, proctitis, bacterial superinfection, tonsillitis, conjunctivitis, encephalitis, and pneumonia.^5,9,13

Images used with permission from Roneet Lev, MD (San Diego, California), and VisualDx.

A high index of suspicion is needed to diagnose mpox infection. The differential diagnosis includes smallpox; varicella-zoster virus (primary or reactivation); secondary syphilis; measles; herpes simplex virus; molluscum contagiosum; hand, foot, and mouth disease; and disseminated gonococcal infection.^2,3 For lesions confined to the genital area, sexually transmitted infections (eg, chancroid, lymphogranuloma venereum) as well as non–sexually related acute genital ulcers (Lipschütz ulcers) should be considered.²

Certain clinical features may help in distinguishing mpox from other diseases. Mpox exhibits synchronous progression and centrifugal distribution when multiple lesions are present; in contrast, the lesions of primary varicella (chickenpox) appear in multiple different stages, and those of localized herpes zoster (shingles) exhibit a dermatomal distribution. When these features are present, mpox causes a greater degree of lymphadenopathy and systemic symptoms than primary varicella.³Clinical diagnosis of mpox is more than 90% sensitive but only 9% to 26% specific.³ To confirm the diagnosis, a viral swab vigorously obtained from active skin lesions should be sent in viral transport media for mpox DNA-specific polymerase chain reaction testing, which is available from major laboratories.^2,3 Other supportive tests include serum studies for anti–mpox virus immunoglobulins and immunohistochemical staining for viral antigens on skin biopsy specimens.² When evaluating suspected and confirmed mpox cases, dermatologists should wear a gown, gloves, a fitted N95 mask, and eye protection to prevent infection.⁵

Treating Mpox

Symptomatic mpox infection can last for up to 2 to 5 weeks.³ The patient is no longer infectious once the lesions have crusted over.^3,11 The majority of cases require supportive care only.^2,3,5,14 However, mpox remains a potentially fatal disease, with 38 deaths to date in the current outbreak.¹ High-risk populations include children younger than 8 years, pregnant women, and individuals who are immunocompromised.¹⁵ Tecovirimat, an antiviral medication approved by the US Food and Drug Administration (FDA) for smallpox, is available via the expanded access Investigational New Drug (EA-IND) protocol to treat severe mpox cases but is not widely available in the United States.^6,16-18 Brincidofovir, a prodrug of the antiviral cidofovir, possesses single-patient emergency use Investigational New Drug (e-IND) status for treatment of mpox but also is not widely available in the United States.¹⁷ Intravenous vaccinia immune globulin is under consideration for high-risk individuals, but little is known regarding its efficacy against mpox.^5,16,17

Two smallpox vaccines—JYNNEOS (Bavarian Nordic) and ACAM2000 (Emergent Bio Solutions)—are available for both preexposure and postexposure prophylaxis against mpox virus.¹⁹ At this time, only JYNNEOS is FDA approved for the prevention of mpox; ACAM2000 can be used against mpox under the FDA’s EA-IND protocol, which involves additional requirements, including informed consent from the patient.²⁰ ACAM2000 is a live, replication-competent vaccine that carries a warning of increased risk for side effects in patients with cardiac disease, pregnancy, immunocompromise, and a history or presence of eczema and other skin conditions.^3,21,22 JYNNEOS is a live but replication-deficient virus and therefore does not carry these warnings.^3,21,22

Final Thoughts

Mpox is no longer an obscure illness occurring in limited geographic areas. Dermatologists must remain highly vigilant when evaluating any patient for new-onset vesicular or pustular eruptions to combat this ongoing public health threat. This issue of Cutis^® also features a thorough mpox update on the clinical presentation, vaccine guidance, and management.²³

The 2022 mpox (monkeypox) virus outbreak represents the latest example of how infectious diseases with previously limited reach can spread in a globalized society. More than 86,000 cases have been reported worldwide, with more than 30,000 cases in the United States as of March 15, 2023.¹ Herein, we summarize the key features of mpox infection for the dermatologist.

Mpox Transmission

The mpox virus is a double-stranded DNA virus of the Orthopoxvirus genus and Poxviridae family.^2,3 There are 2 types of the mpox virus: clade I (formerly the Congo Basin clade) and clade II (formerly the West African clade). Clade I causes more severe disease (10% mortality rate), while clade II is associated with lower mortality (1%–3%) and has been split into subclades of IIa (exhibits zoonotic transmission) and IIb (exhibits human-to-human spread).^3,4 The current outbreak is caused by clade IIb, and patients typically have no travel history to classic endemic regions.^5,6

In endemic countries, mpox transmission is zoonotic from small forest animals. In nonendemic countries, sporadic cases rarely have been reported, including a cluster in the United States in 2003 related to pet prairie dogs. In stark contrast, human-to-human transmission is occurring in the current epidemic mainly via intimate skin-to-skin contact and possibly via sexual fluids, meeting the criteria for a sexually transmitted infection. However, nonsexual transmission does still occur, though it is less common.⁷ Many of the reported cases so far are in young to middle-aged men who have sex with men (MSM).^2,8 However, it is crucial to understand that mpox is not exclusive to the MSM population; the virus has been transmitted to heterosexual males, females, children, and even household pets of infected individuals.^2,9,10 Labeling mpox as exclusive to the MSM community is both inaccurate and inappropriately stigmatizing.

Cutaneous Presentation and Diagnosis of Mpox

Mpox has an incubation time of approximately 9 days (range, 7–21 days), after which affected persons develop macular lesions that evolve over 2 to 4 weeks into papules, vesicles, and deep-seated pustules before crusting over and resolving with possible residual scarring.^{2,3,5,9,11,12} Palmoplantar involvement is a key feature.¹¹ Although in some cases there will be multiple lesions with centrifugal progression, the lesions also may be few in number, with some patients presenting with a single lesion in the anogenital region or on the face, hand, or foot (Figure).^6,9 Systemic symptoms such as prodromal fever, lymphadenopathy, and headache are common but not universal.^9,13 Potential complications include penile edema, proctitis, bacterial superinfection, tonsillitis, conjunctivitis, encephalitis, and pneumonia.^5,9,13

Images used with permission from Roneet Lev, MD (San Diego, California), and VisualDx.

A high index of suspicion is needed to diagnose mpox infection. The differential diagnosis includes smallpox; varicella-zoster virus (primary or reactivation); secondary syphilis; measles; herpes simplex virus; molluscum contagiosum; hand, foot, and mouth disease; and disseminated gonococcal infection.^2,3 For lesions confined to the genital area, sexually transmitted infections (eg, chancroid, lymphogranuloma venereum) as well as non–sexually related acute genital ulcers (Lipschütz ulcers) should be considered.²

Certain clinical features may help in distinguishing mpox from other diseases. Mpox exhibits synchronous progression and centrifugal distribution when multiple lesions are present; in contrast, the lesions of primary varicella (chickenpox) appear in multiple different stages, and those of localized herpes zoster (shingles) exhibit a dermatomal distribution. When these features are present, mpox causes a greater degree of lymphadenopathy and systemic symptoms than primary varicella.³Clinical diagnosis of mpox is more than 90% sensitive but only 9% to 26% specific.³ To confirm the diagnosis, a viral swab vigorously obtained from active skin lesions should be sent in viral transport media for mpox DNA-specific polymerase chain reaction testing, which is available from major laboratories.^2,3 Other supportive tests include serum studies for anti–mpox virus immunoglobulins and immunohistochemical staining for viral antigens on skin biopsy specimens.² When evaluating suspected and confirmed mpox cases, dermatologists should wear a gown, gloves, a fitted N95 mask, and eye protection to prevent infection.⁵

Treating Mpox

Symptomatic mpox infection can last for up to 2 to 5 weeks.³ The patient is no longer infectious once the lesions have crusted over.^3,11 The majority of cases require supportive care only.^2,3,5,14 However, mpox remains a potentially fatal disease, with 38 deaths to date in the current outbreak.¹ High-risk populations include children younger than 8 years, pregnant women, and individuals who are immunocompromised.¹⁵ Tecovirimat, an antiviral medication approved by the US Food and Drug Administration (FDA) for smallpox, is available via the expanded access Investigational New Drug (EA-IND) protocol to treat severe mpox cases but is not widely available in the United States.^6,16-18 Brincidofovir, a prodrug of the antiviral cidofovir, possesses single-patient emergency use Investigational New Drug (e-IND) status for treatment of mpox but also is not widely available in the United States.¹⁷ Intravenous vaccinia immune globulin is under consideration for high-risk individuals, but little is known regarding its efficacy against mpox.^5,16,17

Two smallpox vaccines—JYNNEOS (Bavarian Nordic) and ACAM2000 (Emergent Bio Solutions)—are available for both preexposure and postexposure prophylaxis against mpox virus.¹⁹ At this time, only JYNNEOS is FDA approved for the prevention of mpox; ACAM2000 can be used against mpox under the FDA’s EA-IND protocol, which involves additional requirements, including informed consent from the patient.²⁰ ACAM2000 is a live, replication-competent vaccine that carries a warning of increased risk for side effects in patients with cardiac disease, pregnancy, immunocompromise, and a history or presence of eczema and other skin conditions.^3,21,22 JYNNEOS is a live but replication-deficient virus and therefore does not carry these warnings.^3,21,22

Final Thoughts

Mpox is no longer an obscure illness occurring in limited geographic areas. Dermatologists must remain highly vigilant when evaluating any patient for new-onset vesicular or pustular eruptions to combat this ongoing public health threat. This issue of Cutis^® also features a thorough mpox update on the clinical presentation, vaccine guidance, and management.²³

The 2022 mpox (monkeypox) virus outbreak represents the latest example of how infectious diseases with previously limited reach can spread in a globalized society. More than 86,000 cases have been reported worldwide, with more than 30,000 cases in the United States as of March 15, 2023.¹ Herein, we summarize the key features of mpox infection for the dermatologist.

Mpox Transmission

The mpox virus is a double-stranded DNA virus of the Orthopoxvirus genus and Poxviridae family.^2,3 There are 2 types of the mpox virus: clade I (formerly the Congo Basin clade) and clade II (formerly the West African clade). Clade I causes more severe disease (10% mortality rate), while clade II is associated with lower mortality (1%–3%) and has been split into subclades of IIa (exhibits zoonotic transmission) and IIb (exhibits human-to-human spread).^3,4 The current outbreak is caused by clade IIb, and patients typically have no travel history to classic endemic regions.^5,6

In endemic countries, mpox transmission is zoonotic from small forest animals. In nonendemic countries, sporadic cases rarely have been reported, including a cluster in the United States in 2003 related to pet prairie dogs. In stark contrast, human-to-human transmission is occurring in the current epidemic mainly via intimate skin-to-skin contact and possibly via sexual fluids, meeting the criteria for a sexually transmitted infection. However, nonsexual transmission does still occur, though it is less common.⁷ Many of the reported cases so far are in young to middle-aged men who have sex with men (MSM).^2,8 However, it is crucial to understand that mpox is not exclusive to the MSM population; the virus has been transmitted to heterosexual males, females, children, and even household pets of infected individuals.^2,9,10 Labeling mpox as exclusive to the MSM community is both inaccurate and inappropriately stigmatizing.

Cutaneous Presentation and Diagnosis of Mpox

Mpox has an incubation time of approximately 9 days (range, 7–21 days), after which affected persons develop macular lesions that evolve over 2 to 4 weeks into papules, vesicles, and deep-seated pustules before crusting over and resolving with possible residual scarring.^{2,3,5,9,11,12} Palmoplantar involvement is a key feature.¹¹ Although in some cases there will be multiple lesions with centrifugal progression, the lesions also may be few in number, with some patients presenting with a single lesion in the anogenital region or on the face, hand, or foot (Figure).^6,9 Systemic symptoms such as prodromal fever, lymphadenopathy, and headache are common but not universal.^9,13 Potential complications include penile edema, proctitis, bacterial superinfection, tonsillitis, conjunctivitis, encephalitis, and pneumonia.^5,9,13

Images used with permission from Roneet Lev, MD (San Diego, California), and VisualDx.

A high index of suspicion is needed to diagnose mpox infection. The differential diagnosis includes smallpox; varicella-zoster virus (primary or reactivation); secondary syphilis; measles; herpes simplex virus; molluscum contagiosum; hand, foot, and mouth disease; and disseminated gonococcal infection.^2,3 For lesions confined to the genital area, sexually transmitted infections (eg, chancroid, lymphogranuloma venereum) as well as non–sexually related acute genital ulcers (Lipschütz ulcers) should be considered.²

Certain clinical features may help in distinguishing mpox from other diseases. Mpox exhibits synchronous progression and centrifugal distribution when multiple lesions are present; in contrast, the lesions of primary varicella (chickenpox) appear in multiple different stages, and those of localized herpes zoster (shingles) exhibit a dermatomal distribution. When these features are present, mpox causes a greater degree of lymphadenopathy and systemic symptoms than primary varicella.³Clinical diagnosis of mpox is more than 90% sensitive but only 9% to 26% specific.³ To confirm the diagnosis, a viral swab vigorously obtained from active skin lesions should be sent in viral transport media for mpox DNA-specific polymerase chain reaction testing, which is available from major laboratories.^2,3 Other supportive tests include serum studies for anti–mpox virus immunoglobulins and immunohistochemical staining for viral antigens on skin biopsy specimens.² When evaluating suspected and confirmed mpox cases, dermatologists should wear a gown, gloves, a fitted N95 mask, and eye protection to prevent infection.⁵

Treating Mpox

Symptomatic mpox infection can last for up to 2 to 5 weeks.³ The patient is no longer infectious once the lesions have crusted over.^3,11 The majority of cases require supportive care only.^2,3,5,14 However, mpox remains a potentially fatal disease, with 38 deaths to date in the current outbreak.¹ High-risk populations include children younger than 8 years, pregnant women, and individuals who are immunocompromised.¹⁵ Tecovirimat, an antiviral medication approved by the US Food and Drug Administration (FDA) for smallpox, is available via the expanded access Investigational New Drug (EA-IND) protocol to treat severe mpox cases but is not widely available in the United States.^6,16-18 Brincidofovir, a prodrug of the antiviral cidofovir, possesses single-patient emergency use Investigational New Drug (e-IND) status for treatment of mpox but also is not widely available in the United States.¹⁷ Intravenous vaccinia immune globulin is under consideration for high-risk individuals, but little is known regarding its efficacy against mpox.^5,16,17

Two smallpox vaccines—JYNNEOS (Bavarian Nordic) and ACAM2000 (Emergent Bio Solutions)—are available for both preexposure and postexposure prophylaxis against mpox virus.¹⁹ At this time, only JYNNEOS is FDA approved for the prevention of mpox; ACAM2000 can be used against mpox under the FDA’s EA-IND protocol, which involves additional requirements, including informed consent from the patient.²⁰ ACAM2000 is a live, replication-competent vaccine that carries a warning of increased risk for side effects in patients with cardiac disease, pregnancy, immunocompromise, and a history or presence of eczema and other skin conditions.^3,21,22 JYNNEOS is a live but replication-deficient virus and therefore does not carry these warnings.^3,21,22

Final Thoughts

Mpox is no longer an obscure illness occurring in limited geographic areas. Dermatologists must remain highly vigilant when evaluating any patient for new-onset vesicular or pustular eruptions to combat this ongoing public health threat. This issue of Cutis^® also features a thorough mpox update on the clinical presentation, vaccine guidance, and management.²³