Psoriasis

Over the years, there has been growing concern about the relationship between physicians and pharmaceutical companies. Many studies have demonstrated that pharmaceutical interactions and incentives can influence physicians’ prescribing habits.^1-3 As a result, many academic centers have adopted policies that attempt to limit the pharmaceutical industry’s influence on faculty and in-training physicians. Although these policies can vary greatly, they generally limit access of pharmaceutical representatives to providers and restrict pharmaceutical samples.^4,5 This policy shift has even been reported in private practice.⁶

At the heart of the matter is the question: What really influences physicians to write a prescription for a particular medication? Is it cost, efficacy, or representatives pushing a product? Prior studies illustrate that generic medications are equivalent to their brand-name counterparts. In fact, current regulations require no more than 5% to 7% difference in bioequivalence.^7-9 Although most generic medications are bioequivalent, it may not be universal.¹⁰

Garrison and Levin¹¹ distributed a survey to US-based prescribers in family practice, psychiatry, and internal medicine and found that prescribers deemed patient response and success as the highest priority when determining which drugs to prescribe. In contrast, drug representatives and free samples only slightly contributed.¹¹ Considering the minimum duration for efficacy of a medication such as an antidepressant vs a topical steroid, this pattern may differ with samples in dermatologic settings. Interestingly, another survey concluded that samples were associated with “sticky” prescribing habits, noting that physicians would prescribe a brand-name medication after using a sample, despite increased cost to the patient.¹² Further, it has been suggested that recipients of free samples may experience increased costs in the long run, which contrasts a stated goal of affordability to patients.^12,13

Physician interaction with pharmaceutical companies begins as early as medical school,¹⁴ with physicians reporting interactions as often as 4 times each month.^14-18 Interactions can include meetings with pharmaceutical representatives, sponsored meals, gifts, continuing medical education sponsorship, funding for travel, pharmaceutical representative speakers, research funding, and drug samples.³

A 2014 study reported that prescribing habits are influenced by the free drug samples provided by nongeneric pharmaceutical companies.¹⁹ Nationally, the number of brand-name and branded generic medications constitute 79% of prescriptions, yet together they only comprise 17% of medications prescribed at an academic medical clinic that does not provide samples. The number of medications with samples being prescribed by dermatologists increased by 15% over 9 years, which may correlate with the wider availability of medication samples, more specifically an increase in branded generic samples.¹⁹ This potential interaction is the reason why institutions question the current influence of pharmaceutical companies. Samples may appear convenient, allowing a patient to test the medication prior to committing; however, with brand-name samples being provided to the physician, he/she may become more inclined to prescribe the branded medication.^12,15,19-22 Because brand-name medications are more expensive than generic medications, this practice can increase the cost of health care.¹³ One study found that over 1 year, the overuse of nongeneric medications led to a loss of potential savings throughout 49 states, equating to $229 million just through Medicaid; interestingly, it was noted that in some states, a maximum reimbursement is set by Medicaid, regardless of whether the generic or branded medication is dispensed. The authors also noted variability in the potential savings by state, which may be a function of the state-by-state maximum reimbursements for certain medications.²³ Another study on oral combination medications estimated Medicare spending on branded drugs relative to the cost if generic combinations had been purchased instead. This study examined branded medications for which the active components were available as over-the-counter (OTC), generic, or same-class generic, and the authors estimated that $925 million could have been saved in 2016 by purchasing a generic substitute.²⁴ The overuse of nongeneric medications when generic alternatives are available becomes an issue that not only financially impacts patients but all taxpayers. However, this pattern may differ if limited only to dermatologic medications, which was not the focus of the prior studies.

To limit conflicts of interest in interactions with the pharmaceutical, medical device, and biotechnology industries, the University of South Florida (USF) Morsani College of Medicine (COM)(Tampa, Florida) implemented its own set of regulations that eliminated in-office pharmaceutical samples, in addition to other restrictions. This study aimed to investigate if there was a change in the prescribing habits of academic dermatologists after their medical school implemented these new policies.

We hypothesized that the number of brand-name drugs prescribed by physicians in the Department of Dermatology & Cutaneous Surgery would change following USF Morsani COM pharmaceutical policy changes. We sought to determine how physician prescribing practices within the Department of Dermatology & Cutaneous Surgery changed following USF Morsani COM pharmaceutical policy changes.

Methods

Data Collection
A retrospective review of medical records was conducted to investigate the effect of the USF Morsani COM pharmaceutical policy changes on physician prescribing practices within the Department of Dermatology & Cutaneous Surgery. Medical records of patients seen for common dermatology diagnoses before (January 1, 2010, to May 30, 2010) and after (August 1, 2011, to December 31, 2011) the pharmaceutical policy changes were reviewed, and all medications prescribed were recorded. Data were collected from medical records within the USF Health electronic medical record system and included visits with each of the department’s 3 attending dermatologists. The diagnoses included in the study—acne vulgaris, atopic dermatitis, onychomycosis, psoriasis, and rosacea—were chosen because in-office samples were available. Prescribing data from the first 100 consecutive medical records were collected from each time period, and a medical record was included only if it contained at least 1 of the following diagnoses: acne vulgaris, atopic dermatitis, onychomycosis, psoriasis, or rosacea. The assessment and plan of each progress note were reviewed, and the exact medication name and associated diagnosis were recorded for each prescription. Subsequently, each medication was reviewed and placed in 1 of 3 categories: brand name, generic, and OTC. The total number of prescriptions for each diagnosis (per visit/note); the specific number of brand, generic, and OTC medications prescribed (per visit/note); and the percentage of brand, generic, and OTC medications prescribed (per visit/note and per diagnosis in total) were calculated. To ensure only intended medications were included, each medication recorded in the medical record note was cross-referenced with the prescribed medication in the electronic medical record. The primary objective of this study was to capture the prescribing physician’s intent as proxied by the pattern of prescription. Thus, changes made in prescriptions after the initial plan—whether insurance related or otherwise—were not relevant to this investigation.

The data were collected to compare the percentage of brand vs generic or OTC prescriptions per diagnosis to see if there was a difference in the prescribing habits before and after the pharmaceutical policy changes. Of note, several other pieces of data were collected from each medical record, including age, race, class of insurance (ie, Medicare, Medicaid, private health maintenance organization, private preferred provider organization), subtype diagnoses, and whether the prescription was new or a refill. The information gathered from the written record on the assessment and plan was verified using prescriptions ordered in the Allscripts electronic record, and any difference was noted. No identifying information that could be used to easily identify study participants was recorded.

Differences in prescribing habits across diagnoses before and after the policy changes were ascertained using a Fisher exact test and were further assessed using a mixed effects ordinal logistic regression model that accounted for within-provider clustering and baseline patient characteristics. An ordinal model was chosen to recognize differences in average cost among brand-name, generic, and OTC medications.

Results

In total, 200 medical records were collected. For the period analyzed before the policy change, 252 brand-name medications were prescribed compared to 231 prescribed for the period analyzed after the policy changes. There was insufficient evidence of an overall difference in brand-name medications prescribed before and after the policy changes (P=.145; Fisher exact test)(Table 1). There also was insufficient evidence of an overall difference in generic prescriptions, which totaled 153 before and 134 after the policy changes (P=.872; Fisher exact test)(Table 2). Over-the-counter prescriptions totaled 49 before and 69 after the policy changes. There was insufficient evidence of an overall difference before and after the policy changes for OTC medications (P=.192; Fisher exact test)(Table 3).

The mixed effects ordinal logistic regression model for the dependent variable—prescription type (branded, generic, or OTC)—showed an odds ratio (OR) of 1.27 for prescribing habits before and after the policy changes (OR, 1.27; 95% confidence interval, 0.97-1.67; P=.08) after accounting for provider and baseline characteristics. Despite the P value exceeding the predefined significance level, the confidence interval suggests anywhere from a 3% decrease, no change, and up to a 67% increase in postpolicy odds relative to the prepolicy odds, with a point estimate of a 27% increase in postpolicy odds over prepolicy odds. As an observational study, this suggests moderate evidence of a change based on the odds after the policy change relative to the odds before implementation (Figure).

Comment

Although some medical institutions are diligently working to limit the potential influence pharmaceutical companies have on physician prescribing habits,^4,5,25 the effect on physician prescribing habits is only now being established.¹⁵ Prior studies^12,19,21 have found evidence that medication samples may lead to overuse of brand-name medications, but these findings do not hold true for the USF dermatologists included in this study, perhaps due to the difference in pharmaceutical company interactions or physicians maintaining prior prescription habits that were unrelated to the policy. Although this study focused on policy changes for in-office samples, prior studies either included other forms of interaction²¹ or did not include samples.²²

Pharmaceutical samples allow patients to try a medication before committing to a long-term course of treatment with a particular medication, which has utility for physicians and patients. Although brand-name prescriptions may cost more, a trial period may assist the patient in deciding whether the medication is worth purchasing. Furthermore, physicians may feel more comfortable prescribing a medication once the individual patient has demonstrated a benefit from the sample, which may be particularly true in a specialty such as dermatology in which many branded topical medications contain a different vehicle than generic formulations, resulting in notable variations in active medication delivery and efficacy. Given the higher cost of branded topical medications, proving efficacy in patients through samples can provide a useful tool to the physician to determine the need for a branded formulation.

The benefits described are subjective but should not be disregarded. Although Hurley et al¹⁹ found that the number of brand-name medications prescribed increases as more samples are given out, our study demonstrated that after eliminating medication samples, there was no significant difference in the percentage of brand-name medications prescribed compared to generic and OTC medications.

Physician education concerning the price of each brand-name medication prescribed in office may be one method of reducing the amount of such prescriptions. Physicians generally are uninformed of the cost of the medications being prescribed²⁶ and may not recognize the financial burden one medication may have compared to its alternative. However, educating physicians will empower them to make the conscious decision to prefer or not prefer a brand-name medication. With some generic medications shown to have a difference in bioequivalence compared to their brand-name counterparts, a physician may find more success prescribing the brand-name medications, regardless of pharmaceutical company influence, which is an alternative solution to policy changes that eliminate samples entirely. Although this study found insufficient evidence that removing samples decreases brand-name medication prescriptions, it is imperative that solutions are established to reduce the country’s increasing burden of medical costs.

Possible shortfalls of this study include the short period of time between which prepolicy data and postpolicy data were collected. It is possible that providers did not have enough time to adjust their prescribing habits or that providers would not have changed a prescribing pattern or preference simply because of a policy change. Future studies could allow a time period greater than 2 years to compare prepolicy and postpolicy prescribing habits, or a future study might make comparisons of prescriber patterns at different institutions that have different policies. Another possible shortfall is that providers and patients were limited to those at the Department of Dermatology & Cutaneous Surgery at the USF Morsani COM. Although this study has found insufficient evidence of a difference in prescribing habits, it may be beneficial to conduct a larger study that encompasses multiple academic institutions with similar policy changes. Most importantly, this study only investigated the influence of in-office pharmaceutical samples on prescribing patterns. This study did not look at the many other ways in which providers may be influenced by pharmaceutical companies, which likely is a significant confounding variable in this study. Continued additional studies that specifically examine other methods through which providers may be influenced would be helpful in further examining the many ways in which physician prescription habits are influenced.

Conclusion

Changes in pharmaceutical policy in 2011 at USF Morsani COM specifically banned in-office samples. The totality of evidence in this study shows modest observational evidence of a change in the postpolicy odds relative to prepolicy odds, but the data also are compatible with no change between prescribing habits before and after the policy changes. Further study is needed to fully understand this relationship.

Over the years, there has been growing concern about the relationship between physicians and pharmaceutical companies. Many studies have demonstrated that pharmaceutical interactions and incentives can influence physicians’ prescribing habits.^1-3 As a result, many academic centers have adopted policies that attempt to limit the pharmaceutical industry’s influence on faculty and in-training physicians. Although these policies can vary greatly, they generally limit access of pharmaceutical representatives to providers and restrict pharmaceutical samples.^4,5 This policy shift has even been reported in private practice.⁶

At the heart of the matter is the question: What really influences physicians to write a prescription for a particular medication? Is it cost, efficacy, or representatives pushing a product? Prior studies illustrate that generic medications are equivalent to their brand-name counterparts. In fact, current regulations require no more than 5% to 7% difference in bioequivalence.^7-9 Although most generic medications are bioequivalent, it may not be universal.¹⁰

Garrison and Levin¹¹ distributed a survey to US-based prescribers in family practice, psychiatry, and internal medicine and found that prescribers deemed patient response and success as the highest priority when determining which drugs to prescribe. In contrast, drug representatives and free samples only slightly contributed.¹¹ Considering the minimum duration for efficacy of a medication such as an antidepressant vs a topical steroid, this pattern may differ with samples in dermatologic settings. Interestingly, another survey concluded that samples were associated with “sticky” prescribing habits, noting that physicians would prescribe a brand-name medication after using a sample, despite increased cost to the patient.¹² Further, it has been suggested that recipients of free samples may experience increased costs in the long run, which contrasts a stated goal of affordability to patients.^12,13

Physician interaction with pharmaceutical companies begins as early as medical school,¹⁴ with physicians reporting interactions as often as 4 times each month.^14-18 Interactions can include meetings with pharmaceutical representatives, sponsored meals, gifts, continuing medical education sponsorship, funding for travel, pharmaceutical representative speakers, research funding, and drug samples.³

A 2014 study reported that prescribing habits are influenced by the free drug samples provided by nongeneric pharmaceutical companies.¹⁹ Nationally, the number of brand-name and branded generic medications constitute 79% of prescriptions, yet together they only comprise 17% of medications prescribed at an academic medical clinic that does not provide samples. The number of medications with samples being prescribed by dermatologists increased by 15% over 9 years, which may correlate with the wider availability of medication samples, more specifically an increase in branded generic samples.¹⁹ This potential interaction is the reason why institutions question the current influence of pharmaceutical companies. Samples may appear convenient, allowing a patient to test the medication prior to committing; however, with brand-name samples being provided to the physician, he/she may become more inclined to prescribe the branded medication.^12,15,19-22 Because brand-name medications are more expensive than generic medications, this practice can increase the cost of health care.¹³ One study found that over 1 year, the overuse of nongeneric medications led to a loss of potential savings throughout 49 states, equating to $229 million just through Medicaid; interestingly, it was noted that in some states, a maximum reimbursement is set by Medicaid, regardless of whether the generic or branded medication is dispensed. The authors also noted variability in the potential savings by state, which may be a function of the state-by-state maximum reimbursements for certain medications.²³ Another study on oral combination medications estimated Medicare spending on branded drugs relative to the cost if generic combinations had been purchased instead. This study examined branded medications for which the active components were available as over-the-counter (OTC), generic, or same-class generic, and the authors estimated that $925 million could have been saved in 2016 by purchasing a generic substitute.²⁴ The overuse of nongeneric medications when generic alternatives are available becomes an issue that not only financially impacts patients but all taxpayers. However, this pattern may differ if limited only to dermatologic medications, which was not the focus of the prior studies.

To limit conflicts of interest in interactions with the pharmaceutical, medical device, and biotechnology industries, the University of South Florida (USF) Morsani College of Medicine (COM)(Tampa, Florida) implemented its own set of regulations that eliminated in-office pharmaceutical samples, in addition to other restrictions. This study aimed to investigate if there was a change in the prescribing habits of academic dermatologists after their medical school implemented these new policies.

We hypothesized that the number of brand-name drugs prescribed by physicians in the Department of Dermatology & Cutaneous Surgery would change following USF Morsani COM pharmaceutical policy changes. We sought to determine how physician prescribing practices within the Department of Dermatology & Cutaneous Surgery changed following USF Morsani COM pharmaceutical policy changes.

Methods

Data Collection
A retrospective review of medical records was conducted to investigate the effect of the USF Morsani COM pharmaceutical policy changes on physician prescribing practices within the Department of Dermatology & Cutaneous Surgery. Medical records of patients seen for common dermatology diagnoses before (January 1, 2010, to May 30, 2010) and after (August 1, 2011, to December 31, 2011) the pharmaceutical policy changes were reviewed, and all medications prescribed were recorded. Data were collected from medical records within the USF Health electronic medical record system and included visits with each of the department’s 3 attending dermatologists. The diagnoses included in the study—acne vulgaris, atopic dermatitis, onychomycosis, psoriasis, and rosacea—were chosen because in-office samples were available. Prescribing data from the first 100 consecutive medical records were collected from each time period, and a medical record was included only if it contained at least 1 of the following diagnoses: acne vulgaris, atopic dermatitis, onychomycosis, psoriasis, or rosacea. The assessment and plan of each progress note were reviewed, and the exact medication name and associated diagnosis were recorded for each prescription. Subsequently, each medication was reviewed and placed in 1 of 3 categories: brand name, generic, and OTC. The total number of prescriptions for each diagnosis (per visit/note); the specific number of brand, generic, and OTC medications prescribed (per visit/note); and the percentage of brand, generic, and OTC medications prescribed (per visit/note and per diagnosis in total) were calculated. To ensure only intended medications were included, each medication recorded in the medical record note was cross-referenced with the prescribed medication in the electronic medical record. The primary objective of this study was to capture the prescribing physician’s intent as proxied by the pattern of prescription. Thus, changes made in prescriptions after the initial plan—whether insurance related or otherwise—were not relevant to this investigation.

The data were collected to compare the percentage of brand vs generic or OTC prescriptions per diagnosis to see if there was a difference in the prescribing habits before and after the pharmaceutical policy changes. Of note, several other pieces of data were collected from each medical record, including age, race, class of insurance (ie, Medicare, Medicaid, private health maintenance organization, private preferred provider organization), subtype diagnoses, and whether the prescription was new or a refill. The information gathered from the written record on the assessment and plan was verified using prescriptions ordered in the Allscripts electronic record, and any difference was noted. No identifying information that could be used to easily identify study participants was recorded.

Differences in prescribing habits across diagnoses before and after the policy changes were ascertained using a Fisher exact test and were further assessed using a mixed effects ordinal logistic regression model that accounted for within-provider clustering and baseline patient characteristics. An ordinal model was chosen to recognize differences in average cost among brand-name, generic, and OTC medications.

Results

In total, 200 medical records were collected. For the period analyzed before the policy change, 252 brand-name medications were prescribed compared to 231 prescribed for the period analyzed after the policy changes. There was insufficient evidence of an overall difference in brand-name medications prescribed before and after the policy changes (P=.145; Fisher exact test)(Table 1). There also was insufficient evidence of an overall difference in generic prescriptions, which totaled 153 before and 134 after the policy changes (P=.872; Fisher exact test)(Table 2). Over-the-counter prescriptions totaled 49 before and 69 after the policy changes. There was insufficient evidence of an overall difference before and after the policy changes for OTC medications (P=.192; Fisher exact test)(Table 3).

The mixed effects ordinal logistic regression model for the dependent variable—prescription type (branded, generic, or OTC)—showed an odds ratio (OR) of 1.27 for prescribing habits before and after the policy changes (OR, 1.27; 95% confidence interval, 0.97-1.67; P=.08) after accounting for provider and baseline characteristics. Despite the P value exceeding the predefined significance level, the confidence interval suggests anywhere from a 3% decrease, no change, and up to a 67% increase in postpolicy odds relative to the prepolicy odds, with a point estimate of a 27% increase in postpolicy odds over prepolicy odds. As an observational study, this suggests moderate evidence of a change based on the odds after the policy change relative to the odds before implementation (Figure).

Comment

Although some medical institutions are diligently working to limit the potential influence pharmaceutical companies have on physician prescribing habits,^4,5,25 the effect on physician prescribing habits is only now being established.¹⁵ Prior studies^12,19,21 have found evidence that medication samples may lead to overuse of brand-name medications, but these findings do not hold true for the USF dermatologists included in this study, perhaps due to the difference in pharmaceutical company interactions or physicians maintaining prior prescription habits that were unrelated to the policy. Although this study focused on policy changes for in-office samples, prior studies either included other forms of interaction²¹ or did not include samples.²²

Pharmaceutical samples allow patients to try a medication before committing to a long-term course of treatment with a particular medication, which has utility for physicians and patients. Although brand-name prescriptions may cost more, a trial period may assist the patient in deciding whether the medication is worth purchasing. Furthermore, physicians may feel more comfortable prescribing a medication once the individual patient has demonstrated a benefit from the sample, which may be particularly true in a specialty such as dermatology in which many branded topical medications contain a different vehicle than generic formulations, resulting in notable variations in active medication delivery and efficacy. Given the higher cost of branded topical medications, proving efficacy in patients through samples can provide a useful tool to the physician to determine the need for a branded formulation.

The benefits described are subjective but should not be disregarded. Although Hurley et al¹⁹ found that the number of brand-name medications prescribed increases as more samples are given out, our study demonstrated that after eliminating medication samples, there was no significant difference in the percentage of brand-name medications prescribed compared to generic and OTC medications.

Physician education concerning the price of each brand-name medication prescribed in office may be one method of reducing the amount of such prescriptions. Physicians generally are uninformed of the cost of the medications being prescribed²⁶ and may not recognize the financial burden one medication may have compared to its alternative. However, educating physicians will empower them to make the conscious decision to prefer or not prefer a brand-name medication. With some generic medications shown to have a difference in bioequivalence compared to their brand-name counterparts, a physician may find more success prescribing the brand-name medications, regardless of pharmaceutical company influence, which is an alternative solution to policy changes that eliminate samples entirely. Although this study found insufficient evidence that removing samples decreases brand-name medication prescriptions, it is imperative that solutions are established to reduce the country’s increasing burden of medical costs.

Possible shortfalls of this study include the short period of time between which prepolicy data and postpolicy data were collected. It is possible that providers did not have enough time to adjust their prescribing habits or that providers would not have changed a prescribing pattern or preference simply because of a policy change. Future studies could allow a time period greater than 2 years to compare prepolicy and postpolicy prescribing habits, or a future study might make comparisons of prescriber patterns at different institutions that have different policies. Another possible shortfall is that providers and patients were limited to those at the Department of Dermatology & Cutaneous Surgery at the USF Morsani COM. Although this study has found insufficient evidence of a difference in prescribing habits, it may be beneficial to conduct a larger study that encompasses multiple academic institutions with similar policy changes. Most importantly, this study only investigated the influence of in-office pharmaceutical samples on prescribing patterns. This study did not look at the many other ways in which providers may be influenced by pharmaceutical companies, which likely is a significant confounding variable in this study. Continued additional studies that specifically examine other methods through which providers may be influenced would be helpful in further examining the many ways in which physician prescription habits are influenced.

Conclusion

Changes in pharmaceutical policy in 2011 at USF Morsani COM specifically banned in-office samples. The totality of evidence in this study shows modest observational evidence of a change in the postpolicy odds relative to prepolicy odds, but the data also are compatible with no change between prescribing habits before and after the policy changes. Further study is needed to fully understand this relationship.

Over the years, there has been growing concern about the relationship between physicians and pharmaceutical companies. Many studies have demonstrated that pharmaceutical interactions and incentives can influence physicians’ prescribing habits.^1-3 As a result, many academic centers have adopted policies that attempt to limit the pharmaceutical industry’s influence on faculty and in-training physicians. Although these policies can vary greatly, they generally limit access of pharmaceutical representatives to providers and restrict pharmaceutical samples.^4,5 This policy shift has even been reported in private practice.⁶

At the heart of the matter is the question: What really influences physicians to write a prescription for a particular medication? Is it cost, efficacy, or representatives pushing a product? Prior studies illustrate that generic medications are equivalent to their brand-name counterparts. In fact, current regulations require no more than 5% to 7% difference in bioequivalence.^7-9 Although most generic medications are bioequivalent, it may not be universal.¹⁰

Garrison and Levin¹¹ distributed a survey to US-based prescribers in family practice, psychiatry, and internal medicine and found that prescribers deemed patient response and success as the highest priority when determining which drugs to prescribe. In contrast, drug representatives and free samples only slightly contributed.¹¹ Considering the minimum duration for efficacy of a medication such as an antidepressant vs a topical steroid, this pattern may differ with samples in dermatologic settings. Interestingly, another survey concluded that samples were associated with “sticky” prescribing habits, noting that physicians would prescribe a brand-name medication after using a sample, despite increased cost to the patient.¹² Further, it has been suggested that recipients of free samples may experience increased costs in the long run, which contrasts a stated goal of affordability to patients.^12,13

Physician interaction with pharmaceutical companies begins as early as medical school,¹⁴ with physicians reporting interactions as often as 4 times each month.^14-18 Interactions can include meetings with pharmaceutical representatives, sponsored meals, gifts, continuing medical education sponsorship, funding for travel, pharmaceutical representative speakers, research funding, and drug samples.³

A 2014 study reported that prescribing habits are influenced by the free drug samples provided by nongeneric pharmaceutical companies.¹⁹ Nationally, the number of brand-name and branded generic medications constitute 79% of prescriptions, yet together they only comprise 17% of medications prescribed at an academic medical clinic that does not provide samples. The number of medications with samples being prescribed by dermatologists increased by 15% over 9 years, which may correlate with the wider availability of medication samples, more specifically an increase in branded generic samples.¹⁹ This potential interaction is the reason why institutions question the current influence of pharmaceutical companies. Samples may appear convenient, allowing a patient to test the medication prior to committing; however, with brand-name samples being provided to the physician, he/she may become more inclined to prescribe the branded medication.^12,15,19-22 Because brand-name medications are more expensive than generic medications, this practice can increase the cost of health care.¹³ One study found that over 1 year, the overuse of nongeneric medications led to a loss of potential savings throughout 49 states, equating to $229 million just through Medicaid; interestingly, it was noted that in some states, a maximum reimbursement is set by Medicaid, regardless of whether the generic or branded medication is dispensed. The authors also noted variability in the potential savings by state, which may be a function of the state-by-state maximum reimbursements for certain medications.²³ Another study on oral combination medications estimated Medicare spending on branded drugs relative to the cost if generic combinations had been purchased instead. This study examined branded medications for which the active components were available as over-the-counter (OTC), generic, or same-class generic, and the authors estimated that $925 million could have been saved in 2016 by purchasing a generic substitute.²⁴ The overuse of nongeneric medications when generic alternatives are available becomes an issue that not only financially impacts patients but all taxpayers. However, this pattern may differ if limited only to dermatologic medications, which was not the focus of the prior studies.

To limit conflicts of interest in interactions with the pharmaceutical, medical device, and biotechnology industries, the University of South Florida (USF) Morsani College of Medicine (COM)(Tampa, Florida) implemented its own set of regulations that eliminated in-office pharmaceutical samples, in addition to other restrictions. This study aimed to investigate if there was a change in the prescribing habits of academic dermatologists after their medical school implemented these new policies.

We hypothesized that the number of brand-name drugs prescribed by physicians in the Department of Dermatology & Cutaneous Surgery would change following USF Morsani COM pharmaceutical policy changes. We sought to determine how physician prescribing practices within the Department of Dermatology & Cutaneous Surgery changed following USF Morsani COM pharmaceutical policy changes.

Methods

Data Collection
A retrospective review of medical records was conducted to investigate the effect of the USF Morsani COM pharmaceutical policy changes on physician prescribing practices within the Department of Dermatology & Cutaneous Surgery. Medical records of patients seen for common dermatology diagnoses before (January 1, 2010, to May 30, 2010) and after (August 1, 2011, to December 31, 2011) the pharmaceutical policy changes were reviewed, and all medications prescribed were recorded. Data were collected from medical records within the USF Health electronic medical record system and included visits with each of the department’s 3 attending dermatologists. The diagnoses included in the study—acne vulgaris, atopic dermatitis, onychomycosis, psoriasis, and rosacea—were chosen because in-office samples were available. Prescribing data from the first 100 consecutive medical records were collected from each time period, and a medical record was included only if it contained at least 1 of the following diagnoses: acne vulgaris, atopic dermatitis, onychomycosis, psoriasis, or rosacea. The assessment and plan of each progress note were reviewed, and the exact medication name and associated diagnosis were recorded for each prescription. Subsequently, each medication was reviewed and placed in 1 of 3 categories: brand name, generic, and OTC. The total number of prescriptions for each diagnosis (per visit/note); the specific number of brand, generic, and OTC medications prescribed (per visit/note); and the percentage of brand, generic, and OTC medications prescribed (per visit/note and per diagnosis in total) were calculated. To ensure only intended medications were included, each medication recorded in the medical record note was cross-referenced with the prescribed medication in the electronic medical record. The primary objective of this study was to capture the prescribing physician’s intent as proxied by the pattern of prescription. Thus, changes made in prescriptions after the initial plan—whether insurance related or otherwise—were not relevant to this investigation.

The data were collected to compare the percentage of brand vs generic or OTC prescriptions per diagnosis to see if there was a difference in the prescribing habits before and after the pharmaceutical policy changes. Of note, several other pieces of data were collected from each medical record, including age, race, class of insurance (ie, Medicare, Medicaid, private health maintenance organization, private preferred provider organization), subtype diagnoses, and whether the prescription was new or a refill. The information gathered from the written record on the assessment and plan was verified using prescriptions ordered in the Allscripts electronic record, and any difference was noted. No identifying information that could be used to easily identify study participants was recorded.

Differences in prescribing habits across diagnoses before and after the policy changes were ascertained using a Fisher exact test and were further assessed using a mixed effects ordinal logistic regression model that accounted for within-provider clustering and baseline patient characteristics. An ordinal model was chosen to recognize differences in average cost among brand-name, generic, and OTC medications.

Results

In total, 200 medical records were collected. For the period analyzed before the policy change, 252 brand-name medications were prescribed compared to 231 prescribed for the period analyzed after the policy changes. There was insufficient evidence of an overall difference in brand-name medications prescribed before and after the policy changes (P=.145; Fisher exact test)(Table 1). There also was insufficient evidence of an overall difference in generic prescriptions, which totaled 153 before and 134 after the policy changes (P=.872; Fisher exact test)(Table 2). Over-the-counter prescriptions totaled 49 before and 69 after the policy changes. There was insufficient evidence of an overall difference before and after the policy changes for OTC medications (P=.192; Fisher exact test)(Table 3).

The mixed effects ordinal logistic regression model for the dependent variable—prescription type (branded, generic, or OTC)—showed an odds ratio (OR) of 1.27 for prescribing habits before and after the policy changes (OR, 1.27; 95% confidence interval, 0.97-1.67; P=.08) after accounting for provider and baseline characteristics. Despite the P value exceeding the predefined significance level, the confidence interval suggests anywhere from a 3% decrease, no change, and up to a 67% increase in postpolicy odds relative to the prepolicy odds, with a point estimate of a 27% increase in postpolicy odds over prepolicy odds. As an observational study, this suggests moderate evidence of a change based on the odds after the policy change relative to the odds before implementation (Figure).

Comment

Although some medical institutions are diligently working to limit the potential influence pharmaceutical companies have on physician prescribing habits,^4,5,25 the effect on physician prescribing habits is only now being established.¹⁵ Prior studies^12,19,21 have found evidence that medication samples may lead to overuse of brand-name medications, but these findings do not hold true for the USF dermatologists included in this study, perhaps due to the difference in pharmaceutical company interactions or physicians maintaining prior prescription habits that were unrelated to the policy. Although this study focused on policy changes for in-office samples, prior studies either included other forms of interaction²¹ or did not include samples.²²

Pharmaceutical samples allow patients to try a medication before committing to a long-term course of treatment with a particular medication, which has utility for physicians and patients. Although brand-name prescriptions may cost more, a trial period may assist the patient in deciding whether the medication is worth purchasing. Furthermore, physicians may feel more comfortable prescribing a medication once the individual patient has demonstrated a benefit from the sample, which may be particularly true in a specialty such as dermatology in which many branded topical medications contain a different vehicle than generic formulations, resulting in notable variations in active medication delivery and efficacy. Given the higher cost of branded topical medications, proving efficacy in patients through samples can provide a useful tool to the physician to determine the need for a branded formulation.

The benefits described are subjective but should not be disregarded. Although Hurley et al¹⁹ found that the number of brand-name medications prescribed increases as more samples are given out, our study demonstrated that after eliminating medication samples, there was no significant difference in the percentage of brand-name medications prescribed compared to generic and OTC medications.

Physician education concerning the price of each brand-name medication prescribed in office may be one method of reducing the amount of such prescriptions. Physicians generally are uninformed of the cost of the medications being prescribed²⁶ and may not recognize the financial burden one medication may have compared to its alternative. However, educating physicians will empower them to make the conscious decision to prefer or not prefer a brand-name medication. With some generic medications shown to have a difference in bioequivalence compared to their brand-name counterparts, a physician may find more success prescribing the brand-name medications, regardless of pharmaceutical company influence, which is an alternative solution to policy changes that eliminate samples entirely. Although this study found insufficient evidence that removing samples decreases brand-name medication prescriptions, it is imperative that solutions are established to reduce the country’s increasing burden of medical costs.

Possible shortfalls of this study include the short period of time between which prepolicy data and postpolicy data were collected. It is possible that providers did not have enough time to adjust their prescribing habits or that providers would not have changed a prescribing pattern or preference simply because of a policy change. Future studies could allow a time period greater than 2 years to compare prepolicy and postpolicy prescribing habits, or a future study might make comparisons of prescriber patterns at different institutions that have different policies. Another possible shortfall is that providers and patients were limited to those at the Department of Dermatology & Cutaneous Surgery at the USF Morsani COM. Although this study has found insufficient evidence of a difference in prescribing habits, it may be beneficial to conduct a larger study that encompasses multiple academic institutions with similar policy changes. Most importantly, this study only investigated the influence of in-office pharmaceutical samples on prescribing patterns. This study did not look at the many other ways in which providers may be influenced by pharmaceutical companies, which likely is a significant confounding variable in this study. Continued additional studies that specifically examine other methods through which providers may be influenced would be helpful in further examining the many ways in which physician prescription habits are influenced.

Conclusion

Changes in pharmaceutical policy in 2011 at USF Morsani COM specifically banned in-office samples. The totality of evidence in this study shows modest observational evidence of a change in the postpolicy odds relative to prepolicy odds, but the data also are compatible with no change between prescribing habits before and after the policy changes. Further study is needed to fully understand this relationship.

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

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

Clinical Experience With HP 0.05% in Various Formulations

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

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

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

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

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

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

Comparative Studies With Other TCSs

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

Evolving Management Strategies

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

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

Development of HP Lotion 0.01%

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

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

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

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

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

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

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

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

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

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

Conclusion

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

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

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

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

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

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

Clinical Experience With HP 0.05% in Various Formulations

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

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

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

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

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

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

Comparative Studies With Other TCSs

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

Evolving Management Strategies

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

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

Development of HP Lotion 0.01%

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

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

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

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

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

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

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

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

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

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

Conclusion

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

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

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

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

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

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

Clinical Experience With HP 0.05% in Various Formulations

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

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

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

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

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

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

Comparative Studies With Other TCSs

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

Evolving Management Strategies

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

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

Development of HP Lotion 0.01%

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

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

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

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

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

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

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

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

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

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

Conclusion

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

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

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

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

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

Methods

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

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

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

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

Results

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

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

Discussion

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

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

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

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

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

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

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

Methods

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

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

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

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

Results

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

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

Discussion

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

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

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

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

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

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

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

Methods

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

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

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

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

Results

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

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

Discussion

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

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

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

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

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

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

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

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

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

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

Methods

Study Design

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

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

Assessments

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

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

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

Statistical Analyses

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

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

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

Results

Patients

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

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

Psoriasis Individual Sign Scores for Knee and Elbow Plaques

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

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

Total Sign Score

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

Comment

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

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

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

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

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

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

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

Conclusion

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

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

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

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

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

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

Methods

Study Design

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

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

Assessments

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

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

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

Statistical Analyses

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

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

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

Results

Patients

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

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

Psoriasis Individual Sign Scores for Knee and Elbow Plaques

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

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

Total Sign Score

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

Comment

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

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

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

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

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

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

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

Conclusion

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

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

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

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

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

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

Methods

Study Design

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

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

Assessments

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

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

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

Statistical Analyses

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

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

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

Results

Patients

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

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

Psoriasis Individual Sign Scores for Knee and Elbow Plaques

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

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

Total Sign Score

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

Comment

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

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

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

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

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

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

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

Conclusion

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

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

The connection between psoriasis and increased major adverse cardiovascular events (MACEs) has been well studied. ^1,2 Although treatment of psoriasis can improve skin and joint symptoms, it is less clear whether therapies may mitigate the increased risk for cardiovascular comorbidities. Tumor necrosis factor (TNF) inhibitors in particular have been studied with great interest given the role of TNF in vascular and metabolic functions. ³ Using a retrospective cohort design, Wu and colleagues ⁴ examined if treatment with TNF inhibitors in patients with psoriasis would be associated with a lower risk for MACEs compared to phototherapy. Results suggested a significantly lower hazard of MACEs in patients using TNF inhibitors vs patients treated with phototherapy (adjusted hazard ratio, 0.77; P = .046). Moreover, based on these findings, they calculated that treating approximately 161 patients with TNF inhibitors rather than phototherapy would result in 1 less MACE per year overall. ⁴

Patients with psoriasis have been shown to have a greater noncalcified coronary plaque burden and prevalence of high-risk plaque compared to healthy patients.⁵ Lerman and colleagues⁵ measured the coronary plaque burden of 105 patients with psoriasis and 25 healthy volunteers using coronary computed tomography angiography. Although the patients were on average 10 years younger and had lower cardiovascular risk as measured by traditional risk scores, patients with psoriasis were found to have a greater noncalcified coronary plaque burden compared to 100 patients with hyperlipidemia. This burden was associated with an increased prevalence of high-risk plaques. Furthermore, in patients followed for 1 year, improvements in psoriasis severity were associated with reductions in noncalcified coronary plaque burden, though this finding was across all treatment modalities. However, there was no significant difference in calcified coronary plaque burden associated with reduced psoriasis severity.⁵

Moreover, Pina et al⁶ conducted a prospective study evaluating the use of the TNF inhibitor adalimumab to improve endothelial function and arterial stiffness in patients with moderate to severe psoriasis. Among 29 patients, they found a significant improvement in endothelial function as measured by flow-mediated dilatation after 6 months of adalimumab therapy, with a mean increase from 6.19% to 7.46% (P=.008). They also reported decreases in arterial stiffness by pulse wave velocity (P=.03). Despite a small sample size, these findings provide 2 potential mechanisms by which TNF inhibitor therapy may reduce the risk for cardiovascular events.⁶

A retrospective cohort study evaluating data from the Kaiser Permanente Southern California health plan assessed whether TNF inhibitor therapy was associated with a lower risk for MACE in patients with psoriasis.⁷ A total of 18,194 patients were included; of these, 1463 received TNF inhibitor therapy for at least 2 months. After controlling for other variables, including age at psoriasis diagnosis, sex, race/ethnicity, and other cardiovascular risk factors (eg, history of smoking or alcohol use; use of clopidogrel, antihypertensive agents, antihyperlipidemics, or anticoagulants), patients in the TNF inhibitor cohort demonstrated a significantly lower MACE hazard ratio compared to patients treated with topicals (hazard ratio, 0.80; 95% confidence interval, 0.66-0.98; P<.05).⁷

Conversely, a randomized, placebo-controlled trial of 107 patients found no difference in vascular inflammation of the ascending aorta and the carotids after 16 weeks of adalimumab treatment vs placebo. In this study, however, most patients had only moderate psoriasis based on a mean psoriasis area and severity index score of 9.8.⁸ Given studies finding higher risk burden in patients with more severe skin disease,² it is possible that the effect of TNF inhibitor therapy may not be as pronounced in patients with less skin involvement. There was a significant effect on C-reactive protein levels in patients receiving TNF inhibitor therapy compared to placebo at 16 weeks (P=.012), suggesting TNF does play some role in systemic inflammation, and it is possible it may exert cardiovascular effects through a mechanism other than vascular inflammation.⁸

A second double-blind, randomized trial reported similar results.⁹ Among 97 patients randomized to receive adalimumab, placebo, or phototherapy, no significant difference in vascular inflammation was found after 12 weeks of therapy. In contrast, levels of C-reactive protein, IL-6, and glycoprotein acetylation were markedly reduced. The authors also reported adverse effects of adalimumab therapy on lipid metabolism with reduced cholesterol efflux capacity, a marker of ability of high-density-lipoprotein particles to perform reverse cholesterol transport, and high-density-lipoprotein particles, suggesting these effects may counteract some of the anti-inflammatory effects of TNF inhibitors.⁹

A growing body of data regarding the effect of TNF inhibitors on cardiovascular morbidity in patients with psoriasis is being collected, but no strong conclusions can be made. Given the disconnect of findings across these studies, it is possible that we have yet to elucidate the full mechanism by which TNF inhibitors may affect cardiovascular health. However, there may be additional confounding factors or patient characteristics at play. More large, prospective, randomized, controlled studies are needed to further understand this relationship.

The connection between psoriasis and increased major adverse cardiovascular events (MACEs) has been well studied. ^1,2 Although treatment of psoriasis can improve skin and joint symptoms, it is less clear whether therapies may mitigate the increased risk for cardiovascular comorbidities. Tumor necrosis factor (TNF) inhibitors in particular have been studied with great interest given the role of TNF in vascular and metabolic functions. ³ Using a retrospective cohort design, Wu and colleagues ⁴ examined if treatment with TNF inhibitors in patients with psoriasis would be associated with a lower risk for MACEs compared to phototherapy. Results suggested a significantly lower hazard of MACEs in patients using TNF inhibitors vs patients treated with phototherapy (adjusted hazard ratio, 0.77; P = .046). Moreover, based on these findings, they calculated that treating approximately 161 patients with TNF inhibitors rather than phototherapy would result in 1 less MACE per year overall. ⁴

Patients with psoriasis have been shown to have a greater noncalcified coronary plaque burden and prevalence of high-risk plaque compared to healthy patients.⁵ Lerman and colleagues⁵ measured the coronary plaque burden of 105 patients with psoriasis and 25 healthy volunteers using coronary computed tomography angiography. Although the patients were on average 10 years younger and had lower cardiovascular risk as measured by traditional risk scores, patients with psoriasis were found to have a greater noncalcified coronary plaque burden compared to 100 patients with hyperlipidemia. This burden was associated with an increased prevalence of high-risk plaques. Furthermore, in patients followed for 1 year, improvements in psoriasis severity were associated with reductions in noncalcified coronary plaque burden, though this finding was across all treatment modalities. However, there was no significant difference in calcified coronary plaque burden associated with reduced psoriasis severity.⁵

Moreover, Pina et al⁶ conducted a prospective study evaluating the use of the TNF inhibitor adalimumab to improve endothelial function and arterial stiffness in patients with moderate to severe psoriasis. Among 29 patients, they found a significant improvement in endothelial function as measured by flow-mediated dilatation after 6 months of adalimumab therapy, with a mean increase from 6.19% to 7.46% (P=.008). They also reported decreases in arterial stiffness by pulse wave velocity (P=.03). Despite a small sample size, these findings provide 2 potential mechanisms by which TNF inhibitor therapy may reduce the risk for cardiovascular events.⁶

A retrospective cohort study evaluating data from the Kaiser Permanente Southern California health plan assessed whether TNF inhibitor therapy was associated with a lower risk for MACE in patients with psoriasis.⁷ A total of 18,194 patients were included; of these, 1463 received TNF inhibitor therapy for at least 2 months. After controlling for other variables, including age at psoriasis diagnosis, sex, race/ethnicity, and other cardiovascular risk factors (eg, history of smoking or alcohol use; use of clopidogrel, antihypertensive agents, antihyperlipidemics, or anticoagulants), patients in the TNF inhibitor cohort demonstrated a significantly lower MACE hazard ratio compared to patients treated with topicals (hazard ratio, 0.80; 95% confidence interval, 0.66-0.98; P<.05).⁷

Conversely, a randomized, placebo-controlled trial of 107 patients found no difference in vascular inflammation of the ascending aorta and the carotids after 16 weeks of adalimumab treatment vs placebo. In this study, however, most patients had only moderate psoriasis based on a mean psoriasis area and severity index score of 9.8.⁸ Given studies finding higher risk burden in patients with more severe skin disease,² it is possible that the effect of TNF inhibitor therapy may not be as pronounced in patients with less skin involvement. There was a significant effect on C-reactive protein levels in patients receiving TNF inhibitor therapy compared to placebo at 16 weeks (P=.012), suggesting TNF does play some role in systemic inflammation, and it is possible it may exert cardiovascular effects through a mechanism other than vascular inflammation.⁸

A second double-blind, randomized trial reported similar results.⁹ Among 97 patients randomized to receive adalimumab, placebo, or phototherapy, no significant difference in vascular inflammation was found after 12 weeks of therapy. In contrast, levels of C-reactive protein, IL-6, and glycoprotein acetylation were markedly reduced. The authors also reported adverse effects of adalimumab therapy on lipid metabolism with reduced cholesterol efflux capacity, a marker of ability of high-density-lipoprotein particles to perform reverse cholesterol transport, and high-density-lipoprotein particles, suggesting these effects may counteract some of the anti-inflammatory effects of TNF inhibitors.⁹

A growing body of data regarding the effect of TNF inhibitors on cardiovascular morbidity in patients with psoriasis is being collected, but no strong conclusions can be made. Given the disconnect of findings across these studies, it is possible that we have yet to elucidate the full mechanism by which TNF inhibitors may affect cardiovascular health. However, there may be additional confounding factors or patient characteristics at play. More large, prospective, randomized, controlled studies are needed to further understand this relationship.

The connection between psoriasis and increased major adverse cardiovascular events (MACEs) has been well studied. ^1,2 Although treatment of psoriasis can improve skin and joint symptoms, it is less clear whether therapies may mitigate the increased risk for cardiovascular comorbidities. Tumor necrosis factor (TNF) inhibitors in particular have been studied with great interest given the role of TNF in vascular and metabolic functions. ³ Using a retrospective cohort design, Wu and colleagues ⁴ examined if treatment with TNF inhibitors in patients with psoriasis would be associated with a lower risk for MACEs compared to phototherapy. Results suggested a significantly lower hazard of MACEs in patients using TNF inhibitors vs patients treated with phototherapy (adjusted hazard ratio, 0.77; P = .046). Moreover, based on these findings, they calculated that treating approximately 161 patients with TNF inhibitors rather than phototherapy would result in 1 less MACE per year overall. ⁴

Patients with psoriasis have been shown to have a greater noncalcified coronary plaque burden and prevalence of high-risk plaque compared to healthy patients.⁵ Lerman and colleagues⁵ measured the coronary plaque burden of 105 patients with psoriasis and 25 healthy volunteers using coronary computed tomography angiography. Although the patients were on average 10 years younger and had lower cardiovascular risk as measured by traditional risk scores, patients with psoriasis were found to have a greater noncalcified coronary plaque burden compared to 100 patients with hyperlipidemia. This burden was associated with an increased prevalence of high-risk plaques. Furthermore, in patients followed for 1 year, improvements in psoriasis severity were associated with reductions in noncalcified coronary plaque burden, though this finding was across all treatment modalities. However, there was no significant difference in calcified coronary plaque burden associated with reduced psoriasis severity.⁵

Moreover, Pina et al⁶ conducted a prospective study evaluating the use of the TNF inhibitor adalimumab to improve endothelial function and arterial stiffness in patients with moderate to severe psoriasis. Among 29 patients, they found a significant improvement in endothelial function as measured by flow-mediated dilatation after 6 months of adalimumab therapy, with a mean increase from 6.19% to 7.46% (P=.008). They also reported decreases in arterial stiffness by pulse wave velocity (P=.03). Despite a small sample size, these findings provide 2 potential mechanisms by which TNF inhibitor therapy may reduce the risk for cardiovascular events.⁶

A retrospective cohort study evaluating data from the Kaiser Permanente Southern California health plan assessed whether TNF inhibitor therapy was associated with a lower risk for MACE in patients with psoriasis.⁷ A total of 18,194 patients were included; of these, 1463 received TNF inhibitor therapy for at least 2 months. After controlling for other variables, including age at psoriasis diagnosis, sex, race/ethnicity, and other cardiovascular risk factors (eg, history of smoking or alcohol use; use of clopidogrel, antihypertensive agents, antihyperlipidemics, or anticoagulants), patients in the TNF inhibitor cohort demonstrated a significantly lower MACE hazard ratio compared to patients treated with topicals (hazard ratio, 0.80; 95% confidence interval, 0.66-0.98; P<.05).⁷

Conversely, a randomized, placebo-controlled trial of 107 patients found no difference in vascular inflammation of the ascending aorta and the carotids after 16 weeks of adalimumab treatment vs placebo. In this study, however, most patients had only moderate psoriasis based on a mean psoriasis area and severity index score of 9.8.⁸ Given studies finding higher risk burden in patients with more severe skin disease,² it is possible that the effect of TNF inhibitor therapy may not be as pronounced in patients with less skin involvement. There was a significant effect on C-reactive protein levels in patients receiving TNF inhibitor therapy compared to placebo at 16 weeks (P=.012), suggesting TNF does play some role in systemic inflammation, and it is possible it may exert cardiovascular effects through a mechanism other than vascular inflammation.⁸

A second double-blind, randomized trial reported similar results.⁹ Among 97 patients randomized to receive adalimumab, placebo, or phototherapy, no significant difference in vascular inflammation was found after 12 weeks of therapy. In contrast, levels of C-reactive protein, IL-6, and glycoprotein acetylation were markedly reduced. The authors also reported adverse effects of adalimumab therapy on lipid metabolism with reduced cholesterol efflux capacity, a marker of ability of high-density-lipoprotein particles to perform reverse cholesterol transport, and high-density-lipoprotein particles, suggesting these effects may counteract some of the anti-inflammatory effects of TNF inhibitors.⁹

A growing body of data regarding the effect of TNF inhibitors on cardiovascular morbidity in patients with psoriasis is being collected, but no strong conclusions can be made. Given the disconnect of findings across these studies, it is possible that we have yet to elucidate the full mechanism by which TNF inhibitors may affect cardiovascular health. However, there may be additional confounding factors or patient characteristics at play. More large, prospective, randomized, controlled studies are needed to further understand this relationship.

Imagine a patient suffering with horrible psoriasis for decades having failed “every available treatment.” Imagine him living all that time with “flaking, cracking, painful, itchy skin,” only to develop cirrhosis after exposure to toxic therapies.

Then imagine the experience for that patient when, 2 weeks after initiating treatment with a new interleukin-17 inhibitor, his skin clears completely.

“Two weeks later it’s all gone – it was a moment to behold,” said Joel M. Gelfand, MD, professor of dermatology and epidemiology at the University of Pennsylvania, Philadelphia, who had cared for the man for many years before a psoriasis treatment revolution of sorts took the field of dermatology by storm.

“The progress has been breathtaking – there’s no other way to describe it – and it feels like a miracle every time I see a new patient who has tough disease and I have all these things to offer them,” he continued. “For most patients, I can really help them and make a major difference in their life.”

Much of the progress in psoriasis treatment in the past 50 years unfolded over the past 2 decades, with biologics emerging for psoriasis, said Mark Lebwohl, MD, Waldman professor of dermatology and chair of the Kimberly and Eric J. Waldman department of dermatology at the Icahn School of Medicine at Mount Sinai, New York.

Dr. Lebwohl recounted some of his own experiences with psoriasis patients before the advent of treatments – particularly biologics – that have transformed practice.

There was a time when psoriasis patients had little more to turn to than the effective – but “disgusting” – Goeckerman Regimen involving cycles of UVB light exposure and topical crude coal tar application. Initially, the regimen, which was introduced in the 1920s, was used around the clock on an inpatient basis until the skin cleared, Dr. Lebwohl said.

In the 1970s, the immunosuppressive chemotherapy drug methotrexate became the first oral systemic therapy approved for severe psoriasis. For those with disabling disease, it offered some hope for relief, but only about 40% of patients achieved at least a 75% reduction in the Psoriasis Area and Severity Index score (PASI 75), he said, adding that they did so at the expense of the liver and bone marrow. “But it was the only thing we had for severe psoriasis other than light treatments.”

In the 1980s and 1990s, oral retinoids emerged as a treatment for psoriasis, and the immunosuppressive drug cyclosporine used to prevent organ rejection in some transplant patients was found to clear psoriasis in affected transplant recipients. Although they brought relief to some patients with severe, disabling disease, these also came with a high price. “It’s not that effective, and it has lots of side effects ... and causes kidney damage in essentially 100% of patients,” Dr. Lebwohl said of cyclosporine.

“So we had treatments that worked, but because the side effects were sufficiently severe, a lot of patients were not treated,” he said.

Enter the biologics era

The early 2000s brought the first two approvals for psoriasis: alefacept (Amevive), a “modestly effective, but quite safe” immunosuppressive dimeric fusion protein approved in early 2003 for moderate to severe plaque psoriasis, and efalizumab (Raptiva), a recombinant humanized monoclonal antibody approved in October 2003; both were T-cell–targeted therapies. The former was withdrawn from the market voluntarily as newer agents became available, and the latter was withdrawn in 2009 because of a link with development of progressive multifocal leukoencephalopathy.

Tumor necrosis factor (TNF) blockers, which had been used effectively for RA and Crohn’s disease, emerged next, and were highly effective, much safer than the systemic treatments, and gained “very widespread use,” Dr. Lebwohl said.

Alan Menter, MD, chairman of the division of dermatology at Baylor University Medical Center, Dallas, also a prolific researcher – and chair of the guidelines committee that published two new sets of guidelines for psoriasis treatment in 2019 – said that the field of dermatology was “late to the biologic evolution,” as many of the early biologics were first approved for PsA.

“But over the last 10 years, things have changed dramatically,” he said. “After that we suddenly leapt ahead of everybody. ... We now have 11 biologic drugs approved for psoriasis, which is more than any other disease has available.”

It’s been “highly exciting” to see this “evolution and revolution,” he commented, adding that one of the next challenges is to address the comorbidities, such as cardiovascular disease, associated with psoriasis.

“The big question now ... is if you improve skin and you improve joints, can you potentially reduce the risk of coronary artery disease,” he said. “Everybody is looking at that, and to me it’s one of the most exciting things that we’re doing.”

Work is ongoing to look at whether the IL-17s and IL-23s have “other indications outside of the skin and joints,” both within and outside of dermatology.

Like Dr. Gottlieb, Dr. Menter also mentioned the potential for hidradenitis suppurativa, and also for a condition that is rarely discussed or studied: genital psoriasis. Ixekizumab has recently been shown to work in about 75% of patients with genital psoriasis, he noted.

Another important area of research is the identification of biomarkers for predicting response and relapse, he said. For now, biomarker research has disappointed, he added, predicting that it will take at least 3-5 years before biomarkers to help guide treatment are identified.

Indeed, Dr. Gelfand, who also is director of the Psoriasis and Phototherapy Treatment Center, vice chair of clinical research, and medical director of the dermatology clinical studies unit at the University of Pennsylvania, agreed there is a need for research to improve treatment selection.

Advances are being made in genetics – with more than 80 different genes now identified as being related to psoriasis – and in medical informatics – which allow thousands of patients to be followed for years, he said, noting that this could elucidate immunopathological features that can improve treatments, predict and prevent comorbidity, and further improve outcomes.

“We also need care that is more patient centered,” he said, describing the ongoing pragmatic LITE trial of home- or office-based phototherapy for which he is the lead investigator, and other studies that he hopes will expand access to care.

Kenneth Brian Gordon, MD, chair and professor of dermatology at the Medical College of Wisconsin, Milwaukee, whose career started in the basic science immunology arena, added the need for expanding benefit to patients with more-moderate disease. Like Dr. Menter, he identified psoriasis as the area in medicine that has had the greatest degree of advancement, except perhaps for hepatitis C.

He described the process not as a “bench-to-bedside” story, but as a bedside-to-bench, then “back-to-bedside” story.

It was really about taking those early T-cell–targeted biologics and anti-TNF agents from bedside to bench with the realization of the importance of the IL-23 and IL-17 pathways, and that understanding led back to the bedside with the development of the newest agents – and to a “huge difference in patient’s lives.”

“But we’ve gotten so good at treating patients with severe disease ... the question now is how to take care of those with more-moderate disease,” he said, noting that a focus on cost and better delivery systems will be needed for that population.

That research is underway, and the future looks bright – and clear.
 

“I think with psoriasis therapy and where we’ve come in the last 20 years ... we have a hard time remembering what it was like before we had biologic agents” he said. “Our perspective has changed a lot, and sometimes we forget that.”

In fact, “psoriasis has sort of dragged dermatology into the world of modern clinical trial science, and we can now apply that to all sorts of other diseases,” he said. “The psoriasis trials were the first really well-done large-scale trials in dermatology, and I think that has given dermatology a real leg up in how we do clinical research and how we do evidence-based medicine.”

All of the doctors interviewed for this story have received funds and/or honoraria from, consulted with, are employed with, or served on the advisory boards of manufacturers of biologics. Dr. Gelfand is a copatent holder of resiquimod for treatment of cutaneous T-cell lymphoma and is deputy editor of the Journal of Investigative Dermatology.

[email protected]
 

Imagine a patient suffering with horrible psoriasis for decades having failed “every available treatment.” Imagine him living all that time with “flaking, cracking, painful, itchy skin,” only to develop cirrhosis after exposure to toxic therapies.

Then imagine the experience for that patient when, 2 weeks after initiating treatment with a new interleukin-17 inhibitor, his skin clears completely.

“Two weeks later it’s all gone – it was a moment to behold,” said Joel M. Gelfand, MD, professor of dermatology and epidemiology at the University of Pennsylvania, Philadelphia, who had cared for the man for many years before a psoriasis treatment revolution of sorts took the field of dermatology by storm.

“The progress has been breathtaking – there’s no other way to describe it – and it feels like a miracle every time I see a new patient who has tough disease and I have all these things to offer them,” he continued. “For most patients, I can really help them and make a major difference in their life.”

Much of the progress in psoriasis treatment in the past 50 years unfolded over the past 2 decades, with biologics emerging for psoriasis, said Mark Lebwohl, MD, Waldman professor of dermatology and chair of the Kimberly and Eric J. Waldman department of dermatology at the Icahn School of Medicine at Mount Sinai, New York.

Dr. Lebwohl recounted some of his own experiences with psoriasis patients before the advent of treatments – particularly biologics – that have transformed practice.

There was a time when psoriasis patients had little more to turn to than the effective – but “disgusting” – Goeckerman Regimen involving cycles of UVB light exposure and topical crude coal tar application. Initially, the regimen, which was introduced in the 1920s, was used around the clock on an inpatient basis until the skin cleared, Dr. Lebwohl said.

In the 1970s, the immunosuppressive chemotherapy drug methotrexate became the first oral systemic therapy approved for severe psoriasis. For those with disabling disease, it offered some hope for relief, but only about 40% of patients achieved at least a 75% reduction in the Psoriasis Area and Severity Index score (PASI 75), he said, adding that they did so at the expense of the liver and bone marrow. “But it was the only thing we had for severe psoriasis other than light treatments.”

In the 1980s and 1990s, oral retinoids emerged as a treatment for psoriasis, and the immunosuppressive drug cyclosporine used to prevent organ rejection in some transplant patients was found to clear psoriasis in affected transplant recipients. Although they brought relief to some patients with severe, disabling disease, these also came with a high price. “It’s not that effective, and it has lots of side effects ... and causes kidney damage in essentially 100% of patients,” Dr. Lebwohl said of cyclosporine.

“So we had treatments that worked, but because the side effects were sufficiently severe, a lot of patients were not treated,” he said.

Enter the biologics era

The early 2000s brought the first two approvals for psoriasis: alefacept (Amevive), a “modestly effective, but quite safe” immunosuppressive dimeric fusion protein approved in early 2003 for moderate to severe plaque psoriasis, and efalizumab (Raptiva), a recombinant humanized monoclonal antibody approved in October 2003; both were T-cell–targeted therapies. The former was withdrawn from the market voluntarily as newer agents became available, and the latter was withdrawn in 2009 because of a link with development of progressive multifocal leukoencephalopathy.

Tumor necrosis factor (TNF) blockers, which had been used effectively for RA and Crohn’s disease, emerged next, and were highly effective, much safer than the systemic treatments, and gained “very widespread use,” Dr. Lebwohl said.

Alan Menter, MD, chairman of the division of dermatology at Baylor University Medical Center, Dallas, also a prolific researcher – and chair of the guidelines committee that published two new sets of guidelines for psoriasis treatment in 2019 – said that the field of dermatology was “late to the biologic evolution,” as many of the early biologics were first approved for PsA.

“But over the last 10 years, things have changed dramatically,” he said. “After that we suddenly leapt ahead of everybody. ... We now have 11 biologic drugs approved for psoriasis, which is more than any other disease has available.”

It’s been “highly exciting” to see this “evolution and revolution,” he commented, adding that one of the next challenges is to address the comorbidities, such as cardiovascular disease, associated with psoriasis.

“The big question now ... is if you improve skin and you improve joints, can you potentially reduce the risk of coronary artery disease,” he said. “Everybody is looking at that, and to me it’s one of the most exciting things that we’re doing.”

Work is ongoing to look at whether the IL-17s and IL-23s have “other indications outside of the skin and joints,” both within and outside of dermatology.

Like Dr. Gottlieb, Dr. Menter also mentioned the potential for hidradenitis suppurativa, and also for a condition that is rarely discussed or studied: genital psoriasis. Ixekizumab has recently been shown to work in about 75% of patients with genital psoriasis, he noted.

Another important area of research is the identification of biomarkers for predicting response and relapse, he said. For now, biomarker research has disappointed, he added, predicting that it will take at least 3-5 years before biomarkers to help guide treatment are identified.

Indeed, Dr. Gelfand, who also is director of the Psoriasis and Phototherapy Treatment Center, vice chair of clinical research, and medical director of the dermatology clinical studies unit at the University of Pennsylvania, agreed there is a need for research to improve treatment selection.

Advances are being made in genetics – with more than 80 different genes now identified as being related to psoriasis – and in medical informatics – which allow thousands of patients to be followed for years, he said, noting that this could elucidate immunopathological features that can improve treatments, predict and prevent comorbidity, and further improve outcomes.

“We also need care that is more patient centered,” he said, describing the ongoing pragmatic LITE trial of home- or office-based phototherapy for which he is the lead investigator, and other studies that he hopes will expand access to care.

Kenneth Brian Gordon, MD, chair and professor of dermatology at the Medical College of Wisconsin, Milwaukee, whose career started in the basic science immunology arena, added the need for expanding benefit to patients with more-moderate disease. Like Dr. Menter, he identified psoriasis as the area in medicine that has had the greatest degree of advancement, except perhaps for hepatitis C.

He described the process not as a “bench-to-bedside” story, but as a bedside-to-bench, then “back-to-bedside” story.

It was really about taking those early T-cell–targeted biologics and anti-TNF agents from bedside to bench with the realization of the importance of the IL-23 and IL-17 pathways, and that understanding led back to the bedside with the development of the newest agents – and to a “huge difference in patient’s lives.”

“But we’ve gotten so good at treating patients with severe disease ... the question now is how to take care of those with more-moderate disease,” he said, noting that a focus on cost and better delivery systems will be needed for that population.

That research is underway, and the future looks bright – and clear.
 

“I think with psoriasis therapy and where we’ve come in the last 20 years ... we have a hard time remembering what it was like before we had biologic agents” he said. “Our perspective has changed a lot, and sometimes we forget that.”

In fact, “psoriasis has sort of dragged dermatology into the world of modern clinical trial science, and we can now apply that to all sorts of other diseases,” he said. “The psoriasis trials were the first really well-done large-scale trials in dermatology, and I think that has given dermatology a real leg up in how we do clinical research and how we do evidence-based medicine.”

All of the doctors interviewed for this story have received funds and/or honoraria from, consulted with, are employed with, or served on the advisory boards of manufacturers of biologics. Dr. Gelfand is a copatent holder of resiquimod for treatment of cutaneous T-cell lymphoma and is deputy editor of the Journal of Investigative Dermatology.

[email protected]
 

Imagine a patient suffering with horrible psoriasis for decades having failed “every available treatment.” Imagine him living all that time with “flaking, cracking, painful, itchy skin,” only to develop cirrhosis after exposure to toxic therapies.

Then imagine the experience for that patient when, 2 weeks after initiating treatment with a new interleukin-17 inhibitor, his skin clears completely.

“Two weeks later it’s all gone – it was a moment to behold,” said Joel M. Gelfand, MD, professor of dermatology and epidemiology at the University of Pennsylvania, Philadelphia, who had cared for the man for many years before a psoriasis treatment revolution of sorts took the field of dermatology by storm.

“The progress has been breathtaking – there’s no other way to describe it – and it feels like a miracle every time I see a new patient who has tough disease and I have all these things to offer them,” he continued. “For most patients, I can really help them and make a major difference in their life.”

Much of the progress in psoriasis treatment in the past 50 years unfolded over the past 2 decades, with biologics emerging for psoriasis, said Mark Lebwohl, MD, Waldman professor of dermatology and chair of the Kimberly and Eric J. Waldman department of dermatology at the Icahn School of Medicine at Mount Sinai, New York.

Dr. Lebwohl recounted some of his own experiences with psoriasis patients before the advent of treatments – particularly biologics – that have transformed practice.

There was a time when psoriasis patients had little more to turn to than the effective – but “disgusting” – Goeckerman Regimen involving cycles of UVB light exposure and topical crude coal tar application. Initially, the regimen, which was introduced in the 1920s, was used around the clock on an inpatient basis until the skin cleared, Dr. Lebwohl said.

In the 1970s, the immunosuppressive chemotherapy drug methotrexate became the first oral systemic therapy approved for severe psoriasis. For those with disabling disease, it offered some hope for relief, but only about 40% of patients achieved at least a 75% reduction in the Psoriasis Area and Severity Index score (PASI 75), he said, adding that they did so at the expense of the liver and bone marrow. “But it was the only thing we had for severe psoriasis other than light treatments.”

In the 1980s and 1990s, oral retinoids emerged as a treatment for psoriasis, and the immunosuppressive drug cyclosporine used to prevent organ rejection in some transplant patients was found to clear psoriasis in affected transplant recipients. Although they brought relief to some patients with severe, disabling disease, these also came with a high price. “It’s not that effective, and it has lots of side effects ... and causes kidney damage in essentially 100% of patients,” Dr. Lebwohl said of cyclosporine.

“So we had treatments that worked, but because the side effects were sufficiently severe, a lot of patients were not treated,” he said.

Enter the biologics era

The early 2000s brought the first two approvals for psoriasis: alefacept (Amevive), a “modestly effective, but quite safe” immunosuppressive dimeric fusion protein approved in early 2003 for moderate to severe plaque psoriasis, and efalizumab (Raptiva), a recombinant humanized monoclonal antibody approved in October 2003; both were T-cell–targeted therapies. The former was withdrawn from the market voluntarily as newer agents became available, and the latter was withdrawn in 2009 because of a link with development of progressive multifocal leukoencephalopathy.

Tumor necrosis factor (TNF) blockers, which had been used effectively for RA and Crohn’s disease, emerged next, and were highly effective, much safer than the systemic treatments, and gained “very widespread use,” Dr. Lebwohl said.

Alan Menter, MD, chairman of the division of dermatology at Baylor University Medical Center, Dallas, also a prolific researcher – and chair of the guidelines committee that published two new sets of guidelines for psoriasis treatment in 2019 – said that the field of dermatology was “late to the biologic evolution,” as many of the early biologics were first approved for PsA.

“But over the last 10 years, things have changed dramatically,” he said. “After that we suddenly leapt ahead of everybody. ... We now have 11 biologic drugs approved for psoriasis, which is more than any other disease has available.”

It’s been “highly exciting” to see this “evolution and revolution,” he commented, adding that one of the next challenges is to address the comorbidities, such as cardiovascular disease, associated with psoriasis.

“The big question now ... is if you improve skin and you improve joints, can you potentially reduce the risk of coronary artery disease,” he said. “Everybody is looking at that, and to me it’s one of the most exciting things that we’re doing.”

Work is ongoing to look at whether the IL-17s and IL-23s have “other indications outside of the skin and joints,” both within and outside of dermatology.

Like Dr. Gottlieb, Dr. Menter also mentioned the potential for hidradenitis suppurativa, and also for a condition that is rarely discussed or studied: genital psoriasis. Ixekizumab has recently been shown to work in about 75% of patients with genital psoriasis, he noted.

Another important area of research is the identification of biomarkers for predicting response and relapse, he said. For now, biomarker research has disappointed, he added, predicting that it will take at least 3-5 years before biomarkers to help guide treatment are identified.

Indeed, Dr. Gelfand, who also is director of the Psoriasis and Phototherapy Treatment Center, vice chair of clinical research, and medical director of the dermatology clinical studies unit at the University of Pennsylvania, agreed there is a need for research to improve treatment selection.

Advances are being made in genetics – with more than 80 different genes now identified as being related to psoriasis – and in medical informatics – which allow thousands of patients to be followed for years, he said, noting that this could elucidate immunopathological features that can improve treatments, predict and prevent comorbidity, and further improve outcomes.

“We also need care that is more patient centered,” he said, describing the ongoing pragmatic LITE trial of home- or office-based phototherapy for which he is the lead investigator, and other studies that he hopes will expand access to care.

Kenneth Brian Gordon, MD, chair and professor of dermatology at the Medical College of Wisconsin, Milwaukee, whose career started in the basic science immunology arena, added the need for expanding benefit to patients with more-moderate disease. Like Dr. Menter, he identified psoriasis as the area in medicine that has had the greatest degree of advancement, except perhaps for hepatitis C.

He described the process not as a “bench-to-bedside” story, but as a bedside-to-bench, then “back-to-bedside” story.

It was really about taking those early T-cell–targeted biologics and anti-TNF agents from bedside to bench with the realization of the importance of the IL-23 and IL-17 pathways, and that understanding led back to the bedside with the development of the newest agents – and to a “huge difference in patient’s lives.”

“But we’ve gotten so good at treating patients with severe disease ... the question now is how to take care of those with more-moderate disease,” he said, noting that a focus on cost and better delivery systems will be needed for that population.

That research is underway, and the future looks bright – and clear.
 

“I think with psoriasis therapy and where we’ve come in the last 20 years ... we have a hard time remembering what it was like before we had biologic agents” he said. “Our perspective has changed a lot, and sometimes we forget that.”

In fact, “psoriasis has sort of dragged dermatology into the world of modern clinical trial science, and we can now apply that to all sorts of other diseases,” he said. “The psoriasis trials were the first really well-done large-scale trials in dermatology, and I think that has given dermatology a real leg up in how we do clinical research and how we do evidence-based medicine.”

All of the doctors interviewed for this story have received funds and/or honoraria from, consulted with, are employed with, or served on the advisory boards of manufacturers of biologics. Dr. Gelfand is a copatent holder of resiquimod for treatment of cutaneous T-cell lymphoma and is deputy editor of the Journal of Investigative Dermatology.

[email protected]
 

ATLANTA – Psoriasis type and patient age at presentation among patients with psoriatic arthritis predict the timing of arthritis symptom synchronicity, according to findings from the Psoriatic Arthritis Registry of Turkey International Database.

Sharon Worcester/MDedge News

However, in those who develop arthritis symptoms first, age at onset is not predictive of psoriatic arthritis (PsA) symptom synchronicity, Umut Kalyoncu, MD, reported at the annual meeting of the American College of Rheumatology.

Of 1,631 patients from the registry, 1,251 had psoriasis first, 71 had arthritis first, and 309 had synchronous onset, which was defined as the onset of both psoriasis and arthritis symptoms within a 12-month period. The time from skin disease to PsA was 155.6 months, –67.4 months, and 1.8 months, among the groups, respectively, and the mean age at PsA onset was similar, ranging from about 41 to 42 years in those who developed arthritis first, said Dr. Kalyoncu, of the department of rheumatology at Hacettepe University, Ankara, Turkey.

However, the mean age of PsA onset among those who developed psoriasis first was 29.4 years, compared with 46.3 years in those who developed arthritis first.

“So there is a really big difference between psoriasis beginning age,” he said.

PsA types also differed by onset symptoms: Axial involvement was more common with arthritis-first onset at 38.0%, compared with 28.8% for psoriasis first and 27.8% for synchronous onset). Oligoarthritis occurred more often with arthritis-first onset (45.1% vs. 30.7% and 29.4%, respectively), and polyarthritis occurred less often with arthritis-first onset (33.8% vs. 49.4% and 47.6%, respectively), he said.

Psoriasis type also differed among the groups: Pustular skin involvement was more common in arthritis-first patients (18.3% vs. 11.9% and 16.5% of psoriasis-first and synchronous-onset patients), scalp lesions as the initial lesion were more common in psoriasis-first patients (48.3% vs. 35.2% of arthritis-first patients and 39.8% of synchronous-onset patients), and genital involvement was present more often in arthritis-first patients (12.7% vs. 6.2% and 4.9% of psoriasis-first and synchronous-onset patients).

Early-onset (type 1) psoriasis was more common in psoriasis-first patients (74% vs. 28.1% and 51.8% of arthritis-first and synchronous-onset patients), whereas late-onset (type 2) psoriasis was more common in arthritis-first patients (71.9% vs. 26.0% and 48.2% for psoriasis-first and synchronous-onset patients).

A family history of psoriasis or PsA was more common in psoriasis-first patients (35.6% vs. 26.3% and 28.2% of arthritis-first and synchronous-onset patients), Dr. Kalyoncu said.

Treatment types did not differ between the groups.

Multiple linear regression analysis for the time elapsed from psoriasis to PsA symptom synchronicity, with all other independent variables set to baseline values, showed an overall intercept interval of 66 months, but with nail involvement, family history, or plaque psoriasis, the interval was extended by 28, 24, and 20 months, respectively. However, the presence of pustular psoriasis decreased the intercept interval by 28 months.

A temporal relationship between the onset of skin psoriasis and PsA is a well-known feature of psoriatic disease, with prior studies showing that the majority of cases involve psoriasis-first onset, Dr. Kalyoncu said, adding that heterogeneity in musculoskeletal and skin involvement is also a known feature.

However, little is known about the role of genetics, he noted.

Therefore, he and his colleagues used the Psoriatic Arthritis Registry of Turkey International Database, which was established in 2014 and now also includes data from patients in Canada and Italy, to explore the associations between disease characteristics and the temporal relationship of skin and musculoskeletal disease.

Based on the findings, age at the onset of psoriasis was the main factor that determined PsA symptom synchronicity, he said.

“We know that HLA-Cw6 is important in genetic susceptibility of psoriatic arthritis, but it is important only for early-onset arthritis, not late-onset psoriasis,” Dr. Kalyoncu said. “So our results make an indirect contribution [to the understanding of] these genetic and immunochemical differences between early-onset and late-onset psoriasis, and we need further future studies about this topic.”

Dr. Kalyoncu reported having no relevant disclosures.

[email protected]

SOURCE: Kalyoncu U et al. Arthritis Rheumatol. 2019;71(suppl 10), Abstract 2854.

ATLANTA – Psoriasis type and patient age at presentation among patients with psoriatic arthritis predict the timing of arthritis symptom synchronicity, according to findings from the Psoriatic Arthritis Registry of Turkey International Database.

Sharon Worcester/MDedge News

However, in those who develop arthritis symptoms first, age at onset is not predictive of psoriatic arthritis (PsA) symptom synchronicity, Umut Kalyoncu, MD, reported at the annual meeting of the American College of Rheumatology.

Of 1,631 patients from the registry, 1,251 had psoriasis first, 71 had arthritis first, and 309 had synchronous onset, which was defined as the onset of both psoriasis and arthritis symptoms within a 12-month period. The time from skin disease to PsA was 155.6 months, –67.4 months, and 1.8 months, among the groups, respectively, and the mean age at PsA onset was similar, ranging from about 41 to 42 years in those who developed arthritis first, said Dr. Kalyoncu, of the department of rheumatology at Hacettepe University, Ankara, Turkey.

However, the mean age of PsA onset among those who developed psoriasis first was 29.4 years, compared with 46.3 years in those who developed arthritis first.

“So there is a really big difference between psoriasis beginning age,” he said.

PsA types also differed by onset symptoms: Axial involvement was more common with arthritis-first onset at 38.0%, compared with 28.8% for psoriasis first and 27.8% for synchronous onset). Oligoarthritis occurred more often with arthritis-first onset (45.1% vs. 30.7% and 29.4%, respectively), and polyarthritis occurred less often with arthritis-first onset (33.8% vs. 49.4% and 47.6%, respectively), he said.

Psoriasis type also differed among the groups: Pustular skin involvement was more common in arthritis-first patients (18.3% vs. 11.9% and 16.5% of psoriasis-first and synchronous-onset patients), scalp lesions as the initial lesion were more common in psoriasis-first patients (48.3% vs. 35.2% of arthritis-first patients and 39.8% of synchronous-onset patients), and genital involvement was present more often in arthritis-first patients (12.7% vs. 6.2% and 4.9% of psoriasis-first and synchronous-onset patients).

Early-onset (type 1) psoriasis was more common in psoriasis-first patients (74% vs. 28.1% and 51.8% of arthritis-first and synchronous-onset patients), whereas late-onset (type 2) psoriasis was more common in arthritis-first patients (71.9% vs. 26.0% and 48.2% for psoriasis-first and synchronous-onset patients).

A family history of psoriasis or PsA was more common in psoriasis-first patients (35.6% vs. 26.3% and 28.2% of arthritis-first and synchronous-onset patients), Dr. Kalyoncu said.

Treatment types did not differ between the groups.

Multiple linear regression analysis for the time elapsed from psoriasis to PsA symptom synchronicity, with all other independent variables set to baseline values, showed an overall intercept interval of 66 months, but with nail involvement, family history, or plaque psoriasis, the interval was extended by 28, 24, and 20 months, respectively. However, the presence of pustular psoriasis decreased the intercept interval by 28 months.

A temporal relationship between the onset of skin psoriasis and PsA is a well-known feature of psoriatic disease, with prior studies showing that the majority of cases involve psoriasis-first onset, Dr. Kalyoncu said, adding that heterogeneity in musculoskeletal and skin involvement is also a known feature.

However, little is known about the role of genetics, he noted.

Therefore, he and his colleagues used the Psoriatic Arthritis Registry of Turkey International Database, which was established in 2014 and now also includes data from patients in Canada and Italy, to explore the associations between disease characteristics and the temporal relationship of skin and musculoskeletal disease.

Based on the findings, age at the onset of psoriasis was the main factor that determined PsA symptom synchronicity, he said.

“We know that HLA-Cw6 is important in genetic susceptibility of psoriatic arthritis, but it is important only for early-onset arthritis, not late-onset psoriasis,” Dr. Kalyoncu said. “So our results make an indirect contribution [to the understanding of] these genetic and immunochemical differences between early-onset and late-onset psoriasis, and we need further future studies about this topic.”

Dr. Kalyoncu reported having no relevant disclosures.

[email protected]

SOURCE: Kalyoncu U et al. Arthritis Rheumatol. 2019;71(suppl 10), Abstract 2854.

ATLANTA – Psoriasis type and patient age at presentation among patients with psoriatic arthritis predict the timing of arthritis symptom synchronicity, according to findings from the Psoriatic Arthritis Registry of Turkey International Database.

Sharon Worcester/MDedge News

However, in those who develop arthritis symptoms first, age at onset is not predictive of psoriatic arthritis (PsA) symptom synchronicity, Umut Kalyoncu, MD, reported at the annual meeting of the American College of Rheumatology.

Of 1,631 patients from the registry, 1,251 had psoriasis first, 71 had arthritis first, and 309 had synchronous onset, which was defined as the onset of both psoriasis and arthritis symptoms within a 12-month period. The time from skin disease to PsA was 155.6 months, –67.4 months, and 1.8 months, among the groups, respectively, and the mean age at PsA onset was similar, ranging from about 41 to 42 years in those who developed arthritis first, said Dr. Kalyoncu, of the department of rheumatology at Hacettepe University, Ankara, Turkey.

However, the mean age of PsA onset among those who developed psoriasis first was 29.4 years, compared with 46.3 years in those who developed arthritis first.

“So there is a really big difference between psoriasis beginning age,” he said.

PsA types also differed by onset symptoms: Axial involvement was more common with arthritis-first onset at 38.0%, compared with 28.8% for psoriasis first and 27.8% for synchronous onset). Oligoarthritis occurred more often with arthritis-first onset (45.1% vs. 30.7% and 29.4%, respectively), and polyarthritis occurred less often with arthritis-first onset (33.8% vs. 49.4% and 47.6%, respectively), he said.

Psoriasis type also differed among the groups: Pustular skin involvement was more common in arthritis-first patients (18.3% vs. 11.9% and 16.5% of psoriasis-first and synchronous-onset patients), scalp lesions as the initial lesion were more common in psoriasis-first patients (48.3% vs. 35.2% of arthritis-first patients and 39.8% of synchronous-onset patients), and genital involvement was present more often in arthritis-first patients (12.7% vs. 6.2% and 4.9% of psoriasis-first and synchronous-onset patients).

Early-onset (type 1) psoriasis was more common in psoriasis-first patients (74% vs. 28.1% and 51.8% of arthritis-first and synchronous-onset patients), whereas late-onset (type 2) psoriasis was more common in arthritis-first patients (71.9% vs. 26.0% and 48.2% for psoriasis-first and synchronous-onset patients).

A family history of psoriasis or PsA was more common in psoriasis-first patients (35.6% vs. 26.3% and 28.2% of arthritis-first and synchronous-onset patients), Dr. Kalyoncu said.

Treatment types did not differ between the groups.

Multiple linear regression analysis for the time elapsed from psoriasis to PsA symptom synchronicity, with all other independent variables set to baseline values, showed an overall intercept interval of 66 months, but with nail involvement, family history, or plaque psoriasis, the interval was extended by 28, 24, and 20 months, respectively. However, the presence of pustular psoriasis decreased the intercept interval by 28 months.

A temporal relationship between the onset of skin psoriasis and PsA is a well-known feature of psoriatic disease, with prior studies showing that the majority of cases involve psoriasis-first onset, Dr. Kalyoncu said, adding that heterogeneity in musculoskeletal and skin involvement is also a known feature.

However, little is known about the role of genetics, he noted.

Therefore, he and his colleagues used the Psoriatic Arthritis Registry of Turkey International Database, which was established in 2014 and now also includes data from patients in Canada and Italy, to explore the associations between disease characteristics and the temporal relationship of skin and musculoskeletal disease.

Based on the findings, age at the onset of psoriasis was the main factor that determined PsA symptom synchronicity, he said.

“We know that HLA-Cw6 is important in genetic susceptibility of psoriatic arthritis, but it is important only for early-onset arthritis, not late-onset psoriasis,” Dr. Kalyoncu said. “So our results make an indirect contribution [to the understanding of] these genetic and immunochemical differences between early-onset and late-onset psoriasis, and we need further future studies about this topic.”

Dr. Kalyoncu reported having no relevant disclosures.

[email protected]

SOURCE: Kalyoncu U et al. Arthritis Rheumatol. 2019;71(suppl 10), Abstract 2854.

Low-dose naltrexone (LDN) has shown efficacy in off-label treatment of a variety of inflammatory diseases ranging from Crohn disease to multiple sclerosis.¹ There are limited data about the use of LDN in dermatology, but reports regarding how it works as an anti-inflammatory agent have been published.^1,2

Naltrexone is an opioid receptor antagonist that originally was approved by the US Food and Drug Administration to treat addiction to alcohol, opiates, and heroin.² The dose of naltrexone to treat addiction ranges from 50 to 100 mg/d, and at these levels the effects of opioids are blocked for 24 hours; however, the dosing for LDN is much lower, ranging from 1.5 to 4.5 mg/d.³ At this low dose, naltrexone partially binds to various opioid receptors, leading to a temporary blockade.⁴ One of the downstream effects of this opioid receptor blockade is a paradoxical increase in endogenous endorphins.³

In addition to opioid blockage, lower doses of naltrexone have anti-inflammatory effects by inhibiting nonopioid receptors. Naltrexone blocks toll-like receptor 4, which is found on keratinocytes and also on macrophages such as microglia.⁵ These macrophages also contain inflammatory compounds such as tumor necrosis factor α and IL-6. Low-dose naltrexone can suppress levels of these inflammatory markers. It is important to note that these anti-inflammatory effects have not been observed at the standard higher doses of naltrexone.¹

When to Use

Low-dose naltrexone is a treatment option for inflammatory dermatologic conditions. A recent review of the literature outlined the use of LDN in a variety of inflammatory skin conditions. Improvement was noted in patients with Hailey-Hailey disease, lichen planopilaris, and various types of pruritus (ie, aquagenic, cholestatic, uremic, atopic dermatitis related).³ A case report of LDN successfully treating a patient with psoriasis also has been published.⁶ We often use LDN at the University of Wisconsin (Madison, Wisconsin) to treat patients with psoriasis. Ekelem et al³ also discussed patients with skin conditions that either had no response or worsened with naltrexone treatment, including various types of pruritus (ie, uremic, mycosis fungoides related, other causes of pruritus). Importantly, in the majority of cases without an improved response, the dose used was 50 mg/d.³ Higher doses of naltrexone are not known to have anti-inflammatory effects.

Low-dose naltrexone can be considered as a treatment option in patients with contraindications to other systemic anti-inflammatory treatments; for example, patients with a history of malignancy may prefer to avoid treatment with biologic agents. Low-dose naltrexone also can be considered as a treatment option in patients who are uncomfortable with the side-effect profiles of other systemic anti-inflammatory treatments, such as the risk for leukemias and lymphomas associated with biologic agents, the risk for liver toxicity with methotrexate, or the risk for hyperlipidemia with acitretin.

How to Monitor

The following monitoring information is adapted from the practice of Apple Bodemer, MD, a board-certified dermatologist at the University of Wisconsin (Madison, Wisconsin) who also is fellowship trained in integrative medicine.

There is a paucity of published data about LDN dosing for inflammatory skin diseases. However, prescribers should be aware that LDN can alter thyroid hormone levels, especially in patients with autoimmune thyroid disease. If a thyroid-stimulating hormone (TSH) level within reference range has not been noted in the last year, consider screening with a TSH test and also assessing for a personal or family history of thyroid disease. If the TSH level is within reference range, there generally is no need to monitor while treating with LDN. Consider checking TSH levels every 4 months in patients with thyroid disease while they are on LDN therapy and be sure to educate them about symptoms of hyperthyroidism.

Side Effects

Low-dose naltrexone has a minimal side-effect profile with self-limited side effects that often resolve within approximately 1 week. One of the most commonly reported side effects is sleep disturbance with vivid dreams, which has been reported in 37% of participants.¹ If your patients experience this side effect, you can reassure them that it improves with time. You also can switch to morning dosing to try and alleviate sleep disturbances at night. Another possible side effect is gastrointestinal tract upset. Importantly, there is no known abuse potential for LDN.¹ To stop LDN, patients should be stable for 6 to 12 months, and there is no need to wean them off it.

Cost and Availability

Because use of LDN in dermatology is considered off label and it is not approved by the US Food and Drug Administration to treat any medical conditions, it must be prescribed through a compounding pharmacy, usually without insurance coverage. The monthly cost is approximately $30 depending on the pharmacy (unpublished data), which may be cost prohibitive for patients, so it is important to counsel them about price before starting treatment.

Final Thoughts

Low-dose naltrexone is an alternative treatment option that can be considered in patients with inflammatory skin diseases. It has a favorable side-effect profile, especially compared to other systemic anti-inflammatory agents; however, additional studies are needed to learn more about its safety and efficacy. If patients ask you about LDN, the information provided here can guide you with how it works and how to prescribe it.

Low-dose naltrexone (LDN) has shown efficacy in off-label treatment of a variety of inflammatory diseases ranging from Crohn disease to multiple sclerosis.¹ There are limited data about the use of LDN in dermatology, but reports regarding how it works as an anti-inflammatory agent have been published.^1,2

Naltrexone is an opioid receptor antagonist that originally was approved by the US Food and Drug Administration to treat addiction to alcohol, opiates, and heroin.² The dose of naltrexone to treat addiction ranges from 50 to 100 mg/d, and at these levels the effects of opioids are blocked for 24 hours; however, the dosing for LDN is much lower, ranging from 1.5 to 4.5 mg/d.³ At this low dose, naltrexone partially binds to various opioid receptors, leading to a temporary blockade.⁴ One of the downstream effects of this opioid receptor blockade is a paradoxical increase in endogenous endorphins.³

In addition to opioid blockage, lower doses of naltrexone have anti-inflammatory effects by inhibiting nonopioid receptors. Naltrexone blocks toll-like receptor 4, which is found on keratinocytes and also on macrophages such as microglia.⁵ These macrophages also contain inflammatory compounds such as tumor necrosis factor α and IL-6. Low-dose naltrexone can suppress levels of these inflammatory markers. It is important to note that these anti-inflammatory effects have not been observed at the standard higher doses of naltrexone.¹

When to Use

Low-dose naltrexone is a treatment option for inflammatory dermatologic conditions. A recent review of the literature outlined the use of LDN in a variety of inflammatory skin conditions. Improvement was noted in patients with Hailey-Hailey disease, lichen planopilaris, and various types of pruritus (ie, aquagenic, cholestatic, uremic, atopic dermatitis related).³ A case report of LDN successfully treating a patient with psoriasis also has been published.⁶ We often use LDN at the University of Wisconsin (Madison, Wisconsin) to treat patients with psoriasis. Ekelem et al³ also discussed patients with skin conditions that either had no response or worsened with naltrexone treatment, including various types of pruritus (ie, uremic, mycosis fungoides related, other causes of pruritus). Importantly, in the majority of cases without an improved response, the dose used was 50 mg/d.³ Higher doses of naltrexone are not known to have anti-inflammatory effects.

Low-dose naltrexone can be considered as a treatment option in patients with contraindications to other systemic anti-inflammatory treatments; for example, patients with a history of malignancy may prefer to avoid treatment with biologic agents. Low-dose naltrexone also can be considered as a treatment option in patients who are uncomfortable with the side-effect profiles of other systemic anti-inflammatory treatments, such as the risk for leukemias and lymphomas associated with biologic agents, the risk for liver toxicity with methotrexate, or the risk for hyperlipidemia with acitretin.

How to Monitor

The following monitoring information is adapted from the practice of Apple Bodemer, MD, a board-certified dermatologist at the University of Wisconsin (Madison, Wisconsin) who also is fellowship trained in integrative medicine.

There is a paucity of published data about LDN dosing for inflammatory skin diseases. However, prescribers should be aware that LDN can alter thyroid hormone levels, especially in patients with autoimmune thyroid disease. If a thyroid-stimulating hormone (TSH) level within reference range has not been noted in the last year, consider screening with a TSH test and also assessing for a personal or family history of thyroid disease. If the TSH level is within reference range, there generally is no need to monitor while treating with LDN. Consider checking TSH levels every 4 months in patients with thyroid disease while they are on LDN therapy and be sure to educate them about symptoms of hyperthyroidism.

Side Effects

Low-dose naltrexone has a minimal side-effect profile with self-limited side effects that often resolve within approximately 1 week. One of the most commonly reported side effects is sleep disturbance with vivid dreams, which has been reported in 37% of participants.¹ If your patients experience this side effect, you can reassure them that it improves with time. You also can switch to morning dosing to try and alleviate sleep disturbances at night. Another possible side effect is gastrointestinal tract upset. Importantly, there is no known abuse potential for LDN.¹ To stop LDN, patients should be stable for 6 to 12 months, and there is no need to wean them off it.

Cost and Availability

Because use of LDN in dermatology is considered off label and it is not approved by the US Food and Drug Administration to treat any medical conditions, it must be prescribed through a compounding pharmacy, usually without insurance coverage. The monthly cost is approximately $30 depending on the pharmacy (unpublished data), which may be cost prohibitive for patients, so it is important to counsel them about price before starting treatment.

Final Thoughts

Low-dose naltrexone is an alternative treatment option that can be considered in patients with inflammatory skin diseases. It has a favorable side-effect profile, especially compared to other systemic anti-inflammatory agents; however, additional studies are needed to learn more about its safety and efficacy. If patients ask you about LDN, the information provided here can guide you with how it works and how to prescribe it.

Low-dose naltrexone (LDN) has shown efficacy in off-label treatment of a variety of inflammatory diseases ranging from Crohn disease to multiple sclerosis.¹ There are limited data about the use of LDN in dermatology, but reports regarding how it works as an anti-inflammatory agent have been published.^1,2

Naltrexone is an opioid receptor antagonist that originally was approved by the US Food and Drug Administration to treat addiction to alcohol, opiates, and heroin.² The dose of naltrexone to treat addiction ranges from 50 to 100 mg/d, and at these levels the effects of opioids are blocked for 24 hours; however, the dosing for LDN is much lower, ranging from 1.5 to 4.5 mg/d.³ At this low dose, naltrexone partially binds to various opioid receptors, leading to a temporary blockade.⁴ One of the downstream effects of this opioid receptor blockade is a paradoxical increase in endogenous endorphins.³

In addition to opioid blockage, lower doses of naltrexone have anti-inflammatory effects by inhibiting nonopioid receptors. Naltrexone blocks toll-like receptor 4, which is found on keratinocytes and also on macrophages such as microglia.⁵ These macrophages also contain inflammatory compounds such as tumor necrosis factor α and IL-6. Low-dose naltrexone can suppress levels of these inflammatory markers. It is important to note that these anti-inflammatory effects have not been observed at the standard higher doses of naltrexone.¹

When to Use

Low-dose naltrexone is a treatment option for inflammatory dermatologic conditions. A recent review of the literature outlined the use of LDN in a variety of inflammatory skin conditions. Improvement was noted in patients with Hailey-Hailey disease, lichen planopilaris, and various types of pruritus (ie, aquagenic, cholestatic, uremic, atopic dermatitis related).³ A case report of LDN successfully treating a patient with psoriasis also has been published.⁶ We often use LDN at the University of Wisconsin (Madison, Wisconsin) to treat patients with psoriasis. Ekelem et al³ also discussed patients with skin conditions that either had no response or worsened with naltrexone treatment, including various types of pruritus (ie, uremic, mycosis fungoides related, other causes of pruritus). Importantly, in the majority of cases without an improved response, the dose used was 50 mg/d.³ Higher doses of naltrexone are not known to have anti-inflammatory effects.

Low-dose naltrexone can be considered as a treatment option in patients with contraindications to other systemic anti-inflammatory treatments; for example, patients with a history of malignancy may prefer to avoid treatment with biologic agents. Low-dose naltrexone also can be considered as a treatment option in patients who are uncomfortable with the side-effect profiles of other systemic anti-inflammatory treatments, such as the risk for leukemias and lymphomas associated with biologic agents, the risk for liver toxicity with methotrexate, or the risk for hyperlipidemia with acitretin.

How to Monitor

The following monitoring information is adapted from the practice of Apple Bodemer, MD, a board-certified dermatologist at the University of Wisconsin (Madison, Wisconsin) who also is fellowship trained in integrative medicine.

There is a paucity of published data about LDN dosing for inflammatory skin diseases. However, prescribers should be aware that LDN can alter thyroid hormone levels, especially in patients with autoimmune thyroid disease. If a thyroid-stimulating hormone (TSH) level within reference range has not been noted in the last year, consider screening with a TSH test and also assessing for a personal or family history of thyroid disease. If the TSH level is within reference range, there generally is no need to monitor while treating with LDN. Consider checking TSH levels every 4 months in patients with thyroid disease while they are on LDN therapy and be sure to educate them about symptoms of hyperthyroidism.

Side Effects

Low-dose naltrexone has a minimal side-effect profile with self-limited side effects that often resolve within approximately 1 week. One of the most commonly reported side effects is sleep disturbance with vivid dreams, which has been reported in 37% of participants.¹ If your patients experience this side effect, you can reassure them that it improves with time. You also can switch to morning dosing to try and alleviate sleep disturbances at night. Another possible side effect is gastrointestinal tract upset. Importantly, there is no known abuse potential for LDN.¹ To stop LDN, patients should be stable for 6 to 12 months, and there is no need to wean them off it.

Cost and Availability

Because use of LDN in dermatology is considered off label and it is not approved by the US Food and Drug Administration to treat any medical conditions, it must be prescribed through a compounding pharmacy, usually without insurance coverage. The monthly cost is approximately $30 depending on the pharmacy (unpublished data), which may be cost prohibitive for patients, so it is important to counsel them about price before starting treatment.

Final Thoughts

Low-dose naltrexone is an alternative treatment option that can be considered in patients with inflammatory skin diseases. It has a favorable side-effect profile, especially compared to other systemic anti-inflammatory agents; however, additional studies are needed to learn more about its safety and efficacy. If patients ask you about LDN, the information provided here can guide you with how it works and how to prescribe it.

MADRID – Renowned dermatologic clinical trialist Kim A. Papp, MD, PhD, is known to pick his words carefully, and the word he uses to describe the quality of life improvement documented in psoriasis patients treated with the novel investigational humanized monoclonal antibody bimekizumab is “phenomenal.”

Bruce Jancin/MDedge News

Dr. Papp was lead investigator in the previously reported phase 2b multicenter BE ABLE 1 trial, in which 250 patients with moderate to severe chronic plaque psoriasis were randomized double-blind to various doses of bimekizumab or placebo every 4 weeks for 12 weeks (J Am Acad Dermatol. 2018 Aug;79[2]:277-86.e10. doi: 10.1016/j.jaad.2018.03.037). He was also lead investigator in the 48-week phase 2b BE ABLE 2 extension study. He presented the 60-week quality-of-life BE ABLE 2 results for the first time at the annual congress of the European Academy of Dermatology and Venereology.

“Small numbers, but the results are nonetheless very compelling,” said Dr. Papp, president and founder of Probity Medical Research in Waterloo, Ont.

Bimekizumab is unique in that it selectively neutralizes both interleukin-17A and -17F, two closely related proinflammatory cytokines which, when upregulated, synergize with other proinflammatory cytokines to drive psoriasis and other immune-mediated inflammatory diseases. In contrast, secukinumab (Cosentyx) and ixekizumab (Taltz) specifically inhibit only IL-17A, and brodalumab (Siliq) targets the IL-17 receptor A. The bimekizumab clinical trials program – a work in progress – aims to demonstrate that dual neutralization of IL-17A and -17F provides a more complete therapeutic approach in psoriasis, with greater efficacy and fewer safety concerns than with current biologics, the dermatologist explained.

In BE ABLE 1, the primary endpoint of at least a 90% reduction in Psoriasis Area and Severity Index (PASI90) response was achieved at week 12 in 46%-79% of patients randomized to bimekizumab in dose-dependent fashion. Those PASI90 responses were maintained with additional treatment out to week 60 in BE ABLE 2 in 80%-100% of patients.

Dr. Papp’s focus at EADV 2019 was on the quality-of-life improvement achieved in bimekizumab-treated patients, a benefit not captured by PASI scores. For this purpose, he and coinvestigators turned to the Dermatology Life Quality Index (DLQI), measured in structured fashion every 4 weeks out to week 60.

“We often forget that even though we’re looking at the patient from the outside, what’s really important is how well they respond to our treatments internally. The DLQI is not a perfect tool, but it’s the best tool we have available. It gives us a fairly good survey of the various domains that affect patients’ day-to-day living,” he said.

In BE ABLE 1, the proportion of week-12 PASI90 responders achieving a DLQI of 0 or 1 – indicative of essentially no disease impact on quality of life – increased rapidly up until week 8. At week 12, 70%-100% of the PASI90 responders in the various treatment arms had a DLQI of 0 or 1. This quality-of-life improvement, like the PASI90 response, proved durable: When the week-12 PASI90 responders were assessed at week 60 in BE ABLE 2, 76%-93% of them had a DLQI of 0 or 1.

The improvements in quality of life correlated with clinical response. BE ABLE enrollees had an average PASI score of 19 at baseline. Overall, 79% of those with an absolute PASI score of 0 at week 12 had a DLQI of 0 or 1 at that time, as did 95% of those with a PASI of 0 at week 60. A PASI of 1 was associated with a 77% likelihood of a DLQI of 0 or 1 at week 12 and an 82% rate at week 60. In contrast, patients with an absolute PASI of 2-4 at week 12 had a 46% rate of DLQI 0/1, and those with a PASI 2-4 at week 60 had a 50% chance of having a DLQI of 0/1.

Phase 3 clinical trials of bimekizumab totaling several thousand psoriasis patients are ongoing.

The BE ABLE trials were sponsored by UCB Pharma. Dr. Papp reported serving as a consultant to and/or recipient of research grants from UCB and dozens of other pharmaceutical companies.

[email protected]

SOURCE: Papp KA. EADV 2019 Abstract FC02.02.

MADRID – Renowned dermatologic clinical trialist Kim A. Papp, MD, PhD, is known to pick his words carefully, and the word he uses to describe the quality of life improvement documented in psoriasis patients treated with the novel investigational humanized monoclonal antibody bimekizumab is “phenomenal.”

Bruce Jancin/MDedge News

Dr. Papp was lead investigator in the previously reported phase 2b multicenter BE ABLE 1 trial, in which 250 patients with moderate to severe chronic plaque psoriasis were randomized double-blind to various doses of bimekizumab or placebo every 4 weeks for 12 weeks (J Am Acad Dermatol. 2018 Aug;79[2]:277-86.e10. doi: 10.1016/j.jaad.2018.03.037). He was also lead investigator in the 48-week phase 2b BE ABLE 2 extension study. He presented the 60-week quality-of-life BE ABLE 2 results for the first time at the annual congress of the European Academy of Dermatology and Venereology.

“Small numbers, but the results are nonetheless very compelling,” said Dr. Papp, president and founder of Probity Medical Research in Waterloo, Ont.

Bimekizumab is unique in that it selectively neutralizes both interleukin-17A and -17F, two closely related proinflammatory cytokines which, when upregulated, synergize with other proinflammatory cytokines to drive psoriasis and other immune-mediated inflammatory diseases. In contrast, secukinumab (Cosentyx) and ixekizumab (Taltz) specifically inhibit only IL-17A, and brodalumab (Siliq) targets the IL-17 receptor A. The bimekizumab clinical trials program – a work in progress – aims to demonstrate that dual neutralization of IL-17A and -17F provides a more complete therapeutic approach in psoriasis, with greater efficacy and fewer safety concerns than with current biologics, the dermatologist explained.

In BE ABLE 1, the primary endpoint of at least a 90% reduction in Psoriasis Area and Severity Index (PASI90) response was achieved at week 12 in 46%-79% of patients randomized to bimekizumab in dose-dependent fashion. Those PASI90 responses were maintained with additional treatment out to week 60 in BE ABLE 2 in 80%-100% of patients.

Dr. Papp’s focus at EADV 2019 was on the quality-of-life improvement achieved in bimekizumab-treated patients, a benefit not captured by PASI scores. For this purpose, he and coinvestigators turned to the Dermatology Life Quality Index (DLQI), measured in structured fashion every 4 weeks out to week 60.

“We often forget that even though we’re looking at the patient from the outside, what’s really important is how well they respond to our treatments internally. The DLQI is not a perfect tool, but it’s the best tool we have available. It gives us a fairly good survey of the various domains that affect patients’ day-to-day living,” he said.

In BE ABLE 1, the proportion of week-12 PASI90 responders achieving a DLQI of 0 or 1 – indicative of essentially no disease impact on quality of life – increased rapidly up until week 8. At week 12, 70%-100% of the PASI90 responders in the various treatment arms had a DLQI of 0 or 1. This quality-of-life improvement, like the PASI90 response, proved durable: When the week-12 PASI90 responders were assessed at week 60 in BE ABLE 2, 76%-93% of them had a DLQI of 0 or 1.

The improvements in quality of life correlated with clinical response. BE ABLE enrollees had an average PASI score of 19 at baseline. Overall, 79% of those with an absolute PASI score of 0 at week 12 had a DLQI of 0 or 1 at that time, as did 95% of those with a PASI of 0 at week 60. A PASI of 1 was associated with a 77% likelihood of a DLQI of 0 or 1 at week 12 and an 82% rate at week 60. In contrast, patients with an absolute PASI of 2-4 at week 12 had a 46% rate of DLQI 0/1, and those with a PASI 2-4 at week 60 had a 50% chance of having a DLQI of 0/1.

Phase 3 clinical trials of bimekizumab totaling several thousand psoriasis patients are ongoing.

The BE ABLE trials were sponsored by UCB Pharma. Dr. Papp reported serving as a consultant to and/or recipient of research grants from UCB and dozens of other pharmaceutical companies.

[email protected]

SOURCE: Papp KA. EADV 2019 Abstract FC02.02.

MADRID – Renowned dermatologic clinical trialist Kim A. Papp, MD, PhD, is known to pick his words carefully, and the word he uses to describe the quality of life improvement documented in psoriasis patients treated with the novel investigational humanized monoclonal antibody bimekizumab is “phenomenal.”

Bruce Jancin/MDedge News

Dr. Papp was lead investigator in the previously reported phase 2b multicenter BE ABLE 1 trial, in which 250 patients with moderate to severe chronic plaque psoriasis were randomized double-blind to various doses of bimekizumab or placebo every 4 weeks for 12 weeks (J Am Acad Dermatol. 2018 Aug;79[2]:277-86.e10. doi: 10.1016/j.jaad.2018.03.037). He was also lead investigator in the 48-week phase 2b BE ABLE 2 extension study. He presented the 60-week quality-of-life BE ABLE 2 results for the first time at the annual congress of the European Academy of Dermatology and Venereology.

“Small numbers, but the results are nonetheless very compelling,” said Dr. Papp, president and founder of Probity Medical Research in Waterloo, Ont.

Bimekizumab is unique in that it selectively neutralizes both interleukin-17A and -17F, two closely related proinflammatory cytokines which, when upregulated, synergize with other proinflammatory cytokines to drive psoriasis and other immune-mediated inflammatory diseases. In contrast, secukinumab (Cosentyx) and ixekizumab (Taltz) specifically inhibit only IL-17A, and brodalumab (Siliq) targets the IL-17 receptor A. The bimekizumab clinical trials program – a work in progress – aims to demonstrate that dual neutralization of IL-17A and -17F provides a more complete therapeutic approach in psoriasis, with greater efficacy and fewer safety concerns than with current biologics, the dermatologist explained.

In BE ABLE 1, the primary endpoint of at least a 90% reduction in Psoriasis Area and Severity Index (PASI90) response was achieved at week 12 in 46%-79% of patients randomized to bimekizumab in dose-dependent fashion. Those PASI90 responses were maintained with additional treatment out to week 60 in BE ABLE 2 in 80%-100% of patients.

Dr. Papp’s focus at EADV 2019 was on the quality-of-life improvement achieved in bimekizumab-treated patients, a benefit not captured by PASI scores. For this purpose, he and coinvestigators turned to the Dermatology Life Quality Index (DLQI), measured in structured fashion every 4 weeks out to week 60.

“We often forget that even though we’re looking at the patient from the outside, what’s really important is how well they respond to our treatments internally. The DLQI is not a perfect tool, but it’s the best tool we have available. It gives us a fairly good survey of the various domains that affect patients’ day-to-day living,” he said.

In BE ABLE 1, the proportion of week-12 PASI90 responders achieving a DLQI of 0 or 1 – indicative of essentially no disease impact on quality of life – increased rapidly up until week 8. At week 12, 70%-100% of the PASI90 responders in the various treatment arms had a DLQI of 0 or 1. This quality-of-life improvement, like the PASI90 response, proved durable: When the week-12 PASI90 responders were assessed at week 60 in BE ABLE 2, 76%-93% of them had a DLQI of 0 or 1.

The improvements in quality of life correlated with clinical response. BE ABLE enrollees had an average PASI score of 19 at baseline. Overall, 79% of those with an absolute PASI score of 0 at week 12 had a DLQI of 0 or 1 at that time, as did 95% of those with a PASI of 0 at week 60. A PASI of 1 was associated with a 77% likelihood of a DLQI of 0 or 1 at week 12 and an 82% rate at week 60. In contrast, patients with an absolute PASI of 2-4 at week 12 had a 46% rate of DLQI 0/1, and those with a PASI 2-4 at week 60 had a 50% chance of having a DLQI of 0/1.

Phase 3 clinical trials of bimekizumab totaling several thousand psoriasis patients are ongoing.

The BE ABLE trials were sponsored by UCB Pharma. Dr. Papp reported serving as a consultant to and/or recipient of research grants from UCB and dozens of other pharmaceutical companies.

[email protected]

SOURCE: Papp KA. EADV 2019 Abstract FC02.02.

The ketogenic diet has been therapeutically employed by physicians since the times of Hippocrates, primarily for its effect on the nervous system.¹ The neurologic literature is inundated with the uses of this medicinal diet for applications in the treatment of epilepsy, neurodegenerative disease, malignancy, and enzyme deficiencies, among others.² In recent years, physicians and scientists have moved to study the application of a ketogenic diet in the realms of cardiovascular disease,³ autoimmune disease,⁴ management of diabetes mellitus (DM) and obesity,^3,5 and enhancement of sports and combat performance,⁶ all with promising results. Increased interest in alternative therapies among the lay population and the efficacy purported by many adherents has spurred intrigue by health care professionals. Over the last decade, there has seen a boom in so-called holistic approaches to health; included are the Paleo Diet, Primal Blueprint Diet, Bulletproof Diet, and the ketogenic/low-carbohydrate, high-fat diet. The benefits of ketones in these diets—through intermittent fasting or cyclical ketosis—–for cognitive enhancement, overall well-being, amelioration of chronic disease states, and increased health span have been promulgated to the lay population. But to date, there is a large gap in the literature on the applications of ketones as well as the ketogenic diet in dermatology and skin health and disease.

The aim of this article is not to summarize the uses of ketones and the ketogenic diet in dermatologic applications (because, unfortunately, those studies have not been undertaken) but to provide evidence from all available literature to support the need for targeted research and to encourage dermatologists to investigate ketones and their role in treating skin disease, primarily in an adjunctive manner. In doing so, a clearly medicinal diet may gain a foothold in the disease-treatment repertoire and among health-promoting agents of the dermatologist. Given the amount of capital being spent on health care, there is an ever-increasing need for low-cost, safe, and tolerable treatments that can be used for multiple disease processes and to promote health. We believe the ketogenic diet is such an adjunctive therapeutic option, as it has clearly been proven to be tolerable, safe, and efficacious for many people over the last millennia.

We conducted a PubMed search of articles indexed for MEDLINE using varying combinations of the terms ketones, ketogenic, skin, inflammation, metabolic, oxidation, dermatology, and dermatologic and found 12 articles. Herein, we summarize the relevant articles and the works cited by those articles.

Adverse Effects of the Ketogenic Diet

As with all medical therapies, the ketogenic diet is not without risk of adverse effects, which should be communicated at the outset of this article and with patients in the clinic. The only known absolute contraindications to a ketogenic diet are porphyria and pyruvate carboxylase deficiency secondary to underlying metabolic derangements.⁷ Certain metabolic cytopathies and carnitine deficiency are relative contraindications, and patients with these conditions should be cautiously placed on this diet and closely monitored. Dehydration, acidosis, lethargy, hypoglycemia, dyslipidemia, electrolyte imbalances, prurigo pigmentosa, and gastrointestinal distress may be an acute issue, but these effects are transient and can be managed. Chronic adverse effects are nephrolithiasis (there are recommended screening procedures for those at risk and prophylactic therapies, which is beyond the scope of this article) and weight loss.⁷

NLRP3 Inflammasome Suppression

Youm et al⁸ reported their findings in Nature Medicine that β-hydroxybutyrate, a ketone body that naturally circulates in the human body, specifically suppresses activity of the NLRP3 inflammasome. The NLRP3 inflammasome serves as the activating platform for IL-1β.⁸ Aberrant and elevated IL-1β levels cause or are associated with a number of dermatologic diseases—namely, the autoinflammatory syndromes (familial cold autoinflammatory syndrome, Muckle-Wells syndrome, neonatal-onset multisystemic disease/chronic infantile neurological cutaneous articular syndrome), hyperimmunoglobulinemia D with periodic fever syndrome, tumor necrosis factor–receptor associated periodic syndrome, juvenile idiopathic arthritis, relapsing polychondritis, Schnitzler syndrome, Sweet syndrome, Behçet disease, gout, sunburn and contact hypersensitivity, hidradenitis suppurativa, and metastatic melanoma.⁷ Clearly, the ketogenic diet may be employed in a therapeutic manner (though to what degree, we need further study) for these dermatologic conditions based on the interaction with the NRLP3 inflammasome and IL-1β.

Acne

A link between acne and diet has long been suspected, but a lack of well-controlled studies has caused only speculation to remain. Recent literature suggests that the effects of insulin may be a notable driver of acne through effects on sex hormones and subsequent effects on sebum production and inflammation. Cordain et al⁹ discuss the mechanism by which insulin can worsen acne in a valuable article, which Paoli et al¹⁰ later corroborated. Essentially, insulin propagates acne by 2 known mechanisms. First, an increase in serum insulin causes a rise in insulinlike growth factor 1 levels and a decrease in insulinlike growth factor binding protein 3 levels, which directly influences keratinocyte proliferation and reduces retinoic acid receptor/retinoid X receptor activity in the skin, causing hyperkeratinization and concomitant abnormal desquamation of the follicular epithelium.^9,10 Second, this increase in insulinlike growth factor 1 and insulin causes a decrease in sex hormone–binding globulin and leads to increased androgen production and circulation in the skin, which causes an increase in sebum production. These factors combined with skin that is colonized with Cutibacterium acnes lead to an inflammatory response and the disease known as acne vulgaris.^9,10 A ketogenic diet could help ameliorate acne because it results in very little insulin secretion, unlike the typical Western diet, which causes frequent large spikes in insulin levels. Furthermore, the anti-inflammatory effects of ketones would benefit the inflammatory nature of this disease.

DM and Diabetic Skin Disease

Diabetes mellitus carries with it the risk for skin diseases specific to the diabetic disease process, such as increased risk for bacterial and fungal infections, venous stasis, pruritus (secondary to poor circulation), acanthosis nigricans, diabetic dermopathy, necrobiosis lipoidica diabeticorum, digital sclerosis, and bullosis diabeticorum.¹¹ It is well established that better control of DM results in better disease state outcomes.¹² The ketogenic diet has shown itself to be a formidable and successful treatment in the diseases of carbohydrate intolerance (eg, metabolic syndrome, insulin resistance, type 2 DM) because of several known mechanisms, including less glucose entering the body and thus less fat deposition, end-product glycation, and free-radical production (discussed below); enhanced fat loss and metabolic efficiency; increased insulin sensitivity; and decreased inflammation.¹³ Lowering a patient’s insulin resistance through a ketogenic diet may help prevent or treat diabetic skin disease.

Dermatologic Malignancy

A ketogenic diet has been of interest in oncology research as an adjunctive therapy for several reasons: anti-inflammatory effects, antioxidation effects, possible effects on mammalian target of rapamycin (mTOR) regulation,⁷ and exploitation of the Warburg effect.¹⁴ One article discusses how mTOR, a cell-cycle regulator of particular importance in cancer biology, can be influenced by ketones both directly and indirectly through modulating the inflammatory response.⁷ It has been shown that suppressing mTOR activity limits and slows tumor growth and spread. Ketones also may prove to be a unique method of metabolically exploiting cancer physiology. The Warburg effect, which earned Otto Warburg the Nobel Prize in Physiology or Medicine in 1931, is the observation that cancerous cells produce adenosine triphosphate solely through aerobic glycolysis followed by lactic acid fermentation.¹⁴ This phenomenon is the basis of the positron emission tomography scan. There are several small studies of the effects of ketogenic diets on malignancy, and although none of these studies are of substantial size or control, they show that a ketogenic diet can halt or even reverse tumor growth.¹⁵ The hypothesis is that because cancer cells cannot metabolize ketones (but normal cells can), the Warburg effect can be taken advantage of through a ketogenic diet to aid in the treatment of malignant disease.¹⁴ If further studies find it a formidable treatment, it most certainly would be helpful for the dermatologist involved in the treatment of cutaneous cancers.

Oxidative Stress

Oxidative stress, a state brought about when reactive oxygen species (ROS) production exceeds the antioxidant capacity of the cell and causes damage, is known to be a central part of certain skin diseases (eg, acne, psoriasis, cutaneous malignancy, varicose ulcers, cutaneous allergic reactions, and drug-induced skin photosensitivity).⁷ There are 2 proven mechanisms by which a ketogenic diet can augment the body’s innate antioxidation capacity. First, ketones activate a potent antioxidant upregulating protein known as NRF2, which is bound in cytosol and remains inactive until activated by certain stimuli (ie, ketones).¹⁶ Migration to the nucleus causes transcriptional changes in DNA to upregulate, via a myriad of pathways, antioxidant production in the cell; most notably, it results in increased glutathione levels.¹⁷ NRF2 also targets several genes involved in chronic inflammatory skin diseases that cause an increase in the antioxidant capacity.¹⁸ As an aside, several foods encouraged on a ketogenic diet also activate NRF2 independently of ketones (eg, coffee, broccoli).¹⁹ Second, a ketogenic diet results in fewer produced ROS and an increase in the nicotinamide adenine dinucleotide ratio produced by the mitochondria; in short, it is a more efficient way of producing cellular energy while enhancing mitochondrial function. When fewer ROS are produced, there is less oxidative stress that needs to be attended to by the cell and less cellular damage. Feichtinger et al¹⁹ point out that mitochondrial inefficiency and dysfunction often are overlooked components in several skin diseases, and based on the studies discussed above, these diseases may be aided with a ketogenic diet.

Patient Applications

Clearly, a ketogenic diet is therapeutic, and there are many promising potential roles it may play in the treatment of a wide variety of health and disease states through hormonal normalization, antioxidant effects, anti-inflammatory effects, and improvement of metabolic risk factors. However, there are vast limitations to what is known about the ketogenic diet and how it might be employed, particularly by the dermatologist. First, the ketogenic diet lacks a firm definition. Although processed inflammatory vegetable oils and meats are low in carbohydrates and high in fat by definition, it is impossible to argue that they are healthy options for consumption and disease prevention and treatment. Second, nutrigenomics dictates that there must be an individual role in how the diet is employed (eg, patients who are lactose intolerant will need to stay away from dairy). Third, there are no clear proven clinical results from the ketogenic diet in the realm of dermatology. Fourth, as with everything, there are potential detrimental side effects of the ketogenic diet that must be considered for patients (though there are established screening procedures and prophylactic therapies that are beyond the scope of this article). Further, other diets have shown benefit for many other disease states and health promotion purposes (eg, the Mediterranean diet).²⁰ We do not know yet if the avoidance of certain dietary factors such as processed carbohydrates and fats are more beneficial than adopting a state of ketosis at this time, and therefore we are not claiming superiority of one dietary approach over others that are proven to promote health.

Because there are no large-scale studies of the ketogenic diet, there is no verified standardization of initiating and monitoring it, though certain academic centers do have published methods of doing so.²¹ There are ample anecdotal methods of initiating, maintaining, and monitoring the ketogenic diet.²² In short, drastic restriction of carbohydrate intake and increased fat consumption are the staples of initiating the diet. Medium-chain triglyceride oil supplementation, coffee consumption, intermittent fasting, and low-level aerobic activity also are thought to aid in transition to a ketogenic state. As a result, a dermatologist may recommend that patients interested in this option begin by focusing on fat, fiber, and protein consumption while greatly reducing the amount of carbohydrates in the diet. Morning walks or more intense workouts for fitter patients should be encouraged. Consumption of serum ketone–enhancing foods (eg, coffee, medium-chain triglyceride oil, coconut products) also should be encouraged. A popular beverage known as Bulletproof coffee also may be of interest.²³ A blood ketone meter can be used for biofeedback to reinforce these behaviors by aiming for proper β-hydroxybutyrate levels. Numerous companies and websites exist for supporting those patients wishing to pursue a ketogenic state, some hosted by physicians/researchers with others hosted by laypeople with an interest in the topic; discretion should be used as to the clinical and scientific accuracy of these sites. The dermatologist in particular can follow these patients and assess for changes in severity of skin disease, subjective well-being, need for medications and adjunctive therapies, and status of comorbid conditions.

For more information on the ketogenic diet, consider reading the works of the following physicians and researchers who all have been involved with or are currently conducting research in the medical use of ketones and ketogenic diets: David Perlmutter, MD; Thomas Seyfried, PhD; Dominic D’Agostino, PhD; Terry Wahls, MD; Jeff Volek, PhD; and Peter Attia, MD.

Conclusion

Based on the available data, there is potential for use of the ketogenic diet in an adjunctive manner for dermatologic applications, and studies should be undertaken to establish the efficacy or inefficacy of this diet as a preventive measure or treatment of skin disease. With the large push for complementary and alternative therapies over the last decade, particularly for skin disease, the time for research on the ketogenic diet is ripe. Over the coming years, it is our hope that larger clinical, randomized, controlled trials will be conducted for the benefit of dermatology patients worldwide.

The ketogenic diet has been therapeutically employed by physicians since the times of Hippocrates, primarily for its effect on the nervous system.¹ The neurologic literature is inundated with the uses of this medicinal diet for applications in the treatment of epilepsy, neurodegenerative disease, malignancy, and enzyme deficiencies, among others.² In recent years, physicians and scientists have moved to study the application of a ketogenic diet in the realms of cardiovascular disease,³ autoimmune disease,⁴ management of diabetes mellitus (DM) and obesity,^3,5 and enhancement of sports and combat performance,⁶ all with promising results. Increased interest in alternative therapies among the lay population and the efficacy purported by many adherents has spurred intrigue by health care professionals. Over the last decade, there has seen a boom in so-called holistic approaches to health; included are the Paleo Diet, Primal Blueprint Diet, Bulletproof Diet, and the ketogenic/low-carbohydrate, high-fat diet. The benefits of ketones in these diets—through intermittent fasting or cyclical ketosis—–for cognitive enhancement, overall well-being, amelioration of chronic disease states, and increased health span have been promulgated to the lay population. But to date, there is a large gap in the literature on the applications of ketones as well as the ketogenic diet in dermatology and skin health and disease.

The aim of this article is not to summarize the uses of ketones and the ketogenic diet in dermatologic applications (because, unfortunately, those studies have not been undertaken) but to provide evidence from all available literature to support the need for targeted research and to encourage dermatologists to investigate ketones and their role in treating skin disease, primarily in an adjunctive manner. In doing so, a clearly medicinal diet may gain a foothold in the disease-treatment repertoire and among health-promoting agents of the dermatologist. Given the amount of capital being spent on health care, there is an ever-increasing need for low-cost, safe, and tolerable treatments that can be used for multiple disease processes and to promote health. We believe the ketogenic diet is such an adjunctive therapeutic option, as it has clearly been proven to be tolerable, safe, and efficacious for many people over the last millennia.

We conducted a PubMed search of articles indexed for MEDLINE using varying combinations of the terms ketones, ketogenic, skin, inflammation, metabolic, oxidation, dermatology, and dermatologic and found 12 articles. Herein, we summarize the relevant articles and the works cited by those articles.

Adverse Effects of the Ketogenic Diet

As with all medical therapies, the ketogenic diet is not without risk of adverse effects, which should be communicated at the outset of this article and with patients in the clinic. The only known absolute contraindications to a ketogenic diet are porphyria and pyruvate carboxylase deficiency secondary to underlying metabolic derangements.⁷ Certain metabolic cytopathies and carnitine deficiency are relative contraindications, and patients with these conditions should be cautiously placed on this diet and closely monitored. Dehydration, acidosis, lethargy, hypoglycemia, dyslipidemia, electrolyte imbalances, prurigo pigmentosa, and gastrointestinal distress may be an acute issue, but these effects are transient and can be managed. Chronic adverse effects are nephrolithiasis (there are recommended screening procedures for those at risk and prophylactic therapies, which is beyond the scope of this article) and weight loss.⁷

NLRP3 Inflammasome Suppression

Youm et al⁸ reported their findings in Nature Medicine that β-hydroxybutyrate, a ketone body that naturally circulates in the human body, specifically suppresses activity of the NLRP3 inflammasome. The NLRP3 inflammasome serves as the activating platform for IL-1β.⁸ Aberrant and elevated IL-1β levels cause or are associated with a number of dermatologic diseases—namely, the autoinflammatory syndromes (familial cold autoinflammatory syndrome, Muckle-Wells syndrome, neonatal-onset multisystemic disease/chronic infantile neurological cutaneous articular syndrome), hyperimmunoglobulinemia D with periodic fever syndrome, tumor necrosis factor–receptor associated periodic syndrome, juvenile idiopathic arthritis, relapsing polychondritis, Schnitzler syndrome, Sweet syndrome, Behçet disease, gout, sunburn and contact hypersensitivity, hidradenitis suppurativa, and metastatic melanoma.⁷ Clearly, the ketogenic diet may be employed in a therapeutic manner (though to what degree, we need further study) for these dermatologic conditions based on the interaction with the NRLP3 inflammasome and IL-1β.

Acne

A link between acne and diet has long been suspected, but a lack of well-controlled studies has caused only speculation to remain. Recent literature suggests that the effects of insulin may be a notable driver of acne through effects on sex hormones and subsequent effects on sebum production and inflammation. Cordain et al⁹ discuss the mechanism by which insulin can worsen acne in a valuable article, which Paoli et al¹⁰ later corroborated. Essentially, insulin propagates acne by 2 known mechanisms. First, an increase in serum insulin causes a rise in insulinlike growth factor 1 levels and a decrease in insulinlike growth factor binding protein 3 levels, which directly influences keratinocyte proliferation and reduces retinoic acid receptor/retinoid X receptor activity in the skin, causing hyperkeratinization and concomitant abnormal desquamation of the follicular epithelium.^9,10 Second, this increase in insulinlike growth factor 1 and insulin causes a decrease in sex hormone–binding globulin and leads to increased androgen production and circulation in the skin, which causes an increase in sebum production. These factors combined with skin that is colonized with Cutibacterium acnes lead to an inflammatory response and the disease known as acne vulgaris.^9,10 A ketogenic diet could help ameliorate acne because it results in very little insulin secretion, unlike the typical Western diet, which causes frequent large spikes in insulin levels. Furthermore, the anti-inflammatory effects of ketones would benefit the inflammatory nature of this disease.

DM and Diabetic Skin Disease

Diabetes mellitus carries with it the risk for skin diseases specific to the diabetic disease process, such as increased risk for bacterial and fungal infections, venous stasis, pruritus (secondary to poor circulation), acanthosis nigricans, diabetic dermopathy, necrobiosis lipoidica diabeticorum, digital sclerosis, and bullosis diabeticorum.¹¹ It is well established that better control of DM results in better disease state outcomes.¹² The ketogenic diet has shown itself to be a formidable and successful treatment in the diseases of carbohydrate intolerance (eg, metabolic syndrome, insulin resistance, type 2 DM) because of several known mechanisms, including less glucose entering the body and thus less fat deposition, end-product glycation, and free-radical production (discussed below); enhanced fat loss and metabolic efficiency; increased insulin sensitivity; and decreased inflammation.¹³ Lowering a patient’s insulin resistance through a ketogenic diet may help prevent or treat diabetic skin disease.

Dermatologic Malignancy

A ketogenic diet has been of interest in oncology research as an adjunctive therapy for several reasons: anti-inflammatory effects, antioxidation effects, possible effects on mammalian target of rapamycin (mTOR) regulation,⁷ and exploitation of the Warburg effect.¹⁴ One article discusses how mTOR, a cell-cycle regulator of particular importance in cancer biology, can be influenced by ketones both directly and indirectly through modulating the inflammatory response.⁷ It has been shown that suppressing mTOR activity limits and slows tumor growth and spread. Ketones also may prove to be a unique method of metabolically exploiting cancer physiology. The Warburg effect, which earned Otto Warburg the Nobel Prize in Physiology or Medicine in 1931, is the observation that cancerous cells produce adenosine triphosphate solely through aerobic glycolysis followed by lactic acid fermentation.¹⁴ This phenomenon is the basis of the positron emission tomography scan. There are several small studies of the effects of ketogenic diets on malignancy, and although none of these studies are of substantial size or control, they show that a ketogenic diet can halt or even reverse tumor growth.¹⁵ The hypothesis is that because cancer cells cannot metabolize ketones (but normal cells can), the Warburg effect can be taken advantage of through a ketogenic diet to aid in the treatment of malignant disease.¹⁴ If further studies find it a formidable treatment, it most certainly would be helpful for the dermatologist involved in the treatment of cutaneous cancers.

Oxidative Stress

Oxidative stress, a state brought about when reactive oxygen species (ROS) production exceeds the antioxidant capacity of the cell and causes damage, is known to be a central part of certain skin diseases (eg, acne, psoriasis, cutaneous malignancy, varicose ulcers, cutaneous allergic reactions, and drug-induced skin photosensitivity).⁷ There are 2 proven mechanisms by which a ketogenic diet can augment the body’s innate antioxidation capacity. First, ketones activate a potent antioxidant upregulating protein known as NRF2, which is bound in cytosol and remains inactive until activated by certain stimuli (ie, ketones).¹⁶ Migration to the nucleus causes transcriptional changes in DNA to upregulate, via a myriad of pathways, antioxidant production in the cell; most notably, it results in increased glutathione levels.¹⁷ NRF2 also targets several genes involved in chronic inflammatory skin diseases that cause an increase in the antioxidant capacity.¹⁸ As an aside, several foods encouraged on a ketogenic diet also activate NRF2 independently of ketones (eg, coffee, broccoli).¹⁹ Second, a ketogenic diet results in fewer produced ROS and an increase in the nicotinamide adenine dinucleotide ratio produced by the mitochondria; in short, it is a more efficient way of producing cellular energy while enhancing mitochondrial function. When fewer ROS are produced, there is less oxidative stress that needs to be attended to by the cell and less cellular damage. Feichtinger et al¹⁹ point out that mitochondrial inefficiency and dysfunction often are overlooked components in several skin diseases, and based on the studies discussed above, these diseases may be aided with a ketogenic diet.

Patient Applications

Clearly, a ketogenic diet is therapeutic, and there are many promising potential roles it may play in the treatment of a wide variety of health and disease states through hormonal normalization, antioxidant effects, anti-inflammatory effects, and improvement of metabolic risk factors. However, there are vast limitations to what is known about the ketogenic diet and how it might be employed, particularly by the dermatologist. First, the ketogenic diet lacks a firm definition. Although processed inflammatory vegetable oils and meats are low in carbohydrates and high in fat by definition, it is impossible to argue that they are healthy options for consumption and disease prevention and treatment. Second, nutrigenomics dictates that there must be an individual role in how the diet is employed (eg, patients who are lactose intolerant will need to stay away from dairy). Third, there are no clear proven clinical results from the ketogenic diet in the realm of dermatology. Fourth, as with everything, there are potential detrimental side effects of the ketogenic diet that must be considered for patients (though there are established screening procedures and prophylactic therapies that are beyond the scope of this article). Further, other diets have shown benefit for many other disease states and health promotion purposes (eg, the Mediterranean diet).²⁰ We do not know yet if the avoidance of certain dietary factors such as processed carbohydrates and fats are more beneficial than adopting a state of ketosis at this time, and therefore we are not claiming superiority of one dietary approach over others that are proven to promote health.

Because there are no large-scale studies of the ketogenic diet, there is no verified standardization of initiating and monitoring it, though certain academic centers do have published methods of doing so.²¹ There are ample anecdotal methods of initiating, maintaining, and monitoring the ketogenic diet.²² In short, drastic restriction of carbohydrate intake and increased fat consumption are the staples of initiating the diet. Medium-chain triglyceride oil supplementation, coffee consumption, intermittent fasting, and low-level aerobic activity also are thought to aid in transition to a ketogenic state. As a result, a dermatologist may recommend that patients interested in this option begin by focusing on fat, fiber, and protein consumption while greatly reducing the amount of carbohydrates in the diet. Morning walks or more intense workouts for fitter patients should be encouraged. Consumption of serum ketone–enhancing foods (eg, coffee, medium-chain triglyceride oil, coconut products) also should be encouraged. A popular beverage known as Bulletproof coffee also may be of interest.²³ A blood ketone meter can be used for biofeedback to reinforce these behaviors by aiming for proper β-hydroxybutyrate levels. Numerous companies and websites exist for supporting those patients wishing to pursue a ketogenic state, some hosted by physicians/researchers with others hosted by laypeople with an interest in the topic; discretion should be used as to the clinical and scientific accuracy of these sites. The dermatologist in particular can follow these patients and assess for changes in severity of skin disease, subjective well-being, need for medications and adjunctive therapies, and status of comorbid conditions.

For more information on the ketogenic diet, consider reading the works of the following physicians and researchers who all have been involved with or are currently conducting research in the medical use of ketones and ketogenic diets: David Perlmutter, MD; Thomas Seyfried, PhD; Dominic D’Agostino, PhD; Terry Wahls, MD; Jeff Volek, PhD; and Peter Attia, MD.

Conclusion

Based on the available data, there is potential for use of the ketogenic diet in an adjunctive manner for dermatologic applications, and studies should be undertaken to establish the efficacy or inefficacy of this diet as a preventive measure or treatment of skin disease. With the large push for complementary and alternative therapies over the last decade, particularly for skin disease, the time for research on the ketogenic diet is ripe. Over the coming years, it is our hope that larger clinical, randomized, controlled trials will be conducted for the benefit of dermatology patients worldwide.

The ketogenic diet has been therapeutically employed by physicians since the times of Hippocrates, primarily for its effect on the nervous system.¹ The neurologic literature is inundated with the uses of this medicinal diet for applications in the treatment of epilepsy, neurodegenerative disease, malignancy, and enzyme deficiencies, among others.² In recent years, physicians and scientists have moved to study the application of a ketogenic diet in the realms of cardiovascular disease,³ autoimmune disease,⁴ management of diabetes mellitus (DM) and obesity,^3,5 and enhancement of sports and combat performance,⁶ all with promising results. Increased interest in alternative therapies among the lay population and the efficacy purported by many adherents has spurred intrigue by health care professionals. Over the last decade, there has seen a boom in so-called holistic approaches to health; included are the Paleo Diet, Primal Blueprint Diet, Bulletproof Diet, and the ketogenic/low-carbohydrate, high-fat diet. The benefits of ketones in these diets—through intermittent fasting or cyclical ketosis—–for cognitive enhancement, overall well-being, amelioration of chronic disease states, and increased health span have been promulgated to the lay population. But to date, there is a large gap in the literature on the applications of ketones as well as the ketogenic diet in dermatology and skin health and disease.

The aim of this article is not to summarize the uses of ketones and the ketogenic diet in dermatologic applications (because, unfortunately, those studies have not been undertaken) but to provide evidence from all available literature to support the need for targeted research and to encourage dermatologists to investigate ketones and their role in treating skin disease, primarily in an adjunctive manner. In doing so, a clearly medicinal diet may gain a foothold in the disease-treatment repertoire and among health-promoting agents of the dermatologist. Given the amount of capital being spent on health care, there is an ever-increasing need for low-cost, safe, and tolerable treatments that can be used for multiple disease processes and to promote health. We believe the ketogenic diet is such an adjunctive therapeutic option, as it has clearly been proven to be tolerable, safe, and efficacious for many people over the last millennia.

We conducted a PubMed search of articles indexed for MEDLINE using varying combinations of the terms ketones, ketogenic, skin, inflammation, metabolic, oxidation, dermatology, and dermatologic and found 12 articles. Herein, we summarize the relevant articles and the works cited by those articles.

Adverse Effects of the Ketogenic Diet

As with all medical therapies, the ketogenic diet is not without risk of adverse effects, which should be communicated at the outset of this article and with patients in the clinic. The only known absolute contraindications to a ketogenic diet are porphyria and pyruvate carboxylase deficiency secondary to underlying metabolic derangements.⁷ Certain metabolic cytopathies and carnitine deficiency are relative contraindications, and patients with these conditions should be cautiously placed on this diet and closely monitored. Dehydration, acidosis, lethargy, hypoglycemia, dyslipidemia, electrolyte imbalances, prurigo pigmentosa, and gastrointestinal distress may be an acute issue, but these effects are transient and can be managed. Chronic adverse effects are nephrolithiasis (there are recommended screening procedures for those at risk and prophylactic therapies, which is beyond the scope of this article) and weight loss.⁷

NLRP3 Inflammasome Suppression

Youm et al⁸ reported their findings in Nature Medicine that β-hydroxybutyrate, a ketone body that naturally circulates in the human body, specifically suppresses activity of the NLRP3 inflammasome. The NLRP3 inflammasome serves as the activating platform for IL-1β.⁸ Aberrant and elevated IL-1β levels cause or are associated with a number of dermatologic diseases—namely, the autoinflammatory syndromes (familial cold autoinflammatory syndrome, Muckle-Wells syndrome, neonatal-onset multisystemic disease/chronic infantile neurological cutaneous articular syndrome), hyperimmunoglobulinemia D with periodic fever syndrome, tumor necrosis factor–receptor associated periodic syndrome, juvenile idiopathic arthritis, relapsing polychondritis, Schnitzler syndrome, Sweet syndrome, Behçet disease, gout, sunburn and contact hypersensitivity, hidradenitis suppurativa, and metastatic melanoma.⁷ Clearly, the ketogenic diet may be employed in a therapeutic manner (though to what degree, we need further study) for these dermatologic conditions based on the interaction with the NRLP3 inflammasome and IL-1β.

Acne

A link between acne and diet has long been suspected, but a lack of well-controlled studies has caused only speculation to remain. Recent literature suggests that the effects of insulin may be a notable driver of acne through effects on sex hormones and subsequent effects on sebum production and inflammation. Cordain et al⁹ discuss the mechanism by which insulin can worsen acne in a valuable article, which Paoli et al¹⁰ later corroborated. Essentially, insulin propagates acne by 2 known mechanisms. First, an increase in serum insulin causes a rise in insulinlike growth factor 1 levels and a decrease in insulinlike growth factor binding protein 3 levels, which directly influences keratinocyte proliferation and reduces retinoic acid receptor/retinoid X receptor activity in the skin, causing hyperkeratinization and concomitant abnormal desquamation of the follicular epithelium.^9,10 Second, this increase in insulinlike growth factor 1 and insulin causes a decrease in sex hormone–binding globulin and leads to increased androgen production and circulation in the skin, which causes an increase in sebum production. These factors combined with skin that is colonized with Cutibacterium acnes lead to an inflammatory response and the disease known as acne vulgaris.^9,10 A ketogenic diet could help ameliorate acne because it results in very little insulin secretion, unlike the typical Western diet, which causes frequent large spikes in insulin levels. Furthermore, the anti-inflammatory effects of ketones would benefit the inflammatory nature of this disease.

DM and Diabetic Skin Disease

Diabetes mellitus carries with it the risk for skin diseases specific to the diabetic disease process, such as increased risk for bacterial and fungal infections, venous stasis, pruritus (secondary to poor circulation), acanthosis nigricans, diabetic dermopathy, necrobiosis lipoidica diabeticorum, digital sclerosis, and bullosis diabeticorum.¹¹ It is well established that better control of DM results in better disease state outcomes.¹² The ketogenic diet has shown itself to be a formidable and successful treatment in the diseases of carbohydrate intolerance (eg, metabolic syndrome, insulin resistance, type 2 DM) because of several known mechanisms, including less glucose entering the body and thus less fat deposition, end-product glycation, and free-radical production (discussed below); enhanced fat loss and metabolic efficiency; increased insulin sensitivity; and decreased inflammation.¹³ Lowering a patient’s insulin resistance through a ketogenic diet may help prevent or treat diabetic skin disease.

Dermatologic Malignancy

A ketogenic diet has been of interest in oncology research as an adjunctive therapy for several reasons: anti-inflammatory effects, antioxidation effects, possible effects on mammalian target of rapamycin (mTOR) regulation,⁷ and exploitation of the Warburg effect.¹⁴ One article discusses how mTOR, a cell-cycle regulator of particular importance in cancer biology, can be influenced by ketones both directly and indirectly through modulating the inflammatory response.⁷ It has been shown that suppressing mTOR activity limits and slows tumor growth and spread. Ketones also may prove to be a unique method of metabolically exploiting cancer physiology. The Warburg effect, which earned Otto Warburg the Nobel Prize in Physiology or Medicine in 1931, is the observation that cancerous cells produce adenosine triphosphate solely through aerobic glycolysis followed by lactic acid fermentation.¹⁴ This phenomenon is the basis of the positron emission tomography scan. There are several small studies of the effects of ketogenic diets on malignancy, and although none of these studies are of substantial size or control, they show that a ketogenic diet can halt or even reverse tumor growth.¹⁵ The hypothesis is that because cancer cells cannot metabolize ketones (but normal cells can), the Warburg effect can be taken advantage of through a ketogenic diet to aid in the treatment of malignant disease.¹⁴ If further studies find it a formidable treatment, it most certainly would be helpful for the dermatologist involved in the treatment of cutaneous cancers.

Oxidative Stress

Oxidative stress, a state brought about when reactive oxygen species (ROS) production exceeds the antioxidant capacity of the cell and causes damage, is known to be a central part of certain skin diseases (eg, acne, psoriasis, cutaneous malignancy, varicose ulcers, cutaneous allergic reactions, and drug-induced skin photosensitivity).⁷ There are 2 proven mechanisms by which a ketogenic diet can augment the body’s innate antioxidation capacity. First, ketones activate a potent antioxidant upregulating protein known as NRF2, which is bound in cytosol and remains inactive until activated by certain stimuli (ie, ketones).¹⁶ Migration to the nucleus causes transcriptional changes in DNA to upregulate, via a myriad of pathways, antioxidant production in the cell; most notably, it results in increased glutathione levels.¹⁷ NRF2 also targets several genes involved in chronic inflammatory skin diseases that cause an increase in the antioxidant capacity.¹⁸ As an aside, several foods encouraged on a ketogenic diet also activate NRF2 independently of ketones (eg, coffee, broccoli).¹⁹ Second, a ketogenic diet results in fewer produced ROS and an increase in the nicotinamide adenine dinucleotide ratio produced by the mitochondria; in short, it is a more efficient way of producing cellular energy while enhancing mitochondrial function. When fewer ROS are produced, there is less oxidative stress that needs to be attended to by the cell and less cellular damage. Feichtinger et al¹⁹ point out that mitochondrial inefficiency and dysfunction often are overlooked components in several skin diseases, and based on the studies discussed above, these diseases may be aided with a ketogenic diet.

Patient Applications

Clearly, a ketogenic diet is therapeutic, and there are many promising potential roles it may play in the treatment of a wide variety of health and disease states through hormonal normalization, antioxidant effects, anti-inflammatory effects, and improvement of metabolic risk factors. However, there are vast limitations to what is known about the ketogenic diet and how it might be employed, particularly by the dermatologist. First, the ketogenic diet lacks a firm definition. Although processed inflammatory vegetable oils and meats are low in carbohydrates and high in fat by definition, it is impossible to argue that they are healthy options for consumption and disease prevention and treatment. Second, nutrigenomics dictates that there must be an individual role in how the diet is employed (eg, patients who are lactose intolerant will need to stay away from dairy). Third, there are no clear proven clinical results from the ketogenic diet in the realm of dermatology. Fourth, as with everything, there are potential detrimental side effects of the ketogenic diet that must be considered for patients (though there are established screening procedures and prophylactic therapies that are beyond the scope of this article). Further, other diets have shown benefit for many other disease states and health promotion purposes (eg, the Mediterranean diet).²⁰ We do not know yet if the avoidance of certain dietary factors such as processed carbohydrates and fats are more beneficial than adopting a state of ketosis at this time, and therefore we are not claiming superiority of one dietary approach over others that are proven to promote health.

Because there are no large-scale studies of the ketogenic diet, there is no verified standardization of initiating and monitoring it, though certain academic centers do have published methods of doing so.²¹ There are ample anecdotal methods of initiating, maintaining, and monitoring the ketogenic diet.²² In short, drastic restriction of carbohydrate intake and increased fat consumption are the staples of initiating the diet. Medium-chain triglyceride oil supplementation, coffee consumption, intermittent fasting, and low-level aerobic activity also are thought to aid in transition to a ketogenic state. As a result, a dermatologist may recommend that patients interested in this option begin by focusing on fat, fiber, and protein consumption while greatly reducing the amount of carbohydrates in the diet. Morning walks or more intense workouts for fitter patients should be encouraged. Consumption of serum ketone–enhancing foods (eg, coffee, medium-chain triglyceride oil, coconut products) also should be encouraged. A popular beverage known as Bulletproof coffee also may be of interest.²³ A blood ketone meter can be used for biofeedback to reinforce these behaviors by aiming for proper β-hydroxybutyrate levels. Numerous companies and websites exist for supporting those patients wishing to pursue a ketogenic state, some hosted by physicians/researchers with others hosted by laypeople with an interest in the topic; discretion should be used as to the clinical and scientific accuracy of these sites. The dermatologist in particular can follow these patients and assess for changes in severity of skin disease, subjective well-being, need for medications and adjunctive therapies, and status of comorbid conditions.

For more information on the ketogenic diet, consider reading the works of the following physicians and researchers who all have been involved with or are currently conducting research in the medical use of ketones and ketogenic diets: David Perlmutter, MD; Thomas Seyfried, PhD; Dominic D’Agostino, PhD; Terry Wahls, MD; Jeff Volek, PhD; and Peter Attia, MD.

Conclusion

Based on the available data, there is potential for use of the ketogenic diet in an adjunctive manner for dermatologic applications, and studies should be undertaken to establish the efficacy or inefficacy of this diet as a preventive measure or treatment of skin disease. With the large push for complementary and alternative therapies over the last decade, particularly for skin disease, the time for research on the ketogenic diet is ripe. Over the coming years, it is our hope that larger clinical, randomized, controlled trials will be conducted for the benefit of dermatology patients worldwide.