Pigmentation Disorders

NEW YORK – Many inflammatory diseases, such as psoriasis and atopic dermatitis (AD), can present differently in patients with darker skin types, but it is the pigmentary changes themselves that are often a dominant concern for parents, according to pediatric dermatologist Candrice R. Heath, MD.

Skin diseases pose a greater risk of both hyper- and hypopigmentation in patients with darker skin types, but the fear and concern that this raises for permanent disfigurement is not limited to Blacks, Dr. Heath, assistant professor of pediatric dermatology at Temple University, Philadelphia, said at the Skin of Color Update 2023.

“Culturally, pigmentation changes can be huge. For people of Indian descent, for example, pigmentary changes like light spots on the skin might be an obstacle to marriage, so it can really be life changing,” she added.

In patients with darker skin tones presenting with an inflammatory skin disease, such as AD or psoriasis, Dr. Heath advised asking specifically about change in skin tone even if it is not readily apparent. In pediatric patients, it is also appropriate to include parents in this conversation.
 

Consider the parent’s perspective

“When you are taking care of a child or adolescent, the patient is likely to be concerned about changes in pigmentation, but it is important to remember that the adult in the room might have had their own journey with brown skin and has dealt with the burden of pigment changes,” Dr. Heath said.

For the parent, the pigmentation changes, rather than the inflammation, might be the governing issue and the reason that he or she brought the child to the clinician. Dr. Heath suggested that it is important for caregivers to explicitly recognize their concern, explain that addressing the pigmentary changes is part of the treatment plan, and to create realistic expectations about how long pigmentary changes will take to resolve.

As an example, Dr. Heath recounted a difficult case of a Black infant with disseminated hyperpigmentation and features that did not preclude pathology other than AD. Dr. Heath created a multifaceted treatment plan to address the inflammation in distinct areas of the body that included low-strength topical steroids for the face, stronger steroids for the body, and advice on scalp and skin care.

“I thought this was a great treatment plan out of the gate – I was covering all of the things on my differential list – I thought that the mom would be thinking, this doctor is amazing,” Dr. Heath said.
 

Pigmentary changes are a priority

However, that was not what the patient’s mother was thinking. Having failed to explicitly recognize her concern about the pigmentation changes and how the treatment would address this issue, the mother was disappointed.

“She had one question: Will my baby ever be one color? That was her main concern,” said Dr. Heath, indicating that other clinicians seeing inflammatory diseases in children with darker skin types can learn from her experience.

“Really, you have to acknowledge that the condition you are treating is causing the pigmentation change, and we do see that and that we have a treatment plan in place,” she said.

Because of differences in how inflammatory skin diseases present in darker skin types, there is plenty of room for a delayed diagnosis for clinicians who do not see many of these patients, according to Dr. Heath. Follicular eczema, which is common in skin of color, often presents with pruritus but differences in the appearance of the underlying disease can threaten a delay in diagnosis.

In cases of follicular eczema with itch in darker skin, the bumps look and feel like goose bumps, which “means that the eczema is really active and inflamed,” Dr. Heath said. When the skin becomes smooth and the itch dissipates, “you know that they are under great control.”

Psoriasis is often missed in children with darker skin types based on the misperception that it is rare. Although it is true that it is less common in Blacks than Whites, it is not rare, according to Dr. Heath. In inspecting the telltale erythematous plaque–like lesions, clinicians might start to consider alternative diagnoses when they do not detect the same erythematous appearance, but the reddish tone is often concealed in darker skin.

She said that predominant involvement in the head and neck and diaper area is often more common in children of color and that nail or scalp involvement, when present, is often a clue that psoriasis is the diagnosis.

Again, because many clinicians do not think immediately of psoriasis in darker skin children with lesions in the scalp, Dr. Heath advised this is another reason to include psoriasis in the differential diagnosis.

“If you have a child that has failed multiple courses of treatment for tinea capitis and they have well-demarcated plaques, it’s time to really start to think about pediatric psoriasis,” she said.
 

Restoring skin tone can be the priority

Asked to comment on Dr. Heath’s advice about the importance of acknowledging pigmentary changes associated with inflammatory skin diseases in patients of color, Jenna Lester, MD, the founding director of the Skin of Color Clinic at the University of California, San Francisco, called it an “often unspoken concern of patients.”

“Pigmentary changes that occur secondary to an inflammatory condition should be addressed and treated alongside the inciting condition,” she agreed.

Even if changes in skin color or skin tone are not a specific complaint of the patients, Dr. Lester also urged clinicians to raise the topic. If change in skin pigmentation is part of the clinical picture, this should be targeted in the treatment plan.

“In acne, for example, often times I find that patients are as worried about postinflammatory hyperpigmentation as they are about their acne,” she said, reiterating the advice provided by Dr. Heath.

Dr. Heath has financial relationships with Arcutis, Janssen, Johnson & Johnson, Lilly, and Regeneron. Dr. Lester reported no potential conflicts of interest.

NEW YORK – Many inflammatory diseases, such as psoriasis and atopic dermatitis (AD), can present differently in patients with darker skin types, but it is the pigmentary changes themselves that are often a dominant concern for parents, according to pediatric dermatologist Candrice R. Heath, MD.

Skin diseases pose a greater risk of both hyper- and hypopigmentation in patients with darker skin types, but the fear and concern that this raises for permanent disfigurement is not limited to Blacks, Dr. Heath, assistant professor of pediatric dermatology at Temple University, Philadelphia, said at the Skin of Color Update 2023.

“Culturally, pigmentation changes can be huge. For people of Indian descent, for example, pigmentary changes like light spots on the skin might be an obstacle to marriage, so it can really be life changing,” she added.

In patients with darker skin tones presenting with an inflammatory skin disease, such as AD or psoriasis, Dr. Heath advised asking specifically about change in skin tone even if it is not readily apparent. In pediatric patients, it is also appropriate to include parents in this conversation.
 

Consider the parent’s perspective

“When you are taking care of a child or adolescent, the patient is likely to be concerned about changes in pigmentation, but it is important to remember that the adult in the room might have had their own journey with brown skin and has dealt with the burden of pigment changes,” Dr. Heath said.

For the parent, the pigmentation changes, rather than the inflammation, might be the governing issue and the reason that he or she brought the child to the clinician. Dr. Heath suggested that it is important for caregivers to explicitly recognize their concern, explain that addressing the pigmentary changes is part of the treatment plan, and to create realistic expectations about how long pigmentary changes will take to resolve.

As an example, Dr. Heath recounted a difficult case of a Black infant with disseminated hyperpigmentation and features that did not preclude pathology other than AD. Dr. Heath created a multifaceted treatment plan to address the inflammation in distinct areas of the body that included low-strength topical steroids for the face, stronger steroids for the body, and advice on scalp and skin care.

“I thought this was a great treatment plan out of the gate – I was covering all of the things on my differential list – I thought that the mom would be thinking, this doctor is amazing,” Dr. Heath said.
 

Pigmentary changes are a priority

However, that was not what the patient’s mother was thinking. Having failed to explicitly recognize her concern about the pigmentation changes and how the treatment would address this issue, the mother was disappointed.

“She had one question: Will my baby ever be one color? That was her main concern,” said Dr. Heath, indicating that other clinicians seeing inflammatory diseases in children with darker skin types can learn from her experience.

“Really, you have to acknowledge that the condition you are treating is causing the pigmentation change, and we do see that and that we have a treatment plan in place,” she said.

Because of differences in how inflammatory skin diseases present in darker skin types, there is plenty of room for a delayed diagnosis for clinicians who do not see many of these patients, according to Dr. Heath. Follicular eczema, which is common in skin of color, often presents with pruritus but differences in the appearance of the underlying disease can threaten a delay in diagnosis.

In cases of follicular eczema with itch in darker skin, the bumps look and feel like goose bumps, which “means that the eczema is really active and inflamed,” Dr. Heath said. When the skin becomes smooth and the itch dissipates, “you know that they are under great control.”

Psoriasis is often missed in children with darker skin types based on the misperception that it is rare. Although it is true that it is less common in Blacks than Whites, it is not rare, according to Dr. Heath. In inspecting the telltale erythematous plaque–like lesions, clinicians might start to consider alternative diagnoses when they do not detect the same erythematous appearance, but the reddish tone is often concealed in darker skin.

She said that predominant involvement in the head and neck and diaper area is often more common in children of color and that nail or scalp involvement, when present, is often a clue that psoriasis is the diagnosis.

Again, because many clinicians do not think immediately of psoriasis in darker skin children with lesions in the scalp, Dr. Heath advised this is another reason to include psoriasis in the differential diagnosis.

“If you have a child that has failed multiple courses of treatment for tinea capitis and they have well-demarcated plaques, it’s time to really start to think about pediatric psoriasis,” she said.
 

Restoring skin tone can be the priority

Asked to comment on Dr. Heath’s advice about the importance of acknowledging pigmentary changes associated with inflammatory skin diseases in patients of color, Jenna Lester, MD, the founding director of the Skin of Color Clinic at the University of California, San Francisco, called it an “often unspoken concern of patients.”

“Pigmentary changes that occur secondary to an inflammatory condition should be addressed and treated alongside the inciting condition,” she agreed.

Even if changes in skin color or skin tone are not a specific complaint of the patients, Dr. Lester also urged clinicians to raise the topic. If change in skin pigmentation is part of the clinical picture, this should be targeted in the treatment plan.

“In acne, for example, often times I find that patients are as worried about postinflammatory hyperpigmentation as they are about their acne,” she said, reiterating the advice provided by Dr. Heath.

Dr. Heath has financial relationships with Arcutis, Janssen, Johnson & Johnson, Lilly, and Regeneron. Dr. Lester reported no potential conflicts of interest.

NEW YORK – Many inflammatory diseases, such as psoriasis and atopic dermatitis (AD), can present differently in patients with darker skin types, but it is the pigmentary changes themselves that are often a dominant concern for parents, according to pediatric dermatologist Candrice R. Heath, MD.

Skin diseases pose a greater risk of both hyper- and hypopigmentation in patients with darker skin types, but the fear and concern that this raises for permanent disfigurement is not limited to Blacks, Dr. Heath, assistant professor of pediatric dermatology at Temple University, Philadelphia, said at the Skin of Color Update 2023.

“Culturally, pigmentation changes can be huge. For people of Indian descent, for example, pigmentary changes like light spots on the skin might be an obstacle to marriage, so it can really be life changing,” she added.

In patients with darker skin tones presenting with an inflammatory skin disease, such as AD or psoriasis, Dr. Heath advised asking specifically about change in skin tone even if it is not readily apparent. In pediatric patients, it is also appropriate to include parents in this conversation.
 

Consider the parent’s perspective

“When you are taking care of a child or adolescent, the patient is likely to be concerned about changes in pigmentation, but it is important to remember that the adult in the room might have had their own journey with brown skin and has dealt with the burden of pigment changes,” Dr. Heath said.

For the parent, the pigmentation changes, rather than the inflammation, might be the governing issue and the reason that he or she brought the child to the clinician. Dr. Heath suggested that it is important for caregivers to explicitly recognize their concern, explain that addressing the pigmentary changes is part of the treatment plan, and to create realistic expectations about how long pigmentary changes will take to resolve.

As an example, Dr. Heath recounted a difficult case of a Black infant with disseminated hyperpigmentation and features that did not preclude pathology other than AD. Dr. Heath created a multifaceted treatment plan to address the inflammation in distinct areas of the body that included low-strength topical steroids for the face, stronger steroids for the body, and advice on scalp and skin care.

“I thought this was a great treatment plan out of the gate – I was covering all of the things on my differential list – I thought that the mom would be thinking, this doctor is amazing,” Dr. Heath said.
 

Pigmentary changes are a priority

However, that was not what the patient’s mother was thinking. Having failed to explicitly recognize her concern about the pigmentation changes and how the treatment would address this issue, the mother was disappointed.

“She had one question: Will my baby ever be one color? That was her main concern,” said Dr. Heath, indicating that other clinicians seeing inflammatory diseases in children with darker skin types can learn from her experience.

“Really, you have to acknowledge that the condition you are treating is causing the pigmentation change, and we do see that and that we have a treatment plan in place,” she said.

Because of differences in how inflammatory skin diseases present in darker skin types, there is plenty of room for a delayed diagnosis for clinicians who do not see many of these patients, according to Dr. Heath. Follicular eczema, which is common in skin of color, often presents with pruritus but differences in the appearance of the underlying disease can threaten a delay in diagnosis.

In cases of follicular eczema with itch in darker skin, the bumps look and feel like goose bumps, which “means that the eczema is really active and inflamed,” Dr. Heath said. When the skin becomes smooth and the itch dissipates, “you know that they are under great control.”

Psoriasis is often missed in children with darker skin types based on the misperception that it is rare. Although it is true that it is less common in Blacks than Whites, it is not rare, according to Dr. Heath. In inspecting the telltale erythematous plaque–like lesions, clinicians might start to consider alternative diagnoses when they do not detect the same erythematous appearance, but the reddish tone is often concealed in darker skin.

She said that predominant involvement in the head and neck and diaper area is often more common in children of color and that nail or scalp involvement, when present, is often a clue that psoriasis is the diagnosis.

Again, because many clinicians do not think immediately of psoriasis in darker skin children with lesions in the scalp, Dr. Heath advised this is another reason to include psoriasis in the differential diagnosis.

“If you have a child that has failed multiple courses of treatment for tinea capitis and they have well-demarcated plaques, it’s time to really start to think about pediatric psoriasis,” she said.
 

Restoring skin tone can be the priority

Asked to comment on Dr. Heath’s advice about the importance of acknowledging pigmentary changes associated with inflammatory skin diseases in patients of color, Jenna Lester, MD, the founding director of the Skin of Color Clinic at the University of California, San Francisco, called it an “often unspoken concern of patients.”

“Pigmentary changes that occur secondary to an inflammatory condition should be addressed and treated alongside the inciting condition,” she agreed.

Even if changes in skin color or skin tone are not a specific complaint of the patients, Dr. Lester also urged clinicians to raise the topic. If change in skin pigmentation is part of the clinical picture, this should be targeted in the treatment plan.

“In acne, for example, often times I find that patients are as worried about postinflammatory hyperpigmentation as they are about their acne,” she said, reiterating the advice provided by Dr. Heath.

Dr. Heath has financial relationships with Arcutis, Janssen, Johnson & Johnson, Lilly, and Regeneron. Dr. Lester reported no potential conflicts of interest.

Short-term use of JAK inhibitors for a dermatologic indication appears to not be associated with an increased risk of all-cause mortality, major adverse cardiovascular events (MACE) and venous thromboembolic events (VTE), results from a systematic literature review, and meta-analysis showed.

“There remains a knowledge gap regarding the risk of JAK inhibitor use and VTE and/or MACE in the dermatologic population,” researchers led by Michael S. Garshick, MD, a cardiologist at New York University Langone Health, wrote in their study, which was published online in JAMA Dermatology . “Pooled safety studies suggest that the risk of MACE and VTE may be lower in patients treated with JAK inhibitors for a dermatologic indication than the risk observed in the ORAL Surveillance study, which may be related to the younger age and better health status of those enrolled in trials for dermatologic indications.” The results of that study, which included patients with rheumatoid arthritis only, resulted in the addition of a boxed warning in the labels for topical and oral JAK inhibitors regarding the increased risk of MACE, VTE, serious infections, malignancies, and death .

For the review – thought to be the first to specifically evaluate these risks for dermatologic indications – the researchers searched PubMed and ClinicalTrials.gov from inception through April 1, 2023, for phase 3 dermatology randomized clinical trials (RCTs) to evaluate the risk of MACE, VTE, and all-cause mortality with JAK inhibitors, compared with placebo or an active comparator in the treatment of immune-mediated inflammatory skin diseases. They followed Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines and used a random-effects model and the DerSimonian-Laird method to calculate adverse events with odds ratios.

The database search yielded 35 RCTs with a total of 20,651 patients. Their mean age was 38.5 years, 54% were male, and the mean follow-up time was 4.9 months. Of the 35 trials, most (21) involved patients with atopic dermatitis, followed by psoriasis/psoriatic arthritis (9 trials), alopecia areata (3 trials) and vitiligo (2 trials).

The researchers found no significant difference between JAK inhibitors and placebo/active comparator in composite MACE and all-cause mortality (odds ratio, 0.83; 95% confidence interval, 0.44-1.57) or in VTE (OR, 0.52; 95% CI, 0.26-1.04).

In a secondary analysis, which included additional psoriatic arthritis RCTs, no significant differences between the treatment and placebo/active comparator groups were observed. Similarly, subgroup analyses of oral versus topical JAK inhibitors and a sensitivity analysis that excluded pediatric trials showed no significant differences between patients exposed to JAK inhibitors and those not exposed.

The researchers acknowledged certain limitations of the review, including the lack of access to patient-level data, the fact that most trials only included short-term follow-up, and that the findings have limited generalizability to an older patient population. “It remains unclear if the cardiovascular risks of JAK inhibitors are primarily due to patient level cardiovascular risk factors or are drug mediated,” they concluded. “Dermatologists should carefully select patients and assess baseline cardiovascular risk factors when considering JAK therapy. Cardiovascular risk assessment should continue for the duration of treatment.”

Raj Chovatiya, MD, PhD, assistant professor of dermatology and director of the center for eczema and itch at Northwestern University, Chicago, who was asked to comment on the study results, characterized the findings as reassuring to dermatologists who may be reluctant to initiate therapy with JAK inhibitors based on concerns about safety signals for MACE, VTE, and all-cause mortality.

“These data systematically show that across medications and across conditions, there doesn’t appear to be an increased signal for these events during the short-term, placebo-controlled period which generally spans a few months in most studies,” he told this news organization. The findings, he added, “align well with our clinical experience to date for JAK inhibitor use in inflammatory skin disease. Short-term safety, particularly in relation to boxed warning events such MACE, VTE, and all-cause mortality, have generally been favorable with real-world use. It’s good to have a rigorous statistical analysis to refer to when setting patient expectations.”

However, he noted that these data only examined short-term safety during the placebo or active comparator-controlled periods. “Considering that events like MACE or VTE may take many months or years to manifest, continued long-term data generation is needed to fully answer the question of risk,” he said.

Dr. Garshick disclosed that he received grants from Pfizer and personal fees from Bristol Myers Squibb during the conduct of the study and personal fees from Kiniksa Pharmaceuticals outside the submitted work. Several other coauthors reported having advisory board roles and/or having received funding or support from several pharmaceutical companies. Dr. Chovatiya disclosed that he is a consultant to, a speaker for, investigator, and/or a member of the advisory board for several pharmaceutical companies, including those that develop JAK inhibitors.

Short-term use of JAK inhibitors for a dermatologic indication appears to not be associated with an increased risk of all-cause mortality, major adverse cardiovascular events (MACE) and venous thromboembolic events (VTE), results from a systematic literature review, and meta-analysis showed.

“There remains a knowledge gap regarding the risk of JAK inhibitor use and VTE and/or MACE in the dermatologic population,” researchers led by Michael S. Garshick, MD, a cardiologist at New York University Langone Health, wrote in their study, which was published online in JAMA Dermatology . “Pooled safety studies suggest that the risk of MACE and VTE may be lower in patients treated with JAK inhibitors for a dermatologic indication than the risk observed in the ORAL Surveillance study, which may be related to the younger age and better health status of those enrolled in trials for dermatologic indications.” The results of that study, which included patients with rheumatoid arthritis only, resulted in the addition of a boxed warning in the labels for topical and oral JAK inhibitors regarding the increased risk of MACE, VTE, serious infections, malignancies, and death .

For the review – thought to be the first to specifically evaluate these risks for dermatologic indications – the researchers searched PubMed and ClinicalTrials.gov from inception through April 1, 2023, for phase 3 dermatology randomized clinical trials (RCTs) to evaluate the risk of MACE, VTE, and all-cause mortality with JAK inhibitors, compared with placebo or an active comparator in the treatment of immune-mediated inflammatory skin diseases. They followed Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines and used a random-effects model and the DerSimonian-Laird method to calculate adverse events with odds ratios.

The database search yielded 35 RCTs with a total of 20,651 patients. Their mean age was 38.5 years, 54% were male, and the mean follow-up time was 4.9 months. Of the 35 trials, most (21) involved patients with atopic dermatitis, followed by psoriasis/psoriatic arthritis (9 trials), alopecia areata (3 trials) and vitiligo (2 trials).

The researchers found no significant difference between JAK inhibitors and placebo/active comparator in composite MACE and all-cause mortality (odds ratio, 0.83; 95% confidence interval, 0.44-1.57) or in VTE (OR, 0.52; 95% CI, 0.26-1.04).

In a secondary analysis, which included additional psoriatic arthritis RCTs, no significant differences between the treatment and placebo/active comparator groups were observed. Similarly, subgroup analyses of oral versus topical JAK inhibitors and a sensitivity analysis that excluded pediatric trials showed no significant differences between patients exposed to JAK inhibitors and those not exposed.

The researchers acknowledged certain limitations of the review, including the lack of access to patient-level data, the fact that most trials only included short-term follow-up, and that the findings have limited generalizability to an older patient population. “It remains unclear if the cardiovascular risks of JAK inhibitors are primarily due to patient level cardiovascular risk factors or are drug mediated,” they concluded. “Dermatologists should carefully select patients and assess baseline cardiovascular risk factors when considering JAK therapy. Cardiovascular risk assessment should continue for the duration of treatment.”

Raj Chovatiya, MD, PhD, assistant professor of dermatology and director of the center for eczema and itch at Northwestern University, Chicago, who was asked to comment on the study results, characterized the findings as reassuring to dermatologists who may be reluctant to initiate therapy with JAK inhibitors based on concerns about safety signals for MACE, VTE, and all-cause mortality.

“These data systematically show that across medications and across conditions, there doesn’t appear to be an increased signal for these events during the short-term, placebo-controlled period which generally spans a few months in most studies,” he told this news organization. The findings, he added, “align well with our clinical experience to date for JAK inhibitor use in inflammatory skin disease. Short-term safety, particularly in relation to boxed warning events such MACE, VTE, and all-cause mortality, have generally been favorable with real-world use. It’s good to have a rigorous statistical analysis to refer to when setting patient expectations.”

However, he noted that these data only examined short-term safety during the placebo or active comparator-controlled periods. “Considering that events like MACE or VTE may take many months or years to manifest, continued long-term data generation is needed to fully answer the question of risk,” he said.

Dr. Garshick disclosed that he received grants from Pfizer and personal fees from Bristol Myers Squibb during the conduct of the study and personal fees from Kiniksa Pharmaceuticals outside the submitted work. Several other coauthors reported having advisory board roles and/or having received funding or support from several pharmaceutical companies. Dr. Chovatiya disclosed that he is a consultant to, a speaker for, investigator, and/or a member of the advisory board for several pharmaceutical companies, including those that develop JAK inhibitors.

Short-term use of JAK inhibitors for a dermatologic indication appears to not be associated with an increased risk of all-cause mortality, major adverse cardiovascular events (MACE) and venous thromboembolic events (VTE), results from a systematic literature review, and meta-analysis showed.

“There remains a knowledge gap regarding the risk of JAK inhibitor use and VTE and/or MACE in the dermatologic population,” researchers led by Michael S. Garshick, MD, a cardiologist at New York University Langone Health, wrote in their study, which was published online in JAMA Dermatology . “Pooled safety studies suggest that the risk of MACE and VTE may be lower in patients treated with JAK inhibitors for a dermatologic indication than the risk observed in the ORAL Surveillance study, which may be related to the younger age and better health status of those enrolled in trials for dermatologic indications.” The results of that study, which included patients with rheumatoid arthritis only, resulted in the addition of a boxed warning in the labels for topical and oral JAK inhibitors regarding the increased risk of MACE, VTE, serious infections, malignancies, and death .

For the review – thought to be the first to specifically evaluate these risks for dermatologic indications – the researchers searched PubMed and ClinicalTrials.gov from inception through April 1, 2023, for phase 3 dermatology randomized clinical trials (RCTs) to evaluate the risk of MACE, VTE, and all-cause mortality with JAK inhibitors, compared with placebo or an active comparator in the treatment of immune-mediated inflammatory skin diseases. They followed Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines and used a random-effects model and the DerSimonian-Laird method to calculate adverse events with odds ratios.

The database search yielded 35 RCTs with a total of 20,651 patients. Their mean age was 38.5 years, 54% were male, and the mean follow-up time was 4.9 months. Of the 35 trials, most (21) involved patients with atopic dermatitis, followed by psoriasis/psoriatic arthritis (9 trials), alopecia areata (3 trials) and vitiligo (2 trials).

The researchers found no significant difference between JAK inhibitors and placebo/active comparator in composite MACE and all-cause mortality (odds ratio, 0.83; 95% confidence interval, 0.44-1.57) or in VTE (OR, 0.52; 95% CI, 0.26-1.04).

In a secondary analysis, which included additional psoriatic arthritis RCTs, no significant differences between the treatment and placebo/active comparator groups were observed. Similarly, subgroup analyses of oral versus topical JAK inhibitors and a sensitivity analysis that excluded pediatric trials showed no significant differences between patients exposed to JAK inhibitors and those not exposed.

The researchers acknowledged certain limitations of the review, including the lack of access to patient-level data, the fact that most trials only included short-term follow-up, and that the findings have limited generalizability to an older patient population. “It remains unclear if the cardiovascular risks of JAK inhibitors are primarily due to patient level cardiovascular risk factors or are drug mediated,” they concluded. “Dermatologists should carefully select patients and assess baseline cardiovascular risk factors when considering JAK therapy. Cardiovascular risk assessment should continue for the duration of treatment.”

Raj Chovatiya, MD, PhD, assistant professor of dermatology and director of the center for eczema and itch at Northwestern University, Chicago, who was asked to comment on the study results, characterized the findings as reassuring to dermatologists who may be reluctant to initiate therapy with JAK inhibitors based on concerns about safety signals for MACE, VTE, and all-cause mortality.

“These data systematically show that across medications and across conditions, there doesn’t appear to be an increased signal for these events during the short-term, placebo-controlled period which generally spans a few months in most studies,” he told this news organization. The findings, he added, “align well with our clinical experience to date for JAK inhibitor use in inflammatory skin disease. Short-term safety, particularly in relation to boxed warning events such MACE, VTE, and all-cause mortality, have generally been favorable with real-world use. It’s good to have a rigorous statistical analysis to refer to when setting patient expectations.”

However, he noted that these data only examined short-term safety during the placebo or active comparator-controlled periods. “Considering that events like MACE or VTE may take many months or years to manifest, continued long-term data generation is needed to fully answer the question of risk,” he said.

Dr. Garshick disclosed that he received grants from Pfizer and personal fees from Bristol Myers Squibb during the conduct of the study and personal fees from Kiniksa Pharmaceuticals outside the submitted work. Several other coauthors reported having advisory board roles and/or having received funding or support from several pharmaceutical companies. Dr. Chovatiya disclosed that he is a consultant to, a speaker for, investigator, and/or a member of the advisory board for several pharmaceutical companies, including those that develop JAK inhibitors.

Most subjects covered in this column are botanical ingredients used for multiple conditions in topical skin care. The focus this month, though, is a natural agent garnering attention primarily for one indication. Present in many mammals and in various cells in the human body (and particularly highly concentrated in human milk), cysteamine is a stable aminothiol that acts as an antioxidant as a result of the degradation of coenzyme A and is known to play a protective function.¹ Melasma, an acquired recurrent, chronic hyperpigmentary disorder, continues to be a treatment challenge and is often psychologically troublesome for those affected, approximately 90% of whom are women.² Individuals with Fitzpatrick skin types IV and V who reside in regions where UV exposure is likely are particularly prominent among those with melasma.² While triple combination therapy (also known as Kligman’s formula) continues to be the modern gold standard of care for melasma (over the last 30 years),³ cysteamine, a nonmelanocytotoxic molecule, is considered viable for long-term use and safer than the long-time skin-lightening gold standard over several decades, hydroquinone (HQ), which is associated with safety concerns.⁴This month’s column is a review of recent findings on the efficacy and safety of cysteamine for the treatment of melasma.

Toa55/iStock/Getty Images

Recent history and the 2015 study

Prior to 2015, the quick oxidation and malodorous nature of cysteamine rendered it unsuitable for use as a topical agent. However, stabilization efforts resulted in a product that first began to show efficacy that year.⁵

Mansouri et al. conducted a randomized, double-blind, placebo-controlled trial to assess the efficacy of topical cysteamine 5% to treat epidermal melasma in 2015. Over 4 months, 50 volunteers (25 in each group) applied either cysteamine cream or placebo on lesions once nightly. The mean differences at baseline between pigmented and normal skin were 75.2 ± 37 in the cysteamine group and 68.9 ± 31 in the placebo group. Statistically significant differences between the groups were identified at the 2- and 4-month points. At 2 months, the mean differences were 39.7 ± 16.6 in the cysteamine group and 63.8 ± 28.6 in the placebo group; at 4 months, the respective differences were 26.2 ± 16 and 60.7 ± 27.3. Melasma area severity index (MASI) scores were significantly lower in the cysteamine group compared with the placebo group at the end of the study, and investigator global assessment scores and patient questionnaire results revealed substantial comparative efficacy of cysteamine cream.⁶ Topical cysteamine has also demonstrated notable efficacy in treating senile lentigines, which typically do not respond to topical depigmenting products.⁵

Farshi et al. used Dermacatch as a novel measurement tool to ascertain the efficacy of cysteamine cream for treating epidermal melasma in a 2018 report of a randomized, double-blind, placebo-controlled study with 40 patients. During the 4-month trial, cysteamine cream or placebo was applied nightly before sleep. Investigators measured treatment efficacy through Dermacatch, and Mexameter skin colorimetry, MASI scores, investigator global assessments, and patient questionnaires at baseline, 2 months, and 4 months. Through all measurement methods, cysteamine was found to reduce melanin content of melasma lesions, with Dermacatch performing reliably and comparably to Mexameter.⁷ Since then, cysteamine has been compared to several first-line melasma therapies.
 

Reviews

A 2019 systematic review by Austin et al. of randomized controlled trials (RCTs) on topical treatments for melasma identified 35 original RCTs evaluating a wide range of approximately 20 agents. They identified cysteamine, triple combination therapy, and tranexamic acid as the products netting the most robust recommendations. The researchers characterized cysteamine as conferring strong efficacy and reported anticancer activity while triple combination therapy poses the potential risk of ochronosis and tranexamic acid may present the risk for thrombosis. They concluded that more research is necessary, though, to establish the proper concentration and optimal formulation of cysteamine as a frontline therapy.⁸

More reviews have since been published to further clarify where cysteamine stands among the optimal treatments for melasma. In a May 2022 systematic PubMed review of topical agents used to treat melasma, González-Molina et al. identified 80 papers meeting inclusion criteria (double or single blinded, prospective, controlled or RCTs, reviews of literature, and meta-analysis studies), with tranexamic acid and cysteamine among the novel well-tolerated agents. Cysteamine was not associated with any severe adverse effects and is recommended as an adjuvant and maintenance therapy.³

A September 2022 review by Niazi et al. found that while the signaling mechanisms through which cysteamine suppresses melasma are not well understood, the topical application of cysteamine cream is seen as safe and effective alone or in combination with other products to treat melasma.²

A systematic review and meta-analysis reported by Gomes dos Santos-Neto et al. at the end of 2022 considered the efficacy of depigmenting formulations containing 5% cysteamine for treating melasma. The meta-analysis covered six studies, with 120 melasma patients treated. The conclusion was that 5% cysteamine was effective with adverse effects unlikely.⁹

Baumann Cosmetic & Research Institute

Cysteamine vs. hydroquinone

In 2020, Lima et al. reported the results of a quasi-randomized, multicenter, evaluator-blinded comparative study of topical 0.56% cysteamine and 4% HQ in 40 women with facial melasma. (Note that this study originally claimed a 5% cysteamine concentration, but a letter to the editor of the International Journal of Dermatology in 2020 disputed this and proved it was 0.56%) For 120 days, volunteers applied either 0.56% cysteamine or 4% HQ nightly. Tinted sunscreen (SPF 50; PPD 19) use was required for all participants. There were no differences in colorimetric evaluations between the groups, both of which showed progressive depigmenting, or in photographic assessments. The HQ group demonstrated greater mean decreases in modified melasma area severity index (mMASI) scores (41% for HQ and 24% for cysteamine at 60 days; 53% for HQ and 38% for cysteamine at 120 days). The investigators observed that while cysteamine was safe, well tolerated, and effective, it was outperformed by HQ in terms of mMASI and melasma quality of life (MELASQoL) scores.¹⁰

Early the next year, results of a randomized, double-blind, single-center study in 20 women, conducted by Nguyen et al. comparing the efficacy of cysteamine cream with HQ for melasma treatment were published. Participants were given either treatment over 16 weeks. Ultimately, five volunteers in the cysteamine group and nine in the HQ group completed the study. There was no statistically significant difference in mMASI scores between the groups. In this notably small study, HQ was tolerated better. The researchers concluded that their findings supported the argument of comparable efficacy between cysteamine and HQ, with further studies needed to establish whether cysteamine would be an appropriate alternative to HQ.¹¹ Notably, HQ was banned by the Food and Drug Administration in 2020 in over-the-counter products.
 

Cysteamine vs. Kligman’s formula

Early in 2021, Karrabi et al. published the results of a randomized, double-blind clinical trial of 50 subjects with epidermal melasma to compare cysteamine 5% with Modified Kligman’s formula. Over 4 months, participants applied once daily either cysteamine cream 5% (15 minutes exposure) or the Modified Kligman’s formula (4% hydroquinone, 0.05% retinoic acid and 0.1% betamethasone) for whole night exposure. At 2 and 4 months, a statistically significant difference in mMASI score was noted, with the percentage decline in mMASI score nearly 9% higher in the cysteamine group. The investigators concluded that cysteamine 5% demonstrated greater efficacy than the Modified Kligman’s formula and was also better tolerated.¹²

Cysteamine vs. tranexamic acid

Later that year, Karrabi et al. published the results of a single-blind, randomized clinical trial assessing the efficacy of tranexamic acid mesotherapy compared with cysteamine 5% cream in 54 melasma patients. For 4 consecutive months, the cysteamine 5% cream group applied the cream on lesions 30 minutes before going to sleep. Every 4 weeks until 2 months, a physician performed tranexamic acid mesotherapy (0.05 mL; 4 mg/mL) on individuals in the tranexamic acid group. The researchers concluded, after measurements using both a Dermacatch device and the mMASI, that neither treatment was significantly better than the other but fewer complications were observed in the cysteamine group.¹³

Safety

In 2022, Sepaskhah et al. assessed the effects of a cysteamine 5% cream and compared it with HQ 4%/ascorbic acid 3% cream for epidermal melasma in a single-blind, randomized controlled trial. Sixty-five of 80 patients completed the study. The difference in mMASI scores after 4 months was not significant between the groups nor was the improvement in quality of life, but the melanin index was significantly lower in the HQ/ascorbic acid group compared with the less substantial reduction for the cysteamine group. Nevertheless, the researchers concluded that cysteamine is a safe and suitable substitute for HQ/ascorbic acid.⁴

Conclusion

In the last decade, cysteamine has been established as a potent depigmenting agent. Its suitability and desirability as a top consideration for melasma treatment also appears to be compelling. More RCTs comparing cysteamine and other topline therapies are warranted, but current evidence shows that cysteamine is an effective and safe therapy for melasma.

Dr. Baumann is a private practice dermatologist, researcher, author, and entrepreneur in Miami. She founded the division of cosmetic dermatology at the University of Miami in 1997. The third edition of her bestselling textbook, “Cosmetic Dermatology,” was published in 2022. Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Galderma, Johnson & Johnson, and Burt’s Bees. She is the CEO of Skin Type Solutions Inc., a SaaS company used to generate skin care routines in office and as an ecommerce solution. Write to her at dermnews@mdedge.com.

References

1. Konar MC et al. J Trop Pediatr. 2020 Apr 1;66(2):129-35.

2. Niazi S et al. J Cosmet Dermatol. 2022 Sep;21(9):3867-75.

3. González-Molina V et al. J Clin Aesthet Dermatol. 2022 May;15(5):19-28.

4. Sepaskhah M et al. J Cosmet Dermatol. 2022 Jul;21(7):2871-8.

5. Desai S et al. J Drugs Dermatol. 2021 Dec 1;20(12):1276-9.

6. Mansouri P et al. Br J Dermatol. 2015 Jul;173(1):209-17.

7. Farshi S et al. J Dermatolog Treat. 2018 Mar;29(2):182-9.

8. Austin E et al. J Drugs Dermatol. 2019 Nov 1;18(11):S1545961619P1156X.

9. Gomes dos Santos-Neto A et al. Dermatol Ther. 2022 Dec;35(12):e15961.

10. Lima PB et al. Int J Dermatol. 2020 Dec;59(12):1531-6.

11. Nguyen J et al. Australas J Dermatol. 2021 Feb;62(1):e41-e46.

12. Karrabi M et al. Skin Res Technol. 2021 Jan;27(1):24-31.

13. Karrabi M et al. Arch Dermatol Res. 2021 Sep;313(7):539-47.

Most subjects covered in this column are botanical ingredients used for multiple conditions in topical skin care. The focus this month, though, is a natural agent garnering attention primarily for one indication. Present in many mammals and in various cells in the human body (and particularly highly concentrated in human milk), cysteamine is a stable aminothiol that acts as an antioxidant as a result of the degradation of coenzyme A and is known to play a protective function.¹ Melasma, an acquired recurrent, chronic hyperpigmentary disorder, continues to be a treatment challenge and is often psychologically troublesome for those affected, approximately 90% of whom are women.² Individuals with Fitzpatrick skin types IV and V who reside in regions where UV exposure is likely are particularly prominent among those with melasma.² While triple combination therapy (also known as Kligman’s formula) continues to be the modern gold standard of care for melasma (over the last 30 years),³ cysteamine, a nonmelanocytotoxic molecule, is considered viable for long-term use and safer than the long-time skin-lightening gold standard over several decades, hydroquinone (HQ), which is associated with safety concerns.⁴This month’s column is a review of recent findings on the efficacy and safety of cysteamine for the treatment of melasma.

Toa55/iStock/Getty Images

Recent history and the 2015 study

Prior to 2015, the quick oxidation and malodorous nature of cysteamine rendered it unsuitable for use as a topical agent. However, stabilization efforts resulted in a product that first began to show efficacy that year.⁵

Mansouri et al. conducted a randomized, double-blind, placebo-controlled trial to assess the efficacy of topical cysteamine 5% to treat epidermal melasma in 2015. Over 4 months, 50 volunteers (25 in each group) applied either cysteamine cream or placebo on lesions once nightly. The mean differences at baseline between pigmented and normal skin were 75.2 ± 37 in the cysteamine group and 68.9 ± 31 in the placebo group. Statistically significant differences between the groups were identified at the 2- and 4-month points. At 2 months, the mean differences were 39.7 ± 16.6 in the cysteamine group and 63.8 ± 28.6 in the placebo group; at 4 months, the respective differences were 26.2 ± 16 and 60.7 ± 27.3. Melasma area severity index (MASI) scores were significantly lower in the cysteamine group compared with the placebo group at the end of the study, and investigator global assessment scores and patient questionnaire results revealed substantial comparative efficacy of cysteamine cream.⁶ Topical cysteamine has also demonstrated notable efficacy in treating senile lentigines, which typically do not respond to topical depigmenting products.⁵

Farshi et al. used Dermacatch as a novel measurement tool to ascertain the efficacy of cysteamine cream for treating epidermal melasma in a 2018 report of a randomized, double-blind, placebo-controlled study with 40 patients. During the 4-month trial, cysteamine cream or placebo was applied nightly before sleep. Investigators measured treatment efficacy through Dermacatch, and Mexameter skin colorimetry, MASI scores, investigator global assessments, and patient questionnaires at baseline, 2 months, and 4 months. Through all measurement methods, cysteamine was found to reduce melanin content of melasma lesions, with Dermacatch performing reliably and comparably to Mexameter.⁷ Since then, cysteamine has been compared to several first-line melasma therapies.
 

Reviews

A 2019 systematic review by Austin et al. of randomized controlled trials (RCTs) on topical treatments for melasma identified 35 original RCTs evaluating a wide range of approximately 20 agents. They identified cysteamine, triple combination therapy, and tranexamic acid as the products netting the most robust recommendations. The researchers characterized cysteamine as conferring strong efficacy and reported anticancer activity while triple combination therapy poses the potential risk of ochronosis and tranexamic acid may present the risk for thrombosis. They concluded that more research is necessary, though, to establish the proper concentration and optimal formulation of cysteamine as a frontline therapy.⁸

More reviews have since been published to further clarify where cysteamine stands among the optimal treatments for melasma. In a May 2022 systematic PubMed review of topical agents used to treat melasma, González-Molina et al. identified 80 papers meeting inclusion criteria (double or single blinded, prospective, controlled or RCTs, reviews of literature, and meta-analysis studies), with tranexamic acid and cysteamine among the novel well-tolerated agents. Cysteamine was not associated with any severe adverse effects and is recommended as an adjuvant and maintenance therapy.³

A September 2022 review by Niazi et al. found that while the signaling mechanisms through which cysteamine suppresses melasma are not well understood, the topical application of cysteamine cream is seen as safe and effective alone or in combination with other products to treat melasma.²

A systematic review and meta-analysis reported by Gomes dos Santos-Neto et al. at the end of 2022 considered the efficacy of depigmenting formulations containing 5% cysteamine for treating melasma. The meta-analysis covered six studies, with 120 melasma patients treated. The conclusion was that 5% cysteamine was effective with adverse effects unlikely.⁹

Baumann Cosmetic & Research Institute

Cysteamine vs. hydroquinone

In 2020, Lima et al. reported the results of a quasi-randomized, multicenter, evaluator-blinded comparative study of topical 0.56% cysteamine and 4% HQ in 40 women with facial melasma. (Note that this study originally claimed a 5% cysteamine concentration, but a letter to the editor of the International Journal of Dermatology in 2020 disputed this and proved it was 0.56%) For 120 days, volunteers applied either 0.56% cysteamine or 4% HQ nightly. Tinted sunscreen (SPF 50; PPD 19) use was required for all participants. There were no differences in colorimetric evaluations between the groups, both of which showed progressive depigmenting, or in photographic assessments. The HQ group demonstrated greater mean decreases in modified melasma area severity index (mMASI) scores (41% for HQ and 24% for cysteamine at 60 days; 53% for HQ and 38% for cysteamine at 120 days). The investigators observed that while cysteamine was safe, well tolerated, and effective, it was outperformed by HQ in terms of mMASI and melasma quality of life (MELASQoL) scores.¹⁰

Early the next year, results of a randomized, double-blind, single-center study in 20 women, conducted by Nguyen et al. comparing the efficacy of cysteamine cream with HQ for melasma treatment were published. Participants were given either treatment over 16 weeks. Ultimately, five volunteers in the cysteamine group and nine in the HQ group completed the study. There was no statistically significant difference in mMASI scores between the groups. In this notably small study, HQ was tolerated better. The researchers concluded that their findings supported the argument of comparable efficacy between cysteamine and HQ, with further studies needed to establish whether cysteamine would be an appropriate alternative to HQ.¹¹ Notably, HQ was banned by the Food and Drug Administration in 2020 in over-the-counter products.
 

Cysteamine vs. Kligman’s formula

Early in 2021, Karrabi et al. published the results of a randomized, double-blind clinical trial of 50 subjects with epidermal melasma to compare cysteamine 5% with Modified Kligman’s formula. Over 4 months, participants applied once daily either cysteamine cream 5% (15 minutes exposure) or the Modified Kligman’s formula (4% hydroquinone, 0.05% retinoic acid and 0.1% betamethasone) for whole night exposure. At 2 and 4 months, a statistically significant difference in mMASI score was noted, with the percentage decline in mMASI score nearly 9% higher in the cysteamine group. The investigators concluded that cysteamine 5% demonstrated greater efficacy than the Modified Kligman’s formula and was also better tolerated.¹²

Cysteamine vs. tranexamic acid

Later that year, Karrabi et al. published the results of a single-blind, randomized clinical trial assessing the efficacy of tranexamic acid mesotherapy compared with cysteamine 5% cream in 54 melasma patients. For 4 consecutive months, the cysteamine 5% cream group applied the cream on lesions 30 minutes before going to sleep. Every 4 weeks until 2 months, a physician performed tranexamic acid mesotherapy (0.05 mL; 4 mg/mL) on individuals in the tranexamic acid group. The researchers concluded, after measurements using both a Dermacatch device and the mMASI, that neither treatment was significantly better than the other but fewer complications were observed in the cysteamine group.¹³

Safety

In 2022, Sepaskhah et al. assessed the effects of a cysteamine 5% cream and compared it with HQ 4%/ascorbic acid 3% cream for epidermal melasma in a single-blind, randomized controlled trial. Sixty-five of 80 patients completed the study. The difference in mMASI scores after 4 months was not significant between the groups nor was the improvement in quality of life, but the melanin index was significantly lower in the HQ/ascorbic acid group compared with the less substantial reduction for the cysteamine group. Nevertheless, the researchers concluded that cysteamine is a safe and suitable substitute for HQ/ascorbic acid.⁴

Conclusion

In the last decade, cysteamine has been established as a potent depigmenting agent. Its suitability and desirability as a top consideration for melasma treatment also appears to be compelling. More RCTs comparing cysteamine and other topline therapies are warranted, but current evidence shows that cysteamine is an effective and safe therapy for melasma.

Dr. Baumann is a private practice dermatologist, researcher, author, and entrepreneur in Miami. She founded the division of cosmetic dermatology at the University of Miami in 1997. The third edition of her bestselling textbook, “Cosmetic Dermatology,” was published in 2022. Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Galderma, Johnson & Johnson, and Burt’s Bees. She is the CEO of Skin Type Solutions Inc., a SaaS company used to generate skin care routines in office and as an ecommerce solution. Write to her at dermnews@mdedge.com.

References

1. Konar MC et al. J Trop Pediatr. 2020 Apr 1;66(2):129-35.

2. Niazi S et al. J Cosmet Dermatol. 2022 Sep;21(9):3867-75.

3. González-Molina V et al. J Clin Aesthet Dermatol. 2022 May;15(5):19-28.

4. Sepaskhah M et al. J Cosmet Dermatol. 2022 Jul;21(7):2871-8.

5. Desai S et al. J Drugs Dermatol. 2021 Dec 1;20(12):1276-9.

6. Mansouri P et al. Br J Dermatol. 2015 Jul;173(1):209-17.

7. Farshi S et al. J Dermatolog Treat. 2018 Mar;29(2):182-9.

8. Austin E et al. J Drugs Dermatol. 2019 Nov 1;18(11):S1545961619P1156X.

9. Gomes dos Santos-Neto A et al. Dermatol Ther. 2022 Dec;35(12):e15961.

10. Lima PB et al. Int J Dermatol. 2020 Dec;59(12):1531-6.

11. Nguyen J et al. Australas J Dermatol. 2021 Feb;62(1):e41-e46.

12. Karrabi M et al. Skin Res Technol. 2021 Jan;27(1):24-31.

13. Karrabi M et al. Arch Dermatol Res. 2021 Sep;313(7):539-47.

Most subjects covered in this column are botanical ingredients used for multiple conditions in topical skin care. The focus this month, though, is a natural agent garnering attention primarily for one indication. Present in many mammals and in various cells in the human body (and particularly highly concentrated in human milk), cysteamine is a stable aminothiol that acts as an antioxidant as a result of the degradation of coenzyme A and is known to play a protective function.¹ Melasma, an acquired recurrent, chronic hyperpigmentary disorder, continues to be a treatment challenge and is often psychologically troublesome for those affected, approximately 90% of whom are women.² Individuals with Fitzpatrick skin types IV and V who reside in regions where UV exposure is likely are particularly prominent among those with melasma.² While triple combination therapy (also known as Kligman’s formula) continues to be the modern gold standard of care for melasma (over the last 30 years),³ cysteamine, a nonmelanocytotoxic molecule, is considered viable for long-term use and safer than the long-time skin-lightening gold standard over several decades, hydroquinone (HQ), which is associated with safety concerns.⁴This month’s column is a review of recent findings on the efficacy and safety of cysteamine for the treatment of melasma.

Toa55/iStock/Getty Images

Recent history and the 2015 study

Prior to 2015, the quick oxidation and malodorous nature of cysteamine rendered it unsuitable for use as a topical agent. However, stabilization efforts resulted in a product that first began to show efficacy that year.⁵

Mansouri et al. conducted a randomized, double-blind, placebo-controlled trial to assess the efficacy of topical cysteamine 5% to treat epidermal melasma in 2015. Over 4 months, 50 volunteers (25 in each group) applied either cysteamine cream or placebo on lesions once nightly. The mean differences at baseline between pigmented and normal skin were 75.2 ± 37 in the cysteamine group and 68.9 ± 31 in the placebo group. Statistically significant differences between the groups were identified at the 2- and 4-month points. At 2 months, the mean differences were 39.7 ± 16.6 in the cysteamine group and 63.8 ± 28.6 in the placebo group; at 4 months, the respective differences were 26.2 ± 16 and 60.7 ± 27.3. Melasma area severity index (MASI) scores were significantly lower in the cysteamine group compared with the placebo group at the end of the study, and investigator global assessment scores and patient questionnaire results revealed substantial comparative efficacy of cysteamine cream.⁶ Topical cysteamine has also demonstrated notable efficacy in treating senile lentigines, which typically do not respond to topical depigmenting products.⁵

Farshi et al. used Dermacatch as a novel measurement tool to ascertain the efficacy of cysteamine cream for treating epidermal melasma in a 2018 report of a randomized, double-blind, placebo-controlled study with 40 patients. During the 4-month trial, cysteamine cream or placebo was applied nightly before sleep. Investigators measured treatment efficacy through Dermacatch, and Mexameter skin colorimetry, MASI scores, investigator global assessments, and patient questionnaires at baseline, 2 months, and 4 months. Through all measurement methods, cysteamine was found to reduce melanin content of melasma lesions, with Dermacatch performing reliably and comparably to Mexameter.⁷ Since then, cysteamine has been compared to several first-line melasma therapies.
 

Reviews

A 2019 systematic review by Austin et al. of randomized controlled trials (RCTs) on topical treatments for melasma identified 35 original RCTs evaluating a wide range of approximately 20 agents. They identified cysteamine, triple combination therapy, and tranexamic acid as the products netting the most robust recommendations. The researchers characterized cysteamine as conferring strong efficacy and reported anticancer activity while triple combination therapy poses the potential risk of ochronosis and tranexamic acid may present the risk for thrombosis. They concluded that more research is necessary, though, to establish the proper concentration and optimal formulation of cysteamine as a frontline therapy.⁸

More reviews have since been published to further clarify where cysteamine stands among the optimal treatments for melasma. In a May 2022 systematic PubMed review of topical agents used to treat melasma, González-Molina et al. identified 80 papers meeting inclusion criteria (double or single blinded, prospective, controlled or RCTs, reviews of literature, and meta-analysis studies), with tranexamic acid and cysteamine among the novel well-tolerated agents. Cysteamine was not associated with any severe adverse effects and is recommended as an adjuvant and maintenance therapy.³

A September 2022 review by Niazi et al. found that while the signaling mechanisms through which cysteamine suppresses melasma are not well understood, the topical application of cysteamine cream is seen as safe and effective alone or in combination with other products to treat melasma.²

A systematic review and meta-analysis reported by Gomes dos Santos-Neto et al. at the end of 2022 considered the efficacy of depigmenting formulations containing 5% cysteamine for treating melasma. The meta-analysis covered six studies, with 120 melasma patients treated. The conclusion was that 5% cysteamine was effective with adverse effects unlikely.⁹

Baumann Cosmetic & Research Institute

Cysteamine vs. hydroquinone

In 2020, Lima et al. reported the results of a quasi-randomized, multicenter, evaluator-blinded comparative study of topical 0.56% cysteamine and 4% HQ in 40 women with facial melasma. (Note that this study originally claimed a 5% cysteamine concentration, but a letter to the editor of the International Journal of Dermatology in 2020 disputed this and proved it was 0.56%) For 120 days, volunteers applied either 0.56% cysteamine or 4% HQ nightly. Tinted sunscreen (SPF 50; PPD 19) use was required for all participants. There were no differences in colorimetric evaluations between the groups, both of which showed progressive depigmenting, or in photographic assessments. The HQ group demonstrated greater mean decreases in modified melasma area severity index (mMASI) scores (41% for HQ and 24% for cysteamine at 60 days; 53% for HQ and 38% for cysteamine at 120 days). The investigators observed that while cysteamine was safe, well tolerated, and effective, it was outperformed by HQ in terms of mMASI and melasma quality of life (MELASQoL) scores.¹⁰

Early the next year, results of a randomized, double-blind, single-center study in 20 women, conducted by Nguyen et al. comparing the efficacy of cysteamine cream with HQ for melasma treatment were published. Participants were given either treatment over 16 weeks. Ultimately, five volunteers in the cysteamine group and nine in the HQ group completed the study. There was no statistically significant difference in mMASI scores between the groups. In this notably small study, HQ was tolerated better. The researchers concluded that their findings supported the argument of comparable efficacy between cysteamine and HQ, with further studies needed to establish whether cysteamine would be an appropriate alternative to HQ.¹¹ Notably, HQ was banned by the Food and Drug Administration in 2020 in over-the-counter products.
 

Cysteamine vs. Kligman’s formula

Early in 2021, Karrabi et al. published the results of a randomized, double-blind clinical trial of 50 subjects with epidermal melasma to compare cysteamine 5% with Modified Kligman’s formula. Over 4 months, participants applied once daily either cysteamine cream 5% (15 minutes exposure) or the Modified Kligman’s formula (4% hydroquinone, 0.05% retinoic acid and 0.1% betamethasone) for whole night exposure. At 2 and 4 months, a statistically significant difference in mMASI score was noted, with the percentage decline in mMASI score nearly 9% higher in the cysteamine group. The investigators concluded that cysteamine 5% demonstrated greater efficacy than the Modified Kligman’s formula and was also better tolerated.¹²

Cysteamine vs. tranexamic acid

Later that year, Karrabi et al. published the results of a single-blind, randomized clinical trial assessing the efficacy of tranexamic acid mesotherapy compared with cysteamine 5% cream in 54 melasma patients. For 4 consecutive months, the cysteamine 5% cream group applied the cream on lesions 30 minutes before going to sleep. Every 4 weeks until 2 months, a physician performed tranexamic acid mesotherapy (0.05 mL; 4 mg/mL) on individuals in the tranexamic acid group. The researchers concluded, after measurements using both a Dermacatch device and the mMASI, that neither treatment was significantly better than the other but fewer complications were observed in the cysteamine group.¹³

Safety

In 2022, Sepaskhah et al. assessed the effects of a cysteamine 5% cream and compared it with HQ 4%/ascorbic acid 3% cream for epidermal melasma in a single-blind, randomized controlled trial. Sixty-five of 80 patients completed the study. The difference in mMASI scores after 4 months was not significant between the groups nor was the improvement in quality of life, but the melanin index was significantly lower in the HQ/ascorbic acid group compared with the less substantial reduction for the cysteamine group. Nevertheless, the researchers concluded that cysteamine is a safe and suitable substitute for HQ/ascorbic acid.⁴

Conclusion

In the last decade, cysteamine has been established as a potent depigmenting agent. Its suitability and desirability as a top consideration for melasma treatment also appears to be compelling. More RCTs comparing cysteamine and other topline therapies are warranted, but current evidence shows that cysteamine is an effective and safe therapy for melasma.

Dr. Baumann is a private practice dermatologist, researcher, author, and entrepreneur in Miami. She founded the division of cosmetic dermatology at the University of Miami in 1997. The third edition of her bestselling textbook, “Cosmetic Dermatology,” was published in 2022. Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Galderma, Johnson & Johnson, and Burt’s Bees. She is the CEO of Skin Type Solutions Inc., a SaaS company used to generate skin care routines in office and as an ecommerce solution. Write to her at dermnews@mdedge.com.

References

1. Konar MC et al. J Trop Pediatr. 2020 Apr 1;66(2):129-35.

2. Niazi S et al. J Cosmet Dermatol. 2022 Sep;21(9):3867-75.

3. González-Molina V et al. J Clin Aesthet Dermatol. 2022 May;15(5):19-28.

4. Sepaskhah M et al. J Cosmet Dermatol. 2022 Jul;21(7):2871-8.

5. Desai S et al. J Drugs Dermatol. 2021 Dec 1;20(12):1276-9.

6. Mansouri P et al. Br J Dermatol. 2015 Jul;173(1):209-17.

7. Farshi S et al. J Dermatolog Treat. 2018 Mar;29(2):182-9.

8. Austin E et al. J Drugs Dermatol. 2019 Nov 1;18(11):S1545961619P1156X.

9. Gomes dos Santos-Neto A et al. Dermatol Ther. 2022 Dec;35(12):e15961.

10. Lima PB et al. Int J Dermatol. 2020 Dec;59(12):1531-6.

11. Nguyen J et al. Australas J Dermatol. 2021 Feb;62(1):e41-e46.

12. Karrabi M et al. Skin Res Technol. 2021 Jan;27(1):24-31.

13. Karrabi M et al. Arch Dermatol Res. 2021 Sep;313(7):539-47.

Practice Gap

Proper suture selection is imperative for appropriate wound healing to minimize the risk for infection and inflammation and to reduce scarring. In Mohs micrographic surgery (MMS), suture selection should be given high consideration in patients with skin of color.¹ Using the right type of suture and wound closure technique can lead to favorable aesthetic outcomes by preventing postoperative postinflammatory hyperpigmentation (PIH) and keloids. Data on the choice of suture material in patients with skin of color are limited.

Suture selection depends on a variety of factors including but not limited to the location of the wound on the body, risk for infection, cost, availability, and the personal preference and experience of the MMS surgeon. During the COVID-19 pandemic, suturepreference among dermatologic surgeons shifted to fast-absorbing gut sutures,² offering alternatives to synthetic monofilament polypropylene and nylon sutures. Absorbable sutures reduced the need for in-person follow-up visits without increasing the incidence of postoperative complications.

Despite these benefits, research suggests that natural absorbable gut sutures induce cutaneous inflammation and should be avoided in patients with skin of color.^1,3,4 Nonabsorbable sutures are less reactive, reducing PIH after MMS in patients with skin of color.

Tools and Technique

Use of nonabsorbable stitches is a practical solution to reduce the risk for inflammation in patients with skin of color. Increased inflammation can lead to PIH and increase the risk for keloids in this patient population. Some patients will experience PIH after a surgical procedure regardless of the sutures used to repair the closure; however, one of our goals with patients with skin of color undergoing MMS is to reduce the inflammatory risk that could lead to PIH to ensure optimal aesthetic outcomes.

A middle-aged African woman with darker skin and a history of developing PIH after trauma to the skin presented to our clinic for MMS of a dermatofibrosarcoma protuberans on the upper abdomen. We used a simple running suture with 4-0 nylon to close the surgical wound. We avoided fast-absorbing gut sutures because they have high tissue reactivity^1,4; use of sutures with low tissue reactivity, such as nylon and polypropylene, decreases the risk for inflammation without compromising alignment of wound edges and overall cosmesis of the repair. Prolene also is cost-effective and presents a decreased risk for wound dehiscence.⁵ After cauterizing the wound, we placed multiple synthetic absorbable sutures first to close the wound. We then did a double-running suture of nonabsorbable monofilament suture to reapproximate the epidermal edges with minimal tension. We placed 2 sets of running stitches to minimize the risk for dehiscence along the scar.

The patient was required to return for removal of the nonabsorbable sutures; this postoperative visit was covered by health insurance at no additional cost to the patient. In comparison, long-term repeat visits to treat PIH with a laser or chemical peel would have been more costly. Given that treatment of PIH is considered cosmetic, laser treatment would have been priced at several hundred dollars per session at our institution, and the patient would likely have had a copay for a pretreatment lightening cream such as hydroquinone. Our patient had a favorable cosmetic outcome and reported no or minimal evidence of PIH months after the procedure.

Patients should be instructed to apply petrolatum twice daily, use sun-protective clothing, and cover sutures to minimize exposure to the sun and prevent crusting of the wound. Postinflammatory hyperpigmentation can be proactively treated postoperatively with topical hydroquinone, which was not needed in our patient.

Practice Implications

Although some studies suggest that there are no cosmetic differences between absorbable and nonabsorbable sutures, the effect of suture type in patients with skin of color undergoing MMS often is unreported or is not studied.^6,7 The high reactivity and cutaneous inflammation associated with absorbable gut sutures are important considerations in this patient population.

In patients with skin of color undergoing MMS, we use nonabsorbable epidermal sutures such as nylon and Prolene because of their low reactivity and association with favorable aesthetic outcomes. Nonabsorbable sutures can be safely used in patients of all ages who are undergoing MMS under local anesthesia.

An exception would be the use of the absorbable suture Monocryl (J&J MedTech) in patients with skin of color who need a running subcuticular wound closure because it has low tissue reactivity and maintains high tensile strength. Monocryl has been shown to create less-reactive scars, which decreases the risk for keloids.^8,9

More clinical studies are needed to assess the increased susceptibility to PIH in patients with skin of color when using absorbable gut sutures.

Practice Gap

Proper suture selection is imperative for appropriate wound healing to minimize the risk for infection and inflammation and to reduce scarring. In Mohs micrographic surgery (MMS), suture selection should be given high consideration in patients with skin of color.¹ Using the right type of suture and wound closure technique can lead to favorable aesthetic outcomes by preventing postoperative postinflammatory hyperpigmentation (PIH) and keloids. Data on the choice of suture material in patients with skin of color are limited.

Suture selection depends on a variety of factors including but not limited to the location of the wound on the body, risk for infection, cost, availability, and the personal preference and experience of the MMS surgeon. During the COVID-19 pandemic, suturepreference among dermatologic surgeons shifted to fast-absorbing gut sutures,² offering alternatives to synthetic monofilament polypropylene and nylon sutures. Absorbable sutures reduced the need for in-person follow-up visits without increasing the incidence of postoperative complications.

Despite these benefits, research suggests that natural absorbable gut sutures induce cutaneous inflammation and should be avoided in patients with skin of color.^1,3,4 Nonabsorbable sutures are less reactive, reducing PIH after MMS in patients with skin of color.

Tools and Technique

Use of nonabsorbable stitches is a practical solution to reduce the risk for inflammation in patients with skin of color. Increased inflammation can lead to PIH and increase the risk for keloids in this patient population. Some patients will experience PIH after a surgical procedure regardless of the sutures used to repair the closure; however, one of our goals with patients with skin of color undergoing MMS is to reduce the inflammatory risk that could lead to PIH to ensure optimal aesthetic outcomes.

A middle-aged African woman with darker skin and a history of developing PIH after trauma to the skin presented to our clinic for MMS of a dermatofibrosarcoma protuberans on the upper abdomen. We used a simple running suture with 4-0 nylon to close the surgical wound. We avoided fast-absorbing gut sutures because they have high tissue reactivity^1,4; use of sutures with low tissue reactivity, such as nylon and polypropylene, decreases the risk for inflammation without compromising alignment of wound edges and overall cosmesis of the repair. Prolene also is cost-effective and presents a decreased risk for wound dehiscence.⁵ After cauterizing the wound, we placed multiple synthetic absorbable sutures first to close the wound. We then did a double-running suture of nonabsorbable monofilament suture to reapproximate the epidermal edges with minimal tension. We placed 2 sets of running stitches to minimize the risk for dehiscence along the scar.

The patient was required to return for removal of the nonabsorbable sutures; this postoperative visit was covered by health insurance at no additional cost to the patient. In comparison, long-term repeat visits to treat PIH with a laser or chemical peel would have been more costly. Given that treatment of PIH is considered cosmetic, laser treatment would have been priced at several hundred dollars per session at our institution, and the patient would likely have had a copay for a pretreatment lightening cream such as hydroquinone. Our patient had a favorable cosmetic outcome and reported no or minimal evidence of PIH months after the procedure.

Patients should be instructed to apply petrolatum twice daily, use sun-protective clothing, and cover sutures to minimize exposure to the sun and prevent crusting of the wound. Postinflammatory hyperpigmentation can be proactively treated postoperatively with topical hydroquinone, which was not needed in our patient.

Practice Implications

Although some studies suggest that there are no cosmetic differences between absorbable and nonabsorbable sutures, the effect of suture type in patients with skin of color undergoing MMS often is unreported or is not studied.^6,7 The high reactivity and cutaneous inflammation associated with absorbable gut sutures are important considerations in this patient population.

In patients with skin of color undergoing MMS, we use nonabsorbable epidermal sutures such as nylon and Prolene because of their low reactivity and association with favorable aesthetic outcomes. Nonabsorbable sutures can be safely used in patients of all ages who are undergoing MMS under local anesthesia.

An exception would be the use of the absorbable suture Monocryl (J&J MedTech) in patients with skin of color who need a running subcuticular wound closure because it has low tissue reactivity and maintains high tensile strength. Monocryl has been shown to create less-reactive scars, which decreases the risk for keloids.^8,9

More clinical studies are needed to assess the increased susceptibility to PIH in patients with skin of color when using absorbable gut sutures.

Practice Gap

Proper suture selection is imperative for appropriate wound healing to minimize the risk for infection and inflammation and to reduce scarring. In Mohs micrographic surgery (MMS), suture selection should be given high consideration in patients with skin of color.¹ Using the right type of suture and wound closure technique can lead to favorable aesthetic outcomes by preventing postoperative postinflammatory hyperpigmentation (PIH) and keloids. Data on the choice of suture material in patients with skin of color are limited.

Suture selection depends on a variety of factors including but not limited to the location of the wound on the body, risk for infection, cost, availability, and the personal preference and experience of the MMS surgeon. During the COVID-19 pandemic, suturepreference among dermatologic surgeons shifted to fast-absorbing gut sutures,² offering alternatives to synthetic monofilament polypropylene and nylon sutures. Absorbable sutures reduced the need for in-person follow-up visits without increasing the incidence of postoperative complications.

Despite these benefits, research suggests that natural absorbable gut sutures induce cutaneous inflammation and should be avoided in patients with skin of color.^1,3,4 Nonabsorbable sutures are less reactive, reducing PIH after MMS in patients with skin of color.

Tools and Technique

Use of nonabsorbable stitches is a practical solution to reduce the risk for inflammation in patients with skin of color. Increased inflammation can lead to PIH and increase the risk for keloids in this patient population. Some patients will experience PIH after a surgical procedure regardless of the sutures used to repair the closure; however, one of our goals with patients with skin of color undergoing MMS is to reduce the inflammatory risk that could lead to PIH to ensure optimal aesthetic outcomes.

A middle-aged African woman with darker skin and a history of developing PIH after trauma to the skin presented to our clinic for MMS of a dermatofibrosarcoma protuberans on the upper abdomen. We used a simple running suture with 4-0 nylon to close the surgical wound. We avoided fast-absorbing gut sutures because they have high tissue reactivity^1,4; use of sutures with low tissue reactivity, such as nylon and polypropylene, decreases the risk for inflammation without compromising alignment of wound edges and overall cosmesis of the repair. Prolene also is cost-effective and presents a decreased risk for wound dehiscence.⁵ After cauterizing the wound, we placed multiple synthetic absorbable sutures first to close the wound. We then did a double-running suture of nonabsorbable monofilament suture to reapproximate the epidermal edges with minimal tension. We placed 2 sets of running stitches to minimize the risk for dehiscence along the scar.

The patient was required to return for removal of the nonabsorbable sutures; this postoperative visit was covered by health insurance at no additional cost to the patient. In comparison, long-term repeat visits to treat PIH with a laser or chemical peel would have been more costly. Given that treatment of PIH is considered cosmetic, laser treatment would have been priced at several hundred dollars per session at our institution, and the patient would likely have had a copay for a pretreatment lightening cream such as hydroquinone. Our patient had a favorable cosmetic outcome and reported no or minimal evidence of PIH months after the procedure.

Patients should be instructed to apply petrolatum twice daily, use sun-protective clothing, and cover sutures to minimize exposure to the sun and prevent crusting of the wound. Postinflammatory hyperpigmentation can be proactively treated postoperatively with topical hydroquinone, which was not needed in our patient.

Practice Implications

Although some studies suggest that there are no cosmetic differences between absorbable and nonabsorbable sutures, the effect of suture type in patients with skin of color undergoing MMS often is unreported or is not studied.^6,7 The high reactivity and cutaneous inflammation associated with absorbable gut sutures are important considerations in this patient population.

In patients with skin of color undergoing MMS, we use nonabsorbable epidermal sutures such as nylon and Prolene because of their low reactivity and association with favorable aesthetic outcomes. Nonabsorbable sutures can be safely used in patients of all ages who are undergoing MMS under local anesthesia.

An exception would be the use of the absorbable suture Monocryl (J&J MedTech) in patients with skin of color who need a running subcuticular wound closure because it has low tissue reactivity and maintains high tensile strength. Monocryl has been shown to create less-reactive scars, which decreases the risk for keloids.^8,9

More clinical studies are needed to assess the increased susceptibility to PIH in patients with skin of color when using absorbable gut sutures.

CARLSBAD, CALIF. – According to Delphine J. Lee, MD, PhD, some patients report that their dermatologists tell them there are no effective treatments for vitiligo.

However, this is not supported by the ongoing level of research on vitiligo, with more than 100 randomized controlled trials published over the last 5 years, Dr. Lee, chief of dermatology at Harbor-UCLA Medical Center, Los Angeles, said at the annual symposium of the California Society of Dermatology & Dermatologic Surgery. And, in 2022, ruxolitinib cream became the first FDA-approved treatment for vitiligo. “There’s a lot of research happening now, and I’m pleased to say that despite the fact that some of these medications are not all brand new and exciting, they’re still new in that we have new evidence for them,” she said. “Of the 100 randomized, controlled trials, UV therapy remains a strong part of our armamentarium.”
 

Stabilizing disease

Dr. Lee underscored the importance of stabilizing existing vitiligo and arresting progressive disease, which may be indicated by four key signs: koebnerization; trichrome lesions; inflammation, which can appear as erythema, scaling, and pruritus; and confetti-like macules that are typically 1 mm to 5 mm in size. Key principles of vitiligo treatment are to stop immune destruction and to stimulate melanocyte differentiation, migration, and melanin production, which is “probably why phototherapy is so important and helpful,” she said.

Managing patients’ expectations is also important, added Dr. Lee, who shows patients photos from published clinical trials “so they can see what excellent repigmentation really means.”
 

Dexamethasone vs. mycophenolate

In a randomized, controlled trial published in 2021, researchers compared dexamethasone oral mini-pulse (OMP), 2.5 mg, on two successive days a week, with oral mycophenolate mofetil, 500 mg b.i.d., up to 2 g every day, for 180 days as a stabilizing treatment for patients with progressive, nonsegmental vitiligo, with 90 days of treatment-free follow-up. Assessments included the vitiligo disease activity (VIDA) score, the number of new lesions in the past 30 days, and the Vitiligo Area Scoring Index (VASI). Arrest of disease progression was defined as the absence of any new lesions in the previous 30 days.

Over the treatment and follow-up period, both groups showed a significant trend for reduction in VIDA and in the number of new lesions in the previous 30 days, compared with baseline (P < .001). The difference between VASI at baseline and VASI at 180 and at 270 days was not significant in both groups.

Adverse side effects reported with dexamethasone included acne, weight gain, headache, insomnia, and menstrual irregularity. “The misconception is that because we only give patients a tiny dose of steroids – 2.5 mg two days per week – that they aren’t going to have any side effects,” Dr. Lee commented. “But in fact, they do.” The most common side effects with mycophenolate were nausea and diarrhea. Two patients on mycophenolate discontinued treatment: one for leukopenia and one for transaminitis, but both conditions resolved after treatment was stopped.

The researchers concluded that both dexamethasone OMP and mycophenolate mofetil halt actively spreading vitiligo. “Relapse occurred earlier with mycophenolate, and the relapse rate was higher than with dexamethasone OMP, but this was not statistically significant,” said Dr. Lee, who also leads an immunology research team at The Lundquist Institute at Harbor-UCLA Medical Center.

Other vitiligo treatment options she discussed included the following:

Betamethasone OMP and oral azathioprine. In a comparative study, researchers compared betamethasone OMP with oral azathioprine in arresting disease progression and inducing repigmentation in adults with vitiligo. Significantly more patients in the betamethasone OMP group achieved arrest of progression at 2 months than those in the azathioprine group, but at 6 months the difference was not significant. At 6 months, of the 19 patients who completed 6 months of betamethasone OMP, 2, 2, and 9 patients had more than 20%, 10%-20%, and 5%-10% repigmentation, respectively; and of the 18 patients who completed 6 months of azathioprine, 2 patients had 10%-20% repigmentation, with the remaining patients having no repigmentation or less than 5% repigmentation.

One patient in the azathioprine group developed acute pancreatitis but none developed transaminitis or leukopenia. “Azathioprine is another agent to add to our toolbox,” Dr. Lee said of the study findings. “Both betamethasone OMP and daily azathioprine are effective” in halting disease progression.

Low-dose cyclosporine. In a comparative study, 50 patients with active vitiligo were randomized into two groups: 25 to dexamethasone OMP 2.5 mg on two consecutive days/week for 4 months, and 25 to cyclosporine 3 mg/kg per day for 4 months, stopped treatment, and were then followed up for another 2 months. After 6 months, 84% of patients in the dexamethasone OMP group and 88% of patients in the cyclosporine group achieved arrest of disease progression (P = 1.00), but the mean time to achieve that endpoint was shorter for those in the cyclosporine group, compared with those in the dexamethasone OMP group (a mean of 3.92 weeks vs. 4.12 weeks, respectively; P = .01).

The list of adverse side effects for cyclosporine was “quite lengthy compared to the usual you would expect for dexamethasone,” said Dr. Lee, who was not involved with the study. “This is something we want to take seriously and discuss with our patients. Still, I would say that low-dose cyclosporine is another possibility to add to our toolbox.”

Phototherapy combined with polypodium leucotomos. Dr. Lee highlighted a randomized, controlled trial in which 21 patients with generalized vitiligo received narrow band (NB)-UVB phototherapy plus polypodium leucotomos extract (480 mg b.i.d.) and 21 patients received NB-UVB phototherapy plus placebo. After 6 months of treatment, patients in the NB-UVB plus oral polypodium leucotomos extract group had a better response rate, compared with those in the NB-UVB plus placebo group (47.8% vs. 22%). “We know from studies of polypodium leucotomos that it seems to have an impact on adaptive immunity as well as helps to decrease oxidative stress, so that may help with melanocyte stability in vitiligo,” said Dr. Lee, who was not affiliated with the study. “As with all treatments, the head and neck is very responsive to this combination treatment. The next most responsive area would be the trunk, followed by the extremities, and hands, and feet.”
 

Topical treatments

What about topical options for vitiligo? In a randomized, double-blind, comparative study, researchers evaluated the efficacy and safety of combination treatment with 308-nm excimer light and topical calcipotriol or topical clobetasol ointment for acral vitiligo. Combination treatment (excimer light and topical medication) was applied in the first 12 weeks, followed by topical medication alone for 12 weeks. Calcipotriol 0.005% ointment was applied on one hand vs. clobetasol propionate 0.05% ointment on the other for 24 weeks.

Of the hands treated with excimer light and calcipotriol, 7.7% achieved excellent repigmentation at the end of the combination treatment period and 23% achieved good to excellent improvement after 12 weeks of calcipotriol monotherapy. More than 85% and 77% of the hands treated with calcipotriol-based and clobetasol-based regimens showed some repigmentation at the end of the study, respectively (P < .05). However, no significant difference was found between the two treatments. “The evaluation from study participants was similar in that they felt that there was clearly a difference from baseline, but there was no difference across the two-hand therapy,” Dr. Lee said.

Adverse side effects included the development of blisters in some of patients who received clobetasol. “The take-home here is that you get excellent repigmentation with calcipotriol, though it’s a small percentage, 7.7%,” Dr. Lee said. “No excellent repigmentation was observed with excimer light and topical clobetasol. These data support two possible topical regimens that could be added to phototherapy or excimer light therapy to improve results.”

In another study of 42 patients, researchers compared twice-daily tacrolimus 0.1% ointment with vehicle for facial vitiligo through 24 weeks of intervention and 24 weeks of follow-up. The researchers defined treatment success as a change of 75% or greater in repigmentation of the target lesion between baseline and week 24, as measured by computer imaging software.

They found that 65% of tacrolimus-treated patients achieved therapeutic success, compared with none of the vehicle-treated patients at week 24 (P < .0001). “Tacrolimus is thought to be an old drug, but it does deserve to have continued proper study based on much anecdotal evidence I hear,” Dr. Lee said. “There was also efficacy over vehicle during the 24 weeks of follow-up. I find that tacrolimus works very well on the face. I’ve had very good results in children.”

Another topical option is the cream formulation of the JAK inhibitor ruxolitinib (Opzelura), approved in 2022 for the treatment of nonsegmental vitiligo in patients ages 12 and older, the first FDA-approved treatment for vitiligo. “As with the tacrolimus study, there are patients who achieve 100% repigmentation [with ruxolitinib], but others who may not,” Dr. Lee said. In addition, she noted that the combination of JAK inhibitors with phototherapy is emerging as another possible treatment choice, referring to a recently published systematic review suggesting that concurrent UVB phototherapy appears to improve efficacy of JAK inhibitors for vitiligo.

Dr. Lee reported having no relevant financial disclosures.

CARLSBAD, CALIF. – According to Delphine J. Lee, MD, PhD, some patients report that their dermatologists tell them there are no effective treatments for vitiligo.

However, this is not supported by the ongoing level of research on vitiligo, with more than 100 randomized controlled trials published over the last 5 years, Dr. Lee, chief of dermatology at Harbor-UCLA Medical Center, Los Angeles, said at the annual symposium of the California Society of Dermatology & Dermatologic Surgery. And, in 2022, ruxolitinib cream became the first FDA-approved treatment for vitiligo. “There’s a lot of research happening now, and I’m pleased to say that despite the fact that some of these medications are not all brand new and exciting, they’re still new in that we have new evidence for them,” she said. “Of the 100 randomized, controlled trials, UV therapy remains a strong part of our armamentarium.”
 

Stabilizing disease

Dr. Lee underscored the importance of stabilizing existing vitiligo and arresting progressive disease, which may be indicated by four key signs: koebnerization; trichrome lesions; inflammation, which can appear as erythema, scaling, and pruritus; and confetti-like macules that are typically 1 mm to 5 mm in size. Key principles of vitiligo treatment are to stop immune destruction and to stimulate melanocyte differentiation, migration, and melanin production, which is “probably why phototherapy is so important and helpful,” she said.

Managing patients’ expectations is also important, added Dr. Lee, who shows patients photos from published clinical trials “so they can see what excellent repigmentation really means.”
 

Dexamethasone vs. mycophenolate

In a randomized, controlled trial published in 2021, researchers compared dexamethasone oral mini-pulse (OMP), 2.5 mg, on two successive days a week, with oral mycophenolate mofetil, 500 mg b.i.d., up to 2 g every day, for 180 days as a stabilizing treatment for patients with progressive, nonsegmental vitiligo, with 90 days of treatment-free follow-up. Assessments included the vitiligo disease activity (VIDA) score, the number of new lesions in the past 30 days, and the Vitiligo Area Scoring Index (VASI). Arrest of disease progression was defined as the absence of any new lesions in the previous 30 days.

Over the treatment and follow-up period, both groups showed a significant trend for reduction in VIDA and in the number of new lesions in the previous 30 days, compared with baseline (P < .001). The difference between VASI at baseline and VASI at 180 and at 270 days was not significant in both groups.

Adverse side effects reported with dexamethasone included acne, weight gain, headache, insomnia, and menstrual irregularity. “The misconception is that because we only give patients a tiny dose of steroids – 2.5 mg two days per week – that they aren’t going to have any side effects,” Dr. Lee commented. “But in fact, they do.” The most common side effects with mycophenolate were nausea and diarrhea. Two patients on mycophenolate discontinued treatment: one for leukopenia and one for transaminitis, but both conditions resolved after treatment was stopped.

The researchers concluded that both dexamethasone OMP and mycophenolate mofetil halt actively spreading vitiligo. “Relapse occurred earlier with mycophenolate, and the relapse rate was higher than with dexamethasone OMP, but this was not statistically significant,” said Dr. Lee, who also leads an immunology research team at The Lundquist Institute at Harbor-UCLA Medical Center.

Other vitiligo treatment options she discussed included the following:

Betamethasone OMP and oral azathioprine. In a comparative study, researchers compared betamethasone OMP with oral azathioprine in arresting disease progression and inducing repigmentation in adults with vitiligo. Significantly more patients in the betamethasone OMP group achieved arrest of progression at 2 months than those in the azathioprine group, but at 6 months the difference was not significant. At 6 months, of the 19 patients who completed 6 months of betamethasone OMP, 2, 2, and 9 patients had more than 20%, 10%-20%, and 5%-10% repigmentation, respectively; and of the 18 patients who completed 6 months of azathioprine, 2 patients had 10%-20% repigmentation, with the remaining patients having no repigmentation or less than 5% repigmentation.

One patient in the azathioprine group developed acute pancreatitis but none developed transaminitis or leukopenia. “Azathioprine is another agent to add to our toolbox,” Dr. Lee said of the study findings. “Both betamethasone OMP and daily azathioprine are effective” in halting disease progression.

Low-dose cyclosporine. In a comparative study, 50 patients with active vitiligo were randomized into two groups: 25 to dexamethasone OMP 2.5 mg on two consecutive days/week for 4 months, and 25 to cyclosporine 3 mg/kg per day for 4 months, stopped treatment, and were then followed up for another 2 months. After 6 months, 84% of patients in the dexamethasone OMP group and 88% of patients in the cyclosporine group achieved arrest of disease progression (P = 1.00), but the mean time to achieve that endpoint was shorter for those in the cyclosporine group, compared with those in the dexamethasone OMP group (a mean of 3.92 weeks vs. 4.12 weeks, respectively; P = .01).

The list of adverse side effects for cyclosporine was “quite lengthy compared to the usual you would expect for dexamethasone,” said Dr. Lee, who was not involved with the study. “This is something we want to take seriously and discuss with our patients. Still, I would say that low-dose cyclosporine is another possibility to add to our toolbox.”

Phototherapy combined with polypodium leucotomos. Dr. Lee highlighted a randomized, controlled trial in which 21 patients with generalized vitiligo received narrow band (NB)-UVB phototherapy plus polypodium leucotomos extract (480 mg b.i.d.) and 21 patients received NB-UVB phototherapy plus placebo. After 6 months of treatment, patients in the NB-UVB plus oral polypodium leucotomos extract group had a better response rate, compared with those in the NB-UVB plus placebo group (47.8% vs. 22%). “We know from studies of polypodium leucotomos that it seems to have an impact on adaptive immunity as well as helps to decrease oxidative stress, so that may help with melanocyte stability in vitiligo,” said Dr. Lee, who was not affiliated with the study. “As with all treatments, the head and neck is very responsive to this combination treatment. The next most responsive area would be the trunk, followed by the extremities, and hands, and feet.”
 

Topical treatments

What about topical options for vitiligo? In a randomized, double-blind, comparative study, researchers evaluated the efficacy and safety of combination treatment with 308-nm excimer light and topical calcipotriol or topical clobetasol ointment for acral vitiligo. Combination treatment (excimer light and topical medication) was applied in the first 12 weeks, followed by topical medication alone for 12 weeks. Calcipotriol 0.005% ointment was applied on one hand vs. clobetasol propionate 0.05% ointment on the other for 24 weeks.

Of the hands treated with excimer light and calcipotriol, 7.7% achieved excellent repigmentation at the end of the combination treatment period and 23% achieved good to excellent improvement after 12 weeks of calcipotriol monotherapy. More than 85% and 77% of the hands treated with calcipotriol-based and clobetasol-based regimens showed some repigmentation at the end of the study, respectively (P < .05). However, no significant difference was found between the two treatments. “The evaluation from study participants was similar in that they felt that there was clearly a difference from baseline, but there was no difference across the two-hand therapy,” Dr. Lee said.

Adverse side effects included the development of blisters in some of patients who received clobetasol. “The take-home here is that you get excellent repigmentation with calcipotriol, though it’s a small percentage, 7.7%,” Dr. Lee said. “No excellent repigmentation was observed with excimer light and topical clobetasol. These data support two possible topical regimens that could be added to phototherapy or excimer light therapy to improve results.”

In another study of 42 patients, researchers compared twice-daily tacrolimus 0.1% ointment with vehicle for facial vitiligo through 24 weeks of intervention and 24 weeks of follow-up. The researchers defined treatment success as a change of 75% or greater in repigmentation of the target lesion between baseline and week 24, as measured by computer imaging software.

They found that 65% of tacrolimus-treated patients achieved therapeutic success, compared with none of the vehicle-treated patients at week 24 (P < .0001). “Tacrolimus is thought to be an old drug, but it does deserve to have continued proper study based on much anecdotal evidence I hear,” Dr. Lee said. “There was also efficacy over vehicle during the 24 weeks of follow-up. I find that tacrolimus works very well on the face. I’ve had very good results in children.”

Another topical option is the cream formulation of the JAK inhibitor ruxolitinib (Opzelura), approved in 2022 for the treatment of nonsegmental vitiligo in patients ages 12 and older, the first FDA-approved treatment for vitiligo. “As with the tacrolimus study, there are patients who achieve 100% repigmentation [with ruxolitinib], but others who may not,” Dr. Lee said. In addition, she noted that the combination of JAK inhibitors with phototherapy is emerging as another possible treatment choice, referring to a recently published systematic review suggesting that concurrent UVB phototherapy appears to improve efficacy of JAK inhibitors for vitiligo.

Dr. Lee reported having no relevant financial disclosures.

CARLSBAD, CALIF. – According to Delphine J. Lee, MD, PhD, some patients report that their dermatologists tell them there are no effective treatments for vitiligo.

However, this is not supported by the ongoing level of research on vitiligo, with more than 100 randomized controlled trials published over the last 5 years, Dr. Lee, chief of dermatology at Harbor-UCLA Medical Center, Los Angeles, said at the annual symposium of the California Society of Dermatology & Dermatologic Surgery. And, in 2022, ruxolitinib cream became the first FDA-approved treatment for vitiligo. “There’s a lot of research happening now, and I’m pleased to say that despite the fact that some of these medications are not all brand new and exciting, they’re still new in that we have new evidence for them,” she said. “Of the 100 randomized, controlled trials, UV therapy remains a strong part of our armamentarium.”
 

Stabilizing disease

Dr. Lee underscored the importance of stabilizing existing vitiligo and arresting progressive disease, which may be indicated by four key signs: koebnerization; trichrome lesions; inflammation, which can appear as erythema, scaling, and pruritus; and confetti-like macules that are typically 1 mm to 5 mm in size. Key principles of vitiligo treatment are to stop immune destruction and to stimulate melanocyte differentiation, migration, and melanin production, which is “probably why phototherapy is so important and helpful,” she said.

Managing patients’ expectations is also important, added Dr. Lee, who shows patients photos from published clinical trials “so they can see what excellent repigmentation really means.”
 

Dexamethasone vs. mycophenolate

In a randomized, controlled trial published in 2021, researchers compared dexamethasone oral mini-pulse (OMP), 2.5 mg, on two successive days a week, with oral mycophenolate mofetil, 500 mg b.i.d., up to 2 g every day, for 180 days as a stabilizing treatment for patients with progressive, nonsegmental vitiligo, with 90 days of treatment-free follow-up. Assessments included the vitiligo disease activity (VIDA) score, the number of new lesions in the past 30 days, and the Vitiligo Area Scoring Index (VASI). Arrest of disease progression was defined as the absence of any new lesions in the previous 30 days.

Over the treatment and follow-up period, both groups showed a significant trend for reduction in VIDA and in the number of new lesions in the previous 30 days, compared with baseline (P < .001). The difference between VASI at baseline and VASI at 180 and at 270 days was not significant in both groups.

Adverse side effects reported with dexamethasone included acne, weight gain, headache, insomnia, and menstrual irregularity. “The misconception is that because we only give patients a tiny dose of steroids – 2.5 mg two days per week – that they aren’t going to have any side effects,” Dr. Lee commented. “But in fact, they do.” The most common side effects with mycophenolate were nausea and diarrhea. Two patients on mycophenolate discontinued treatment: one for leukopenia and one for transaminitis, but both conditions resolved after treatment was stopped.

The researchers concluded that both dexamethasone OMP and mycophenolate mofetil halt actively spreading vitiligo. “Relapse occurred earlier with mycophenolate, and the relapse rate was higher than with dexamethasone OMP, but this was not statistically significant,” said Dr. Lee, who also leads an immunology research team at The Lundquist Institute at Harbor-UCLA Medical Center.

Other vitiligo treatment options she discussed included the following:

Betamethasone OMP and oral azathioprine. In a comparative study, researchers compared betamethasone OMP with oral azathioprine in arresting disease progression and inducing repigmentation in adults with vitiligo. Significantly more patients in the betamethasone OMP group achieved arrest of progression at 2 months than those in the azathioprine group, but at 6 months the difference was not significant. At 6 months, of the 19 patients who completed 6 months of betamethasone OMP, 2, 2, and 9 patients had more than 20%, 10%-20%, and 5%-10% repigmentation, respectively; and of the 18 patients who completed 6 months of azathioprine, 2 patients had 10%-20% repigmentation, with the remaining patients having no repigmentation or less than 5% repigmentation.

One patient in the azathioprine group developed acute pancreatitis but none developed transaminitis or leukopenia. “Azathioprine is another agent to add to our toolbox,” Dr. Lee said of the study findings. “Both betamethasone OMP and daily azathioprine are effective” in halting disease progression.

Low-dose cyclosporine. In a comparative study, 50 patients with active vitiligo were randomized into two groups: 25 to dexamethasone OMP 2.5 mg on two consecutive days/week for 4 months, and 25 to cyclosporine 3 mg/kg per day for 4 months, stopped treatment, and were then followed up for another 2 months. After 6 months, 84% of patients in the dexamethasone OMP group and 88% of patients in the cyclosporine group achieved arrest of disease progression (P = 1.00), but the mean time to achieve that endpoint was shorter for those in the cyclosporine group, compared with those in the dexamethasone OMP group (a mean of 3.92 weeks vs. 4.12 weeks, respectively; P = .01).

The list of adverse side effects for cyclosporine was “quite lengthy compared to the usual you would expect for dexamethasone,” said Dr. Lee, who was not involved with the study. “This is something we want to take seriously and discuss with our patients. Still, I would say that low-dose cyclosporine is another possibility to add to our toolbox.”

Phototherapy combined with polypodium leucotomos. Dr. Lee highlighted a randomized, controlled trial in which 21 patients with generalized vitiligo received narrow band (NB)-UVB phototherapy plus polypodium leucotomos extract (480 mg b.i.d.) and 21 patients received NB-UVB phototherapy plus placebo. After 6 months of treatment, patients in the NB-UVB plus oral polypodium leucotomos extract group had a better response rate, compared with those in the NB-UVB plus placebo group (47.8% vs. 22%). “We know from studies of polypodium leucotomos that it seems to have an impact on adaptive immunity as well as helps to decrease oxidative stress, so that may help with melanocyte stability in vitiligo,” said Dr. Lee, who was not affiliated with the study. “As with all treatments, the head and neck is very responsive to this combination treatment. The next most responsive area would be the trunk, followed by the extremities, and hands, and feet.”
 

Topical treatments

What about topical options for vitiligo? In a randomized, double-blind, comparative study, researchers evaluated the efficacy and safety of combination treatment with 308-nm excimer light and topical calcipotriol or topical clobetasol ointment for acral vitiligo. Combination treatment (excimer light and topical medication) was applied in the first 12 weeks, followed by topical medication alone for 12 weeks. Calcipotriol 0.005% ointment was applied on one hand vs. clobetasol propionate 0.05% ointment on the other for 24 weeks.

Of the hands treated with excimer light and calcipotriol, 7.7% achieved excellent repigmentation at the end of the combination treatment period and 23% achieved good to excellent improvement after 12 weeks of calcipotriol monotherapy. More than 85% and 77% of the hands treated with calcipotriol-based and clobetasol-based regimens showed some repigmentation at the end of the study, respectively (P < .05). However, no significant difference was found between the two treatments. “The evaluation from study participants was similar in that they felt that there was clearly a difference from baseline, but there was no difference across the two-hand therapy,” Dr. Lee said.

Adverse side effects included the development of blisters in some of patients who received clobetasol. “The take-home here is that you get excellent repigmentation with calcipotriol, though it’s a small percentage, 7.7%,” Dr. Lee said. “No excellent repigmentation was observed with excimer light and topical clobetasol. These data support two possible topical regimens that could be added to phototherapy or excimer light therapy to improve results.”

In another study of 42 patients, researchers compared twice-daily tacrolimus 0.1% ointment with vehicle for facial vitiligo through 24 weeks of intervention and 24 weeks of follow-up. The researchers defined treatment success as a change of 75% or greater in repigmentation of the target lesion between baseline and week 24, as measured by computer imaging software.

They found that 65% of tacrolimus-treated patients achieved therapeutic success, compared with none of the vehicle-treated patients at week 24 (P < .0001). “Tacrolimus is thought to be an old drug, but it does deserve to have continued proper study based on much anecdotal evidence I hear,” Dr. Lee said. “There was also efficacy over vehicle during the 24 weeks of follow-up. I find that tacrolimus works very well on the face. I’ve had very good results in children.”

Another topical option is the cream formulation of the JAK inhibitor ruxolitinib (Opzelura), approved in 2022 for the treatment of nonsegmental vitiligo in patients ages 12 and older, the first FDA-approved treatment for vitiligo. “As with the tacrolimus study, there are patients who achieve 100% repigmentation [with ruxolitinib], but others who may not,” Dr. Lee said. In addition, she noted that the combination of JAK inhibitors with phototherapy is emerging as another possible treatment choice, referring to a recently published systematic review suggesting that concurrent UVB phototherapy appears to improve efficacy of JAK inhibitors for vitiligo.

Dr. Lee reported having no relevant financial disclosures.

TOPLINE:

Direct health care costs for patients with vitiligo eclipse those of matched control persons.

METHODOLOGY:

• No published studies have quantified the medical costs and health care resource utilization (HCRU) among patients with vitiligo in the United States, compared with the general population.
• Drawing from the Merative MarketScan Commercial Claims and Encounters database, researchers reviewed the records of 49,512 patients diagnosed with vitiligo between Jan. 1, 2008, and Dec. 31, 2020, and those of 99,024 matched control persons who did not have vitiligo.
• Costs were in 2021 dollars during a 1-year postindex period. The student t test and chi square analysis were used to determine P values.

TAKEAWAY:

• In both cohorts, the median age of patients was 43 years, 79.2% were female, and most (39%) were from the southern region of the United States.
• All-cause total health care costs for patients with vitiligo were significantly higher than those of matched controls ($15,551 vs. $7,735; P < .0001).
• Similarly, medical costs for patients with vitiligo were significantly higher than those of control persons ($11,953 vs. $5,722), as were pharmacy costs ($3,598 vs. $2,014; P < .001 for both associations).
• A significantly greater proportion of patients with vitiligo had higher all-cause HCRU, compared with matched control persons. That included at least one ED visit (17.5% vs 13.4%), at least one inpatient visit (12.9% vs 6.8%), and at least one outpatient visit (99.8% vs. 88.3%; P < .0001 for all associations).

IN PRACTICE:

“These findings reveal an unmet need for cost-effective treatments and highlight the importance of fully identifying the drivers of economic burden for patients with vitiligo,” the authors concluded.

SOURCE:

Khaled Ezzedine, MD, PhD, of the department of dermatology at the Henri Mondor University Hospital, Créteil, France, led the study, which was published in the Journal of Investigative Dermatology.

LIMITATIONS:

The investigators did not evaluate indirect medical costs of vitiligo, such as work productivity, early retirement, and lost opportunities. Also, the results may not be generalizable to populations outside of the United States.

DISCLOSURES:

Dr. Ezzedine has received honoraria as a consultant for AbbVie, Incyte, La Roche–Posay, Pfizer, Pierre Fabre, Sanofi, and Viela Bio. One author is an investigator for Incyte and is a consultant for several pharmaceutical companies. Three authors are AbbVie employees.

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

TOPLINE:

Direct health care costs for patients with vitiligo eclipse those of matched control persons.

METHODOLOGY:

• No published studies have quantified the medical costs and health care resource utilization (HCRU) among patients with vitiligo in the United States, compared with the general population.
• Drawing from the Merative MarketScan Commercial Claims and Encounters database, researchers reviewed the records of 49,512 patients diagnosed with vitiligo between Jan. 1, 2008, and Dec. 31, 2020, and those of 99,024 matched control persons who did not have vitiligo.
• Costs were in 2021 dollars during a 1-year postindex period. The student t test and chi square analysis were used to determine P values.

TAKEAWAY:

• In both cohorts, the median age of patients was 43 years, 79.2% were female, and most (39%) were from the southern region of the United States.
• All-cause total health care costs for patients with vitiligo were significantly higher than those of matched controls ($15,551 vs. $7,735; P < .0001).
• Similarly, medical costs for patients with vitiligo were significantly higher than those of control persons ($11,953 vs. $5,722), as were pharmacy costs ($3,598 vs. $2,014; P < .001 for both associations).
• A significantly greater proportion of patients with vitiligo had higher all-cause HCRU, compared with matched control persons. That included at least one ED visit (17.5% vs 13.4%), at least one inpatient visit (12.9% vs 6.8%), and at least one outpatient visit (99.8% vs. 88.3%; P < .0001 for all associations).

IN PRACTICE:

“These findings reveal an unmet need for cost-effective treatments and highlight the importance of fully identifying the drivers of economic burden for patients with vitiligo,” the authors concluded.

SOURCE:

Khaled Ezzedine, MD, PhD, of the department of dermatology at the Henri Mondor University Hospital, Créteil, France, led the study, which was published in the Journal of Investigative Dermatology.

LIMITATIONS:

The investigators did not evaluate indirect medical costs of vitiligo, such as work productivity, early retirement, and lost opportunities. Also, the results may not be generalizable to populations outside of the United States.

DISCLOSURES:

Dr. Ezzedine has received honoraria as a consultant for AbbVie, Incyte, La Roche–Posay, Pfizer, Pierre Fabre, Sanofi, and Viela Bio. One author is an investigator for Incyte and is a consultant for several pharmaceutical companies. Three authors are AbbVie employees.

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

TOPLINE:

Direct health care costs for patients with vitiligo eclipse those of matched control persons.

METHODOLOGY:

• No published studies have quantified the medical costs and health care resource utilization (HCRU) among patients with vitiligo in the United States, compared with the general population.
• Drawing from the Merative MarketScan Commercial Claims and Encounters database, researchers reviewed the records of 49,512 patients diagnosed with vitiligo between Jan. 1, 2008, and Dec. 31, 2020, and those of 99,024 matched control persons who did not have vitiligo.
• Costs were in 2021 dollars during a 1-year postindex period. The student t test and chi square analysis were used to determine P values.

TAKEAWAY:

• In both cohorts, the median age of patients was 43 years, 79.2% were female, and most (39%) were from the southern region of the United States.
• All-cause total health care costs for patients with vitiligo were significantly higher than those of matched controls ($15,551 vs. $7,735; P < .0001).
• Similarly, medical costs for patients with vitiligo were significantly higher than those of control persons ($11,953 vs. $5,722), as were pharmacy costs ($3,598 vs. $2,014; P < .001 for both associations).
• A significantly greater proportion of patients with vitiligo had higher all-cause HCRU, compared with matched control persons. That included at least one ED visit (17.5% vs 13.4%), at least one inpatient visit (12.9% vs 6.8%), and at least one outpatient visit (99.8% vs. 88.3%; P < .0001 for all associations).

IN PRACTICE:

“These findings reveal an unmet need for cost-effective treatments and highlight the importance of fully identifying the drivers of economic burden for patients with vitiligo,” the authors concluded.

SOURCE:

Khaled Ezzedine, MD, PhD, of the department of dermatology at the Henri Mondor University Hospital, Créteil, France, led the study, which was published in the Journal of Investigative Dermatology.

LIMITATIONS:

The investigators did not evaluate indirect medical costs of vitiligo, such as work productivity, early retirement, and lost opportunities. Also, the results may not be generalizable to populations outside of the United States.

DISCLOSURES:

Dr. Ezzedine has received honoraria as a consultant for AbbVie, Incyte, La Roche–Posay, Pfizer, Pierre Fabre, Sanofi, and Viela Bio. One author is an investigator for Incyte and is a consultant for several pharmaceutical companies. Three authors are AbbVie employees.

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

The Diagnosis: Galli-Galli Disease

Several cutaneous conditions can present as reticulated hyperpigmentation or keratotic papules. Although genetic testing can help identify some of these dermatoses, biopsy typically is sufficient for diagnosis, and genetic testing can be considered for more clinically challenging cases. In our case, the clinical evidence and histopathologic findings were diagnostic of Galli-Galli disease (GGD), an autosomal-dominant genodermatosis with incomplete penetrance. Our patient was unaware of any family members with a diagnosis of GGD; however, she reported a great uncle with similar clinical findings.

Galli-Galli disease is a rare allelic variant of Dowling- Degos disease (DDD), both caused by a loss-of-function mutation in the keratin 5 gene, KRT5. Both conditions present as reticulated papules distributed symmetrically in the flexural regions, most commonly the axillae and groin, but also as comedolike papules, typically in patients aged 30 to 50 years.¹ Cutaneous lesions primarily are of cosmetic concern but can be extremely pruritic, especially for patients with GGD. Gene mutations in protein O-fucosyltransferase 1, POFUT1; protein O-glucosyltransferase 1, POGLUT1; and presenilin enhancer 2, PSENEN, also have been discovered in cases of DDD and GGD.^2,3

Galli-Galli disease and DDD are distinguishable by their histologic appearance. Both diseases show elongated fingerlike rete ridges and a thin suprapapillary epidermis. The basal projections often are described as bulbous or resembling antler horns.⁴ Galli-Galli disease can be differentiated from DDD by focal suprabasal acantholysis with minimal dyskeratosis (quiz images).⁵ Due to the genetic and clinical similarities, many consider GGD an acantholytic variant of DDD rather than its own entity. Indeed, some patients have shown acantholysis in one area of biopsy but not others.⁶

Hailey-Hailey disease (HHD)(also known as benign familial or benign chronic pemphigus) is an autosomaldominant disorder caused by mutation of the ATPase secretory pathway Ca2+ transporting 1 gene, ATP2C1. Clinically, patients tend to present at a wide age range with fragile flaccid vesicles that commonly develop on the neck, axillae, and groin. Histologically, the epidermis is acanthotic with a dilapidated brick wall– like appearance from a few persistent intercellular connections amid widespread acantholysis (Figure 1).⁷ Unlike in autoimmune pemphigus, direct immunofluorescence is negative, and acantholysis spares the adnexal structures. Hailey-Hailey disease does not involve reticulated hyperpigmentation or the elongated bulbous rete seen in GGD. Confluent and reticulated papillomatosis is a rare, typically asymptomatic, hyperpigmented dermatosis. It presents as a conglomeration of scaly hyperpigmented macules or papillomatous papules that coalesce centrally and are reticulated toward the periphery.

Confluent and reticulated papillomatosis most commonly is seen on the trunk, initially presenting in adolescents and young adults. Confluent and reticulated papillomatosis is histologically similar to acanthosis nigricans. Histopathology will show hyperkeratosis, papillomatosis, and minimal to no inflammatory infiltrate, with no elongated rete ridges or acantholysis (Figure 2).⁸

Pemphigus vulgaris is a blistering disease resulting from the development of autoantibodies against desmogleins 1 and 3. Similar to GGD, there is suprabasal acantholysis, which often results in a tombstonelike appearance consisting of separation between the basal layer cells of the epidermis but with maintained attachment to the underlying basement membrane zone. Unlike HHD, the acantholysis tends to involve the follicular epithelium in pemphigus vulgaris (Figure 3). Clinically, the blisters are positive for Nikolsky sign and can be both cutaneous or mucosal, commonly arising initially in the mouth during the fourth or fifth decades of life. Ruptured blisters can result in painful and hemorrhagic erosions.⁹ Direct immunofluorescence exhibits a classic chicken wire–like deposition of IgG and C3 between keratinocytes of the epidermis. Although sometimes difficult to appreciate, the deposition can be more prominent in the lower epidermis, in contrast to pemphigus foliaceus, which can have more prominent deposition in the upper epidermis.

Darier disease (or dyskeratosis follicularis) is an autosomal-dominant genodermatosis caused by mutation of the ATPase sarcoplasmic/endoplasmic reticulum Ca2+ transporting 2 gene, ATP2A2. Clinically, this disorder arises in adolescents as red-brown, greasy, crusted papules in seborrheic areas that may coalesce into papillomatous clusters. Palmar punctate keratoses and pits also are common. Histologically, Darier disease can appear similar to GGD, as both can show acantholysis and dyskeratosis. Darier disease will tend to show more prominent dyskeratosis with corps ronds and grains, as well as thicker villilike projections of keratinocytes into the papillary dermis, in contrast to the thinner, fingerlike or bulbous projections that hang down from the epidermis in GGD (Figure 4).¹⁰

The Diagnosis: Galli-Galli Disease

Several cutaneous conditions can present as reticulated hyperpigmentation or keratotic papules. Although genetic testing can help identify some of these dermatoses, biopsy typically is sufficient for diagnosis, and genetic testing can be considered for more clinically challenging cases. In our case, the clinical evidence and histopathologic findings were diagnostic of Galli-Galli disease (GGD), an autosomal-dominant genodermatosis with incomplete penetrance. Our patient was unaware of any family members with a diagnosis of GGD; however, she reported a great uncle with similar clinical findings.

Galli-Galli disease is a rare allelic variant of Dowling- Degos disease (DDD), both caused by a loss-of-function mutation in the keratin 5 gene, KRT5. Both conditions present as reticulated papules distributed symmetrically in the flexural regions, most commonly the axillae and groin, but also as comedolike papules, typically in patients aged 30 to 50 years.¹ Cutaneous lesions primarily are of cosmetic concern but can be extremely pruritic, especially for patients with GGD. Gene mutations in protein O-fucosyltransferase 1, POFUT1; protein O-glucosyltransferase 1, POGLUT1; and presenilin enhancer 2, PSENEN, also have been discovered in cases of DDD and GGD.^2,3

Galli-Galli disease and DDD are distinguishable by their histologic appearance. Both diseases show elongated fingerlike rete ridges and a thin suprapapillary epidermis. The basal projections often are described as bulbous or resembling antler horns.⁴ Galli-Galli disease can be differentiated from DDD by focal suprabasal acantholysis with minimal dyskeratosis (quiz images).⁵ Due to the genetic and clinical similarities, many consider GGD an acantholytic variant of DDD rather than its own entity. Indeed, some patients have shown acantholysis in one area of biopsy but not others.⁶

Hailey-Hailey disease (HHD)(also known as benign familial or benign chronic pemphigus) is an autosomaldominant disorder caused by mutation of the ATPase secretory pathway Ca2+ transporting 1 gene, ATP2C1. Clinically, patients tend to present at a wide age range with fragile flaccid vesicles that commonly develop on the neck, axillae, and groin. Histologically, the epidermis is acanthotic with a dilapidated brick wall– like appearance from a few persistent intercellular connections amid widespread acantholysis (Figure 1).⁷ Unlike in autoimmune pemphigus, direct immunofluorescence is negative, and acantholysis spares the adnexal structures. Hailey-Hailey disease does not involve reticulated hyperpigmentation or the elongated bulbous rete seen in GGD. Confluent and reticulated papillomatosis is a rare, typically asymptomatic, hyperpigmented dermatosis. It presents as a conglomeration of scaly hyperpigmented macules or papillomatous papules that coalesce centrally and are reticulated toward the periphery.

Confluent and reticulated papillomatosis most commonly is seen on the trunk, initially presenting in adolescents and young adults. Confluent and reticulated papillomatosis is histologically similar to acanthosis nigricans. Histopathology will show hyperkeratosis, papillomatosis, and minimal to no inflammatory infiltrate, with no elongated rete ridges or acantholysis (Figure 2).⁸

Pemphigus vulgaris is a blistering disease resulting from the development of autoantibodies against desmogleins 1 and 3. Similar to GGD, there is suprabasal acantholysis, which often results in a tombstonelike appearance consisting of separation between the basal layer cells of the epidermis but with maintained attachment to the underlying basement membrane zone. Unlike HHD, the acantholysis tends to involve the follicular epithelium in pemphigus vulgaris (Figure 3). Clinically, the blisters are positive for Nikolsky sign and can be both cutaneous or mucosal, commonly arising initially in the mouth during the fourth or fifth decades of life. Ruptured blisters can result in painful and hemorrhagic erosions.⁹ Direct immunofluorescence exhibits a classic chicken wire–like deposition of IgG and C3 between keratinocytes of the epidermis. Although sometimes difficult to appreciate, the deposition can be more prominent in the lower epidermis, in contrast to pemphigus foliaceus, which can have more prominent deposition in the upper epidermis.

Darier disease (or dyskeratosis follicularis) is an autosomal-dominant genodermatosis caused by mutation of the ATPase sarcoplasmic/endoplasmic reticulum Ca2+ transporting 2 gene, ATP2A2. Clinically, this disorder arises in adolescents as red-brown, greasy, crusted papules in seborrheic areas that may coalesce into papillomatous clusters. Palmar punctate keratoses and pits also are common. Histologically, Darier disease can appear similar to GGD, as both can show acantholysis and dyskeratosis. Darier disease will tend to show more prominent dyskeratosis with corps ronds and grains, as well as thicker villilike projections of keratinocytes into the papillary dermis, in contrast to the thinner, fingerlike or bulbous projections that hang down from the epidermis in GGD (Figure 4).¹⁰

The Diagnosis: Galli-Galli Disease

Several cutaneous conditions can present as reticulated hyperpigmentation or keratotic papules. Although genetic testing can help identify some of these dermatoses, biopsy typically is sufficient for diagnosis, and genetic testing can be considered for more clinically challenging cases. In our case, the clinical evidence and histopathologic findings were diagnostic of Galli-Galli disease (GGD), an autosomal-dominant genodermatosis with incomplete penetrance. Our patient was unaware of any family members with a diagnosis of GGD; however, she reported a great uncle with similar clinical findings.

Galli-Galli disease is a rare allelic variant of Dowling- Degos disease (DDD), both caused by a loss-of-function mutation in the keratin 5 gene, KRT5. Both conditions present as reticulated papules distributed symmetrically in the flexural regions, most commonly the axillae and groin, but also as comedolike papules, typically in patients aged 30 to 50 years.¹ Cutaneous lesions primarily are of cosmetic concern but can be extremely pruritic, especially for patients with GGD. Gene mutations in protein O-fucosyltransferase 1, POFUT1; protein O-glucosyltransferase 1, POGLUT1; and presenilin enhancer 2, PSENEN, also have been discovered in cases of DDD and GGD.^2,3

Galli-Galli disease and DDD are distinguishable by their histologic appearance. Both diseases show elongated fingerlike rete ridges and a thin suprapapillary epidermis. The basal projections often are described as bulbous or resembling antler horns.⁴ Galli-Galli disease can be differentiated from DDD by focal suprabasal acantholysis with minimal dyskeratosis (quiz images).⁵ Due to the genetic and clinical similarities, many consider GGD an acantholytic variant of DDD rather than its own entity. Indeed, some patients have shown acantholysis in one area of biopsy but not others.⁶

Hailey-Hailey disease (HHD)(also known as benign familial or benign chronic pemphigus) is an autosomaldominant disorder caused by mutation of the ATPase secretory pathway Ca2+ transporting 1 gene, ATP2C1. Clinically, patients tend to present at a wide age range with fragile flaccid vesicles that commonly develop on the neck, axillae, and groin. Histologically, the epidermis is acanthotic with a dilapidated brick wall– like appearance from a few persistent intercellular connections amid widespread acantholysis (Figure 1).⁷ Unlike in autoimmune pemphigus, direct immunofluorescence is negative, and acantholysis spares the adnexal structures. Hailey-Hailey disease does not involve reticulated hyperpigmentation or the elongated bulbous rete seen in GGD. Confluent and reticulated papillomatosis is a rare, typically asymptomatic, hyperpigmented dermatosis. It presents as a conglomeration of scaly hyperpigmented macules or papillomatous papules that coalesce centrally and are reticulated toward the periphery.

Confluent and reticulated papillomatosis most commonly is seen on the trunk, initially presenting in adolescents and young adults. Confluent and reticulated papillomatosis is histologically similar to acanthosis nigricans. Histopathology will show hyperkeratosis, papillomatosis, and minimal to no inflammatory infiltrate, with no elongated rete ridges or acantholysis (Figure 2).⁸

Pemphigus vulgaris is a blistering disease resulting from the development of autoantibodies against desmogleins 1 and 3. Similar to GGD, there is suprabasal acantholysis, which often results in a tombstonelike appearance consisting of separation between the basal layer cells of the epidermis but with maintained attachment to the underlying basement membrane zone. Unlike HHD, the acantholysis tends to involve the follicular epithelium in pemphigus vulgaris (Figure 3). Clinically, the blisters are positive for Nikolsky sign and can be both cutaneous or mucosal, commonly arising initially in the mouth during the fourth or fifth decades of life. Ruptured blisters can result in painful and hemorrhagic erosions.⁹ Direct immunofluorescence exhibits a classic chicken wire–like deposition of IgG and C3 between keratinocytes of the epidermis. Although sometimes difficult to appreciate, the deposition can be more prominent in the lower epidermis, in contrast to pemphigus foliaceus, which can have more prominent deposition in the upper epidermis.

Darier disease (or dyskeratosis follicularis) is an autosomal-dominant genodermatosis caused by mutation of the ATPase sarcoplasmic/endoplasmic reticulum Ca2+ transporting 2 gene, ATP2A2. Clinically, this disorder arises in adolescents as red-brown, greasy, crusted papules in seborrheic areas that may coalesce into papillomatous clusters. Palmar punctate keratoses and pits also are common. Histologically, Darier disease can appear similar to GGD, as both can show acantholysis and dyskeratosis. Darier disease will tend to show more prominent dyskeratosis with corps ronds and grains, as well as thicker villilike projections of keratinocytes into the papillary dermis, in contrast to the thinner, fingerlike or bulbous projections that hang down from the epidermis in GGD (Figure 4).¹⁰

Melasma is a complex, long-lasting, acquired dermatologic pigmentation disorder resulting in grey-brown patches that last for more than 3 months. Sun-exposed areas including the nose, cheeks, forehead, and forearms are most likely to be affected.¹ In Southeast Asia, 0.25% to 4% of the population affected by melasma is aged 30 to 40 years.² In particular, melasma is a concern among pregnant women due to increased levels of melanocyte-stimulating hormones (MSHs) and is impacted by genetics, hormonal influence, and exposure to UV light.^3,4 In Pakistan, approximately 46% of women are affected by melasma during pregnancy.^2,5 Although few studies have focused on the clinical approaches to melasma in darker skin types, it continues to disproportionately affect the skin of color population.⁴

The areas of hyperpigmentation seen in melasma exhibit increased deposition of melanin in the epidermis and dermis, but melanocytes are not elevated. However, in areas of hyperpigmentation, the melanocytes are larger and more dendritic and demonstrate an increased level of melanogenesis.⁶ During pregnancy, especially in the third trimester, elevated levels of estrogen, progesterone, and MSH often are found in association with melasma.⁷ Tyrosinase (TYR) activity increases and cellular proliferation is reduced after treatment of melanocytes in culture with β-estradiol.⁸ Sex steroids increase transcription of genes encoding melanogenic enzymes in normal human melanocytes, especially TYR.⁹ These results are consistent with the notable increases in melanin synthesis and TYR activity reported for normal human melanocytes under similar conditions in culture.¹⁰ Because melanocytes contain both cytosolic and nuclear estrogen receptors, melanocytes in patients with melasma may be inherently more sensitive to the stimulatory effects of estrogens and possibly other steroid hormones.¹¹

The current treatment options for melasma have varying levels of success and include topical depigmenting agents such as hydroquinone, tretinoin, azelaic acid, kojic acid, and corticosteroids; dermabrasion; and chemical peels.^12-14 Chemical peels with glycolic acid, salicylic acid, lactic acid, trichloroacetic acid, and phenol, as well as laser therapy, are reliable management options.^13,14 Traditionally, melasma has been treated with a combination of modalities along with photoprotection and trigger avoidance.¹²

The efficacy and safety of the available therapies for melasma are still controversial and require further exploration. In recent years, off-label tranexamic acid (TA) has emerged as a potential therapy for melasma. Although the mechanism of action remains unclear, TA may inhibit melanin synthesis by blocking the interaction between melanocytes and keratinocytes.¹⁵ Tranexamic acid also may reverse the abnormal dermal changes associated with melasma by inhibiting melanogenesis and angiogenesis.¹⁶

Although various therapeutic options exist for melasma, the search for a reliable option in patients with darker skin types continues.¹³ We sought to evaluate the efficacy of TA solution 5% in reducing the severity of melasma in South Asian patients, thereby improving patient outcomes and maximizing patient satisfaction. Topical TA is inexpensive and readily accessible and does not cause systemic side effects. These qualities make it a promising treatment compared to traditional therapies.

Methods

We conducted a randomized controlled trial at Rawalpindi Medical Institute (Punjab, Pakistan). The researchers obtained informed consent for all enrolled patients. Cases were sampled from the original patient population seen at the office using nonprobability consecutive sampling. The sample size was calculated with a 95% CI, margin of error of 9%, and expected percentage of efficacy of 86.1% by using TA solution 5%. South Asian male and female patients aged 20 to 45 years with melasma were included in the analysis. Patients were excluded if they were already taking TA, oral contraceptive pills, or photosensitizing drugs (eg, nonsteroidal anti-inflammatory drugs, tetracyclines, phenytoin, carbamazepine); were pregnant; had chronic kidney disease (creatinine >2.0 mg/dL); had cardiac abnormalities (abnormal electrocardiogram); had hematologic disorders (international normalized ratio >2); or had received another melasma treatment within the last 3 to 6 months.

All enrolled patients underwent a detailed history and physical examination. Patient demographics were subsequently noted, including age, sex, history of diabetes mellitus or hypertension, and duration of melasma. The melasma area and severity index (MASI) score of each patient was calculated at baseline, and a corresponding photograph was taken.

The topical solution was prepared with 5 g of TA dissolved in 10 cc of ethanol at 96 °F, 10 cc of 1,3-butanediol, and distilled water up to 100 cc. The TA solution was applied to the affected areas once daily by the patient for 12 weeks. Each application covered the affected areas completely. Patients were instructed to apply sunscreen with sun protection factor 60 to those same areas for UV protection after 15 minutes of TA application. Biweekly follow-ups were scheduled during the trial, and the MASI score was recorded at these visits. If the mean MASI score was reduced by half after 12 weeks of treatment, then the treatment was considered efficacious with a 95% CI.

The percentage reduction from baseline was calculated as follows: percentage reduction=(baseline score– follow-up score)/baseline score×100.

Statistical Analysis—Data were analyzed in SPSS Statistics 25 (IBM). The quantitative variables of age, duration of melasma, and body mass index were presented as mean (SD). Qualitative variables such as sex, history of diabetes mellitus or hypertension, site of melasma, and efficacy were presented as frequencies and percentages. Mean MASI scores at baseline and 12 weeks posttreatment were compared using a paired t test (P≤.05). Data were stratified for age, sex, history of diabetes mellitus or hypertension, site of melasma, and duration of melasma, and a χ² test was applied to compare efficacy in stratified groups (P≤.05).

Results

Sixty patients were enrolled in the study. Of them, 17 (28.33%) were male, and 43 (71.67%) were female (2:5 ratio). They ranged in age from 20 to 45 years (mean [SD], 31.93 [6.26] years). Thirty-seven patients (61.67%) were aged 31 to 45 years of age (Table 1). The mean (SD) duration of disease was 10.18 (2.10) months. The response to TA was recorded based on patient distribution according to the site of melasma as well as history of diabetes mellitus and hypertension.

Topical TA was found to be efficacious for melasma in 50 (83.33%) patients. The mean (SD) baseline and week 12 MASI scores were 23.15 (5.02) and 12.71 (4.10)(P<.0001), respectively (Table 2). The stratification of efficacy with respect to age, sex, duration of melasma, site of melasma, and history of diabetes mellitus or hypertension is shown in the eTable. The site of melasma was significant with respect to stratification of efficacy. On the forehead, TA was found to be efficacious in 11 patients and nonefficacious in 0 patients (P=.036). In the malar region, it was efficacious in 16 patients and nonefficacious in 1 patient (P=.036). Finally, on the chin, it was efficacious in 23 patients and nonefficacious in 9 patients (P=.036).

Comment

Melasma Presentation and Development—Melasma is a chronic skin condition that more often affects patients with darker skin types. This condition is characterized by hyperpigmentation of skin that is directly exposed to the sun, such as the cheek, nose, forehead, and above the upper lip.¹⁷ Although the mechanism behind how melasma develops is unknown, one theory suggests that UV light can lead to increased plasmin in keratinocytes.¹⁸ This increased plasmin will thereby increase the arachidonic acid and α-MSH, leading to the observed uneven hyperpigmentation that is notable in melasma. Melasma is common in patients using oral contraceptives or expired cosmetic drugs; in those who are pregnant; and in those with liver dysfunction.¹⁸ Melasma has a negative impact on patients’ quality of life because of substantial psychological and social distress. Thus, finding an accessible treatment is imperative.¹⁹

Melasma Management—The most common treatments for melasma have been topical bleaching agents and photoprotection. Combination therapy options include chemical peels, dermabrasion, and laser treatments, though they present with limited efficacy.^17,20 Because melasma focuses on pigmentation correction, topical treatments work to disturb melanocyte pigment production at the enzymatic level.²¹ Tyrosinase is rate limiting in melanin production, as it converts L-tyrosinase to L-3,4-dihydroxyphenylalanine, using copper to interact with L-3,4-dihydroxyphenylalanine as a cofactor in the active site.²² Therefore, tyrosine is a major target for many drugs that have been developed for melasma to decrease melaninization.²¹

Recently, research has focused on the effects of topical, intradermal, and oral TA for melasma.¹⁷ Tranexamic acid most commonly has been used in medicine as a fibrinolytic agent because of its antiplasmin properties. It has been hypothesized that TA can inhibit the release of paracrine melanogenic factors that normally act to stimulate melanocytes.¹⁷ Although studies have supported the safety and efficacy of TA, there remains a lack of clinical studies that are sufficiently powered. No definitive consensus on the use of TA for melasma currently exists, which indicates the need for large-scale, randomized, controlled trials.²³

One trial (N=25) found that TA solution 5% achieved efficacy (>50% reduction in MASI score from baseline) in 86.1% of patients with melasma.²⁴ In another study (N=18), topical TA 5% achieved efficacy (>50% reduction in MASI score) in 86% of patients with melasma.²⁵

Melasma Comorbidities—To determine if certain comorbidities, such as diabetes mellitus or hypertension, influenced the progression of melasma, we stratified the efficacy results for patients with these 2 comorbidities, which showed no significant difference (P=.794 and P=.101, respectively). Thus, the relatively higher prevalence of diabetes mellitus (16 patients) and hypertension (11 patients) did not contribute to the efficacy of TA in lowering MASI scores over the 12-week period, which supports the findings of Doolan and Gupta,²⁶ who investigated the endocrinologic conditions associated with melasma and found no such association with diabetes mellitus or hypertension.

TA Formulations for Melasma—The efficacy of topical TA has been explored in several studies. Six studies with sample sizes of 13 to 50 patients each showed statistically significant differences in MASI scores between baseline and following TA treatment (P<.001).^27-32 Several formulations and regimens were utilized, including TA cream 3% for 12 weeks, TA gel 5% for 12 weeks, TA solution 3% for 12 weeks, TA liposome 5% for 12 weeks, and TA solution 2% for 12 weeks.¹⁸ Additionally, these studies found TA to be effective in limiting dyschromia and decreasing MASI scores. There were no statistically significant differences between formulations and method of application. Topical TA has been found to be just as effective as other treatments for melasma, including intradermal TA injections, topical hydroquinone, and a combination of topical hydroquinone and dexamethasone.¹⁸

Further study of the efficacy of intradermal TA is necessary because many human trials have lacked statistical significance or a control group. Lee et al³² conducted a trial of 100 female patients who received weekly intradermal TA microinjections for 12 weeks. After 8 and 12 weeks, MASI scores decreased significantly (P<.01).³² Similarly, Badran et al³³ observed 60 female patients in 3 trial groups: group A received TA (4 mg/mL) intradermal injections every 2 weeks, group B received TA (10 mg/mL) intradermal injections every 2 weeks, and group C received TA cream 10% twice daily. Although all groups showed improvement in MASI, group B, which had the highest intradermal TA concentration, exhibited the most improvement. Thus, it was determined that intradermal application led to better results, but the cream was still effective.³³

Saki et al³⁴ conducted a randomized, split-face trial of 37 patients comparing the efficacy of intradermal TA and topical hydroquinone. Each group was treated with either monthly intradermal TA injections or nightly hydroquinone for 3 months. After 4 weeks of treatment, TA initially had a greater improvement. However, after 20 weeks, the overall changes were not significant between the 2 groups.³⁴ Pazyar et al³⁵ conducted a randomized, split-face trial of 49 patients comparing the efficacy of intradermal TA and hydroquinone cream. After 24 weeks of biweekly TA injections or twice-daily hydroquinone, there were no statistically significant differences in the decreased MASI scores between treatments.³⁵ Additional large, double-blind, controlled trials are needed to thoroughly assess the role of intradermal TA in comparison to its treatment counterpart of hydroquinone.

Ebrahimi and Naeini²⁹ conducted a 12-week, double-blind, split-phase trial of 50 Iranian melasma patients, which showed that 27.3% of patients rated the improvement in melasma as excellent, 42.4% as good, and 30.3% as fair after using TA solution 3%. Wu et al³⁶ also showed a total melasma improvement rate of 80.9% in 256 patients with long-term oral use of TA. In a study by Kim et al³¹ (N=245), the mean MASI score considerably decreased after topical TA use, with a total response rate of 95.6%. In another study, Atefi et al³⁷ presented significantly increased levels of satisfaction in patients treated with topical TA 5% vs hydroquinone (P=.015).

Melasma in Patients With Darker Skin Types—Special attention must be given to choosing the appropriate medication in melasma patients with darker skin types, as there is an increased risk for postinflammatory hyperpigmentation. Currently, few randomized controlled trials exist that fulfill the criteria of evaluating pharmacologic options for patients with melasma, and even fewer studies solely focus on patients with darker skin types.³⁸ In addition to treatment advances, patients must be educated on the need to avoid sun exposure when possible or to use photoprotection, especially in the South Asian region, where these practices rarely are taught. Our study provided a unique analysis regarding the efficacy of TA solution 5% for the treatment of melasma in patients of South Asian descent. Clinicians can use these findings as a foundation for treating all patients with melasma but particularly those with darker skin types.

Study Limitations—Our study consisted of 60 patients; although our study had more patients than similar trials, larger studies are needed. Additionally, other variables were excluded from our analysis, such as comorbidities beyond diabetes mellitus and hypertension.

Conclusion

This study contributes to the growing field of melasma therapeutics by evaluating the efficacy of using TA solution 5% for the treatment of melasma in South Asian patients with darker skin types. Clinicians may use our study to broaden their treatment options for a common condition while also addressing the lack of clinical options for patients with darker skin types. Further studies investigating the effectiveness of TA in large clinical trials in humans are warranted to understand the efficacy and the risk for any complications.

Melasma is a complex, long-lasting, acquired dermatologic pigmentation disorder resulting in grey-brown patches that last for more than 3 months. Sun-exposed areas including the nose, cheeks, forehead, and forearms are most likely to be affected.¹ In Southeast Asia, 0.25% to 4% of the population affected by melasma is aged 30 to 40 years.² In particular, melasma is a concern among pregnant women due to increased levels of melanocyte-stimulating hormones (MSHs) and is impacted by genetics, hormonal influence, and exposure to UV light.^3,4 In Pakistan, approximately 46% of women are affected by melasma during pregnancy.^2,5 Although few studies have focused on the clinical approaches to melasma in darker skin types, it continues to disproportionately affect the skin of color population.⁴

The areas of hyperpigmentation seen in melasma exhibit increased deposition of melanin in the epidermis and dermis, but melanocytes are not elevated. However, in areas of hyperpigmentation, the melanocytes are larger and more dendritic and demonstrate an increased level of melanogenesis.⁶ During pregnancy, especially in the third trimester, elevated levels of estrogen, progesterone, and MSH often are found in association with melasma.⁷ Tyrosinase (TYR) activity increases and cellular proliferation is reduced after treatment of melanocytes in culture with β-estradiol.⁸ Sex steroids increase transcription of genes encoding melanogenic enzymes in normal human melanocytes, especially TYR.⁹ These results are consistent with the notable increases in melanin synthesis and TYR activity reported for normal human melanocytes under similar conditions in culture.¹⁰ Because melanocytes contain both cytosolic and nuclear estrogen receptors, melanocytes in patients with melasma may be inherently more sensitive to the stimulatory effects of estrogens and possibly other steroid hormones.¹¹

The current treatment options for melasma have varying levels of success and include topical depigmenting agents such as hydroquinone, tretinoin, azelaic acid, kojic acid, and corticosteroids; dermabrasion; and chemical peels.^12-14 Chemical peels with glycolic acid, salicylic acid, lactic acid, trichloroacetic acid, and phenol, as well as laser therapy, are reliable management options.^13,14 Traditionally, melasma has been treated with a combination of modalities along with photoprotection and trigger avoidance.¹²

The efficacy and safety of the available therapies for melasma are still controversial and require further exploration. In recent years, off-label tranexamic acid (TA) has emerged as a potential therapy for melasma. Although the mechanism of action remains unclear, TA may inhibit melanin synthesis by blocking the interaction between melanocytes and keratinocytes.¹⁵ Tranexamic acid also may reverse the abnormal dermal changes associated with melasma by inhibiting melanogenesis and angiogenesis.¹⁶

Although various therapeutic options exist for melasma, the search for a reliable option in patients with darker skin types continues.¹³ We sought to evaluate the efficacy of TA solution 5% in reducing the severity of melasma in South Asian patients, thereby improving patient outcomes and maximizing patient satisfaction. Topical TA is inexpensive and readily accessible and does not cause systemic side effects. These qualities make it a promising treatment compared to traditional therapies.

Methods

We conducted a randomized controlled trial at Rawalpindi Medical Institute (Punjab, Pakistan). The researchers obtained informed consent for all enrolled patients. Cases were sampled from the original patient population seen at the office using nonprobability consecutive sampling. The sample size was calculated with a 95% CI, margin of error of 9%, and expected percentage of efficacy of 86.1% by using TA solution 5%. South Asian male and female patients aged 20 to 45 years with melasma were included in the analysis. Patients were excluded if they were already taking TA, oral contraceptive pills, or photosensitizing drugs (eg, nonsteroidal anti-inflammatory drugs, tetracyclines, phenytoin, carbamazepine); were pregnant; had chronic kidney disease (creatinine >2.0 mg/dL); had cardiac abnormalities (abnormal electrocardiogram); had hematologic disorders (international normalized ratio >2); or had received another melasma treatment within the last 3 to 6 months.

All enrolled patients underwent a detailed history and physical examination. Patient demographics were subsequently noted, including age, sex, history of diabetes mellitus or hypertension, and duration of melasma. The melasma area and severity index (MASI) score of each patient was calculated at baseline, and a corresponding photograph was taken.

The topical solution was prepared with 5 g of TA dissolved in 10 cc of ethanol at 96 °F, 10 cc of 1,3-butanediol, and distilled water up to 100 cc. The TA solution was applied to the affected areas once daily by the patient for 12 weeks. Each application covered the affected areas completely. Patients were instructed to apply sunscreen with sun protection factor 60 to those same areas for UV protection after 15 minutes of TA application. Biweekly follow-ups were scheduled during the trial, and the MASI score was recorded at these visits. If the mean MASI score was reduced by half after 12 weeks of treatment, then the treatment was considered efficacious with a 95% CI.

The percentage reduction from baseline was calculated as follows: percentage reduction=(baseline score– follow-up score)/baseline score×100.

Statistical Analysis—Data were analyzed in SPSS Statistics 25 (IBM). The quantitative variables of age, duration of melasma, and body mass index were presented as mean (SD). Qualitative variables such as sex, history of diabetes mellitus or hypertension, site of melasma, and efficacy were presented as frequencies and percentages. Mean MASI scores at baseline and 12 weeks posttreatment were compared using a paired t test (P≤.05). Data were stratified for age, sex, history of diabetes mellitus or hypertension, site of melasma, and duration of melasma, and a χ² test was applied to compare efficacy in stratified groups (P≤.05).

Results

Sixty patients were enrolled in the study. Of them, 17 (28.33%) were male, and 43 (71.67%) were female (2:5 ratio). They ranged in age from 20 to 45 years (mean [SD], 31.93 [6.26] years). Thirty-seven patients (61.67%) were aged 31 to 45 years of age (Table 1). The mean (SD) duration of disease was 10.18 (2.10) months. The response to TA was recorded based on patient distribution according to the site of melasma as well as history of diabetes mellitus and hypertension.

Topical TA was found to be efficacious for melasma in 50 (83.33%) patients. The mean (SD) baseline and week 12 MASI scores were 23.15 (5.02) and 12.71 (4.10)(P<.0001), respectively (Table 2). The stratification of efficacy with respect to age, sex, duration of melasma, site of melasma, and history of diabetes mellitus or hypertension is shown in the eTable. The site of melasma was significant with respect to stratification of efficacy. On the forehead, TA was found to be efficacious in 11 patients and nonefficacious in 0 patients (P=.036). In the malar region, it was efficacious in 16 patients and nonefficacious in 1 patient (P=.036). Finally, on the chin, it was efficacious in 23 patients and nonefficacious in 9 patients (P=.036).

Comment

Melasma Presentation and Development—Melasma is a chronic skin condition that more often affects patients with darker skin types. This condition is characterized by hyperpigmentation of skin that is directly exposed to the sun, such as the cheek, nose, forehead, and above the upper lip.¹⁷ Although the mechanism behind how melasma develops is unknown, one theory suggests that UV light can lead to increased plasmin in keratinocytes.¹⁸ This increased plasmin will thereby increase the arachidonic acid and α-MSH, leading to the observed uneven hyperpigmentation that is notable in melasma. Melasma is common in patients using oral contraceptives or expired cosmetic drugs; in those who are pregnant; and in those with liver dysfunction.¹⁸ Melasma has a negative impact on patients’ quality of life because of substantial psychological and social distress. Thus, finding an accessible treatment is imperative.¹⁹

Melasma Management—The most common treatments for melasma have been topical bleaching agents and photoprotection. Combination therapy options include chemical peels, dermabrasion, and laser treatments, though they present with limited efficacy.^17,20 Because melasma focuses on pigmentation correction, topical treatments work to disturb melanocyte pigment production at the enzymatic level.²¹ Tyrosinase is rate limiting in melanin production, as it converts L-tyrosinase to L-3,4-dihydroxyphenylalanine, using copper to interact with L-3,4-dihydroxyphenylalanine as a cofactor in the active site.²² Therefore, tyrosine is a major target for many drugs that have been developed for melasma to decrease melaninization.²¹

Recently, research has focused on the effects of topical, intradermal, and oral TA for melasma.¹⁷ Tranexamic acid most commonly has been used in medicine as a fibrinolytic agent because of its antiplasmin properties. It has been hypothesized that TA can inhibit the release of paracrine melanogenic factors that normally act to stimulate melanocytes.¹⁷ Although studies have supported the safety and efficacy of TA, there remains a lack of clinical studies that are sufficiently powered. No definitive consensus on the use of TA for melasma currently exists, which indicates the need for large-scale, randomized, controlled trials.²³

One trial (N=25) found that TA solution 5% achieved efficacy (>50% reduction in MASI score from baseline) in 86.1% of patients with melasma.²⁴ In another study (N=18), topical TA 5% achieved efficacy (>50% reduction in MASI score) in 86% of patients with melasma.²⁵

Melasma Comorbidities—To determine if certain comorbidities, such as diabetes mellitus or hypertension, influenced the progression of melasma, we stratified the efficacy results for patients with these 2 comorbidities, which showed no significant difference (P=.794 and P=.101, respectively). Thus, the relatively higher prevalence of diabetes mellitus (16 patients) and hypertension (11 patients) did not contribute to the efficacy of TA in lowering MASI scores over the 12-week period, which supports the findings of Doolan and Gupta,²⁶ who investigated the endocrinologic conditions associated with melasma and found no such association with diabetes mellitus or hypertension.

TA Formulations for Melasma—The efficacy of topical TA has been explored in several studies. Six studies with sample sizes of 13 to 50 patients each showed statistically significant differences in MASI scores between baseline and following TA treatment (P<.001).^27-32 Several formulations and regimens were utilized, including TA cream 3% for 12 weeks, TA gel 5% for 12 weeks, TA solution 3% for 12 weeks, TA liposome 5% for 12 weeks, and TA solution 2% for 12 weeks.¹⁸ Additionally, these studies found TA to be effective in limiting dyschromia and decreasing MASI scores. There were no statistically significant differences between formulations and method of application. Topical TA has been found to be just as effective as other treatments for melasma, including intradermal TA injections, topical hydroquinone, and a combination of topical hydroquinone and dexamethasone.¹⁸

Further study of the efficacy of intradermal TA is necessary because many human trials have lacked statistical significance or a control group. Lee et al³² conducted a trial of 100 female patients who received weekly intradermal TA microinjections for 12 weeks. After 8 and 12 weeks, MASI scores decreased significantly (P<.01).³² Similarly, Badran et al³³ observed 60 female patients in 3 trial groups: group A received TA (4 mg/mL) intradermal injections every 2 weeks, group B received TA (10 mg/mL) intradermal injections every 2 weeks, and group C received TA cream 10% twice daily. Although all groups showed improvement in MASI, group B, which had the highest intradermal TA concentration, exhibited the most improvement. Thus, it was determined that intradermal application led to better results, but the cream was still effective.³³

Saki et al³⁴ conducted a randomized, split-face trial of 37 patients comparing the efficacy of intradermal TA and topical hydroquinone. Each group was treated with either monthly intradermal TA injections or nightly hydroquinone for 3 months. After 4 weeks of treatment, TA initially had a greater improvement. However, after 20 weeks, the overall changes were not significant between the 2 groups.³⁴ Pazyar et al³⁵ conducted a randomized, split-face trial of 49 patients comparing the efficacy of intradermal TA and hydroquinone cream. After 24 weeks of biweekly TA injections or twice-daily hydroquinone, there were no statistically significant differences in the decreased MASI scores between treatments.³⁵ Additional large, double-blind, controlled trials are needed to thoroughly assess the role of intradermal TA in comparison to its treatment counterpart of hydroquinone.

Ebrahimi and Naeini²⁹ conducted a 12-week, double-blind, split-phase trial of 50 Iranian melasma patients, which showed that 27.3% of patients rated the improvement in melasma as excellent, 42.4% as good, and 30.3% as fair after using TA solution 3%. Wu et al³⁶ also showed a total melasma improvement rate of 80.9% in 256 patients with long-term oral use of TA. In a study by Kim et al³¹ (N=245), the mean MASI score considerably decreased after topical TA use, with a total response rate of 95.6%. In another study, Atefi et al³⁷ presented significantly increased levels of satisfaction in patients treated with topical TA 5% vs hydroquinone (P=.015).

Melasma in Patients With Darker Skin Types—Special attention must be given to choosing the appropriate medication in melasma patients with darker skin types, as there is an increased risk for postinflammatory hyperpigmentation. Currently, few randomized controlled trials exist that fulfill the criteria of evaluating pharmacologic options for patients with melasma, and even fewer studies solely focus on patients with darker skin types.³⁸ In addition to treatment advances, patients must be educated on the need to avoid sun exposure when possible or to use photoprotection, especially in the South Asian region, where these practices rarely are taught. Our study provided a unique analysis regarding the efficacy of TA solution 5% for the treatment of melasma in patients of South Asian descent. Clinicians can use these findings as a foundation for treating all patients with melasma but particularly those with darker skin types.

Study Limitations—Our study consisted of 60 patients; although our study had more patients than similar trials, larger studies are needed. Additionally, other variables were excluded from our analysis, such as comorbidities beyond diabetes mellitus and hypertension.

Conclusion

This study contributes to the growing field of melasma therapeutics by evaluating the efficacy of using TA solution 5% for the treatment of melasma in South Asian patients with darker skin types. Clinicians may use our study to broaden their treatment options for a common condition while also addressing the lack of clinical options for patients with darker skin types. Further studies investigating the effectiveness of TA in large clinical trials in humans are warranted to understand the efficacy and the risk for any complications.

Melasma is a complex, long-lasting, acquired dermatologic pigmentation disorder resulting in grey-brown patches that last for more than 3 months. Sun-exposed areas including the nose, cheeks, forehead, and forearms are most likely to be affected.¹ In Southeast Asia, 0.25% to 4% of the population affected by melasma is aged 30 to 40 years.² In particular, melasma is a concern among pregnant women due to increased levels of melanocyte-stimulating hormones (MSHs) and is impacted by genetics, hormonal influence, and exposure to UV light.^3,4 In Pakistan, approximately 46% of women are affected by melasma during pregnancy.^2,5 Although few studies have focused on the clinical approaches to melasma in darker skin types, it continues to disproportionately affect the skin of color population.⁴

The areas of hyperpigmentation seen in melasma exhibit increased deposition of melanin in the epidermis and dermis, but melanocytes are not elevated. However, in areas of hyperpigmentation, the melanocytes are larger and more dendritic and demonstrate an increased level of melanogenesis.⁶ During pregnancy, especially in the third trimester, elevated levels of estrogen, progesterone, and MSH often are found in association with melasma.⁷ Tyrosinase (TYR) activity increases and cellular proliferation is reduced after treatment of melanocytes in culture with β-estradiol.⁸ Sex steroids increase transcription of genes encoding melanogenic enzymes in normal human melanocytes, especially TYR.⁹ These results are consistent with the notable increases in melanin synthesis and TYR activity reported for normal human melanocytes under similar conditions in culture.¹⁰ Because melanocytes contain both cytosolic and nuclear estrogen receptors, melanocytes in patients with melasma may be inherently more sensitive to the stimulatory effects of estrogens and possibly other steroid hormones.¹¹

The current treatment options for melasma have varying levels of success and include topical depigmenting agents such as hydroquinone, tretinoin, azelaic acid, kojic acid, and corticosteroids; dermabrasion; and chemical peels.^12-14 Chemical peels with glycolic acid, salicylic acid, lactic acid, trichloroacetic acid, and phenol, as well as laser therapy, are reliable management options.^13,14 Traditionally, melasma has been treated with a combination of modalities along with photoprotection and trigger avoidance.¹²

The efficacy and safety of the available therapies for melasma are still controversial and require further exploration. In recent years, off-label tranexamic acid (TA) has emerged as a potential therapy for melasma. Although the mechanism of action remains unclear, TA may inhibit melanin synthesis by blocking the interaction between melanocytes and keratinocytes.¹⁵ Tranexamic acid also may reverse the abnormal dermal changes associated with melasma by inhibiting melanogenesis and angiogenesis.¹⁶

Although various therapeutic options exist for melasma, the search for a reliable option in patients with darker skin types continues.¹³ We sought to evaluate the efficacy of TA solution 5% in reducing the severity of melasma in South Asian patients, thereby improving patient outcomes and maximizing patient satisfaction. Topical TA is inexpensive and readily accessible and does not cause systemic side effects. These qualities make it a promising treatment compared to traditional therapies.

Methods

We conducted a randomized controlled trial at Rawalpindi Medical Institute (Punjab, Pakistan). The researchers obtained informed consent for all enrolled patients. Cases were sampled from the original patient population seen at the office using nonprobability consecutive sampling. The sample size was calculated with a 95% CI, margin of error of 9%, and expected percentage of efficacy of 86.1% by using TA solution 5%. South Asian male and female patients aged 20 to 45 years with melasma were included in the analysis. Patients were excluded if they were already taking TA, oral contraceptive pills, or photosensitizing drugs (eg, nonsteroidal anti-inflammatory drugs, tetracyclines, phenytoin, carbamazepine); were pregnant; had chronic kidney disease (creatinine >2.0 mg/dL); had cardiac abnormalities (abnormal electrocardiogram); had hematologic disorders (international normalized ratio >2); or had received another melasma treatment within the last 3 to 6 months.

All enrolled patients underwent a detailed history and physical examination. Patient demographics were subsequently noted, including age, sex, history of diabetes mellitus or hypertension, and duration of melasma. The melasma area and severity index (MASI) score of each patient was calculated at baseline, and a corresponding photograph was taken.

The topical solution was prepared with 5 g of TA dissolved in 10 cc of ethanol at 96 °F, 10 cc of 1,3-butanediol, and distilled water up to 100 cc. The TA solution was applied to the affected areas once daily by the patient for 12 weeks. Each application covered the affected areas completely. Patients were instructed to apply sunscreen with sun protection factor 60 to those same areas for UV protection after 15 minutes of TA application. Biweekly follow-ups were scheduled during the trial, and the MASI score was recorded at these visits. If the mean MASI score was reduced by half after 12 weeks of treatment, then the treatment was considered efficacious with a 95% CI.

The percentage reduction from baseline was calculated as follows: percentage reduction=(baseline score– follow-up score)/baseline score×100.

Statistical Analysis—Data were analyzed in SPSS Statistics 25 (IBM). The quantitative variables of age, duration of melasma, and body mass index were presented as mean (SD). Qualitative variables such as sex, history of diabetes mellitus or hypertension, site of melasma, and efficacy were presented as frequencies and percentages. Mean MASI scores at baseline and 12 weeks posttreatment were compared using a paired t test (P≤.05). Data were stratified for age, sex, history of diabetes mellitus or hypertension, site of melasma, and duration of melasma, and a χ² test was applied to compare efficacy in stratified groups (P≤.05).

Results

Sixty patients were enrolled in the study. Of them, 17 (28.33%) were male, and 43 (71.67%) were female (2:5 ratio). They ranged in age from 20 to 45 years (mean [SD], 31.93 [6.26] years). Thirty-seven patients (61.67%) were aged 31 to 45 years of age (Table 1). The mean (SD) duration of disease was 10.18 (2.10) months. The response to TA was recorded based on patient distribution according to the site of melasma as well as history of diabetes mellitus and hypertension.

Topical TA was found to be efficacious for melasma in 50 (83.33%) patients. The mean (SD) baseline and week 12 MASI scores were 23.15 (5.02) and 12.71 (4.10)(P<.0001), respectively (Table 2). The stratification of efficacy with respect to age, sex, duration of melasma, site of melasma, and history of diabetes mellitus or hypertension is shown in the eTable. The site of melasma was significant with respect to stratification of efficacy. On the forehead, TA was found to be efficacious in 11 patients and nonefficacious in 0 patients (P=.036). In the malar region, it was efficacious in 16 patients and nonefficacious in 1 patient (P=.036). Finally, on the chin, it was efficacious in 23 patients and nonefficacious in 9 patients (P=.036).

Comment

Melasma Presentation and Development—Melasma is a chronic skin condition that more often affects patients with darker skin types. This condition is characterized by hyperpigmentation of skin that is directly exposed to the sun, such as the cheek, nose, forehead, and above the upper lip.¹⁷ Although the mechanism behind how melasma develops is unknown, one theory suggests that UV light can lead to increased plasmin in keratinocytes.¹⁸ This increased plasmin will thereby increase the arachidonic acid and α-MSH, leading to the observed uneven hyperpigmentation that is notable in melasma. Melasma is common in patients using oral contraceptives or expired cosmetic drugs; in those who are pregnant; and in those with liver dysfunction.¹⁸ Melasma has a negative impact on patients’ quality of life because of substantial psychological and social distress. Thus, finding an accessible treatment is imperative.¹⁹

Melasma Management—The most common treatments for melasma have been topical bleaching agents and photoprotection. Combination therapy options include chemical peels, dermabrasion, and laser treatments, though they present with limited efficacy.^17,20 Because melasma focuses on pigmentation correction, topical treatments work to disturb melanocyte pigment production at the enzymatic level.²¹ Tyrosinase is rate limiting in melanin production, as it converts L-tyrosinase to L-3,4-dihydroxyphenylalanine, using copper to interact with L-3,4-dihydroxyphenylalanine as a cofactor in the active site.²² Therefore, tyrosine is a major target for many drugs that have been developed for melasma to decrease melaninization.²¹

Recently, research has focused on the effects of topical, intradermal, and oral TA for melasma.¹⁷ Tranexamic acid most commonly has been used in medicine as a fibrinolytic agent because of its antiplasmin properties. It has been hypothesized that TA can inhibit the release of paracrine melanogenic factors that normally act to stimulate melanocytes.¹⁷ Although studies have supported the safety and efficacy of TA, there remains a lack of clinical studies that are sufficiently powered. No definitive consensus on the use of TA for melasma currently exists, which indicates the need for large-scale, randomized, controlled trials.²³

One trial (N=25) found that TA solution 5% achieved efficacy (>50% reduction in MASI score from baseline) in 86.1% of patients with melasma.²⁴ In another study (N=18), topical TA 5% achieved efficacy (>50% reduction in MASI score) in 86% of patients with melasma.²⁵

Melasma Comorbidities—To determine if certain comorbidities, such as diabetes mellitus or hypertension, influenced the progression of melasma, we stratified the efficacy results for patients with these 2 comorbidities, which showed no significant difference (P=.794 and P=.101, respectively). Thus, the relatively higher prevalence of diabetes mellitus (16 patients) and hypertension (11 patients) did not contribute to the efficacy of TA in lowering MASI scores over the 12-week period, which supports the findings of Doolan and Gupta,²⁶ who investigated the endocrinologic conditions associated with melasma and found no such association with diabetes mellitus or hypertension.

TA Formulations for Melasma—The efficacy of topical TA has been explored in several studies. Six studies with sample sizes of 13 to 50 patients each showed statistically significant differences in MASI scores between baseline and following TA treatment (P<.001).^27-32 Several formulations and regimens were utilized, including TA cream 3% for 12 weeks, TA gel 5% for 12 weeks, TA solution 3% for 12 weeks, TA liposome 5% for 12 weeks, and TA solution 2% for 12 weeks.¹⁸ Additionally, these studies found TA to be effective in limiting dyschromia and decreasing MASI scores. There were no statistically significant differences between formulations and method of application. Topical TA has been found to be just as effective as other treatments for melasma, including intradermal TA injections, topical hydroquinone, and a combination of topical hydroquinone and dexamethasone.¹⁸

Further study of the efficacy of intradermal TA is necessary because many human trials have lacked statistical significance or a control group. Lee et al³² conducted a trial of 100 female patients who received weekly intradermal TA microinjections for 12 weeks. After 8 and 12 weeks, MASI scores decreased significantly (P<.01).³² Similarly, Badran et al³³ observed 60 female patients in 3 trial groups: group A received TA (4 mg/mL) intradermal injections every 2 weeks, group B received TA (10 mg/mL) intradermal injections every 2 weeks, and group C received TA cream 10% twice daily. Although all groups showed improvement in MASI, group B, which had the highest intradermal TA concentration, exhibited the most improvement. Thus, it was determined that intradermal application led to better results, but the cream was still effective.³³

Saki et al³⁴ conducted a randomized, split-face trial of 37 patients comparing the efficacy of intradermal TA and topical hydroquinone. Each group was treated with either monthly intradermal TA injections or nightly hydroquinone for 3 months. After 4 weeks of treatment, TA initially had a greater improvement. However, after 20 weeks, the overall changes were not significant between the 2 groups.³⁴ Pazyar et al³⁵ conducted a randomized, split-face trial of 49 patients comparing the efficacy of intradermal TA and hydroquinone cream. After 24 weeks of biweekly TA injections or twice-daily hydroquinone, there were no statistically significant differences in the decreased MASI scores between treatments.³⁵ Additional large, double-blind, controlled trials are needed to thoroughly assess the role of intradermal TA in comparison to its treatment counterpart of hydroquinone.

Ebrahimi and Naeini²⁹ conducted a 12-week, double-blind, split-phase trial of 50 Iranian melasma patients, which showed that 27.3% of patients rated the improvement in melasma as excellent, 42.4% as good, and 30.3% as fair after using TA solution 3%. Wu et al³⁶ also showed a total melasma improvement rate of 80.9% in 256 patients with long-term oral use of TA. In a study by Kim et al³¹ (N=245), the mean MASI score considerably decreased after topical TA use, with a total response rate of 95.6%. In another study, Atefi et al³⁷ presented significantly increased levels of satisfaction in patients treated with topical TA 5% vs hydroquinone (P=.015).

Melasma in Patients With Darker Skin Types—Special attention must be given to choosing the appropriate medication in melasma patients with darker skin types, as there is an increased risk for postinflammatory hyperpigmentation. Currently, few randomized controlled trials exist that fulfill the criteria of evaluating pharmacologic options for patients with melasma, and even fewer studies solely focus on patients with darker skin types.³⁸ In addition to treatment advances, patients must be educated on the need to avoid sun exposure when possible or to use photoprotection, especially in the South Asian region, where these practices rarely are taught. Our study provided a unique analysis regarding the efficacy of TA solution 5% for the treatment of melasma in patients of South Asian descent. Clinicians can use these findings as a foundation for treating all patients with melasma but particularly those with darker skin types.

Study Limitations—Our study consisted of 60 patients; although our study had more patients than similar trials, larger studies are needed. Additionally, other variables were excluded from our analysis, such as comorbidities beyond diabetes mellitus and hypertension.

Conclusion

This study contributes to the growing field of melasma therapeutics by evaluating the efficacy of using TA solution 5% for the treatment of melasma in South Asian patients with darker skin types. Clinicians may use our study to broaden their treatment options for a common condition while also addressing the lack of clinical options for patients with darker skin types. Further studies investigating the effectiveness of TA in large clinical trials in humans are warranted to understand the efficacy and the risk for any complications.

A year after celebrating the approval of the first treatment for repigmentation of vitiligo, dermatologists describe how topical ruxolitinib has advanced the outlook for patients with the disease and what’s next in the pipeline.

The Food and Drug Administration approved the cream formulation of ruxolitinib (Opzelura), a JAK inhibitor, for repigmentation of nonsegmental vitiligo in July 2022 for people aged 12 years and older.

Raj Chovatiya, MD, PhD, assistant professor of dermatology at Northwestern University, Chicago, said that he likes to use ruxolitinib cream in combination with other treatments.

Dr. Chovatiya

“In the real world with vitiligo patients, we’re oftentimes doing combinatorial therapy anyway. So phototherapy, specifically, narrow-band UVB, is something that we have a lot of clinical evidence for over the years, and it’s a modality that can combine with topical steroids and topical calcineurin inhibitors.”

He said trials to study combinations will yield better guidance on optimal use of ruxolitinib cream. “In general, vitiligo patients can really benefit from phototherapy,” he said in an interview. (Labeling recommends against combination with other JAK inhibitors, biologics, or potent immunosuppressants, such as azathioprine or cyclosporine.)

This first year has shown that ruxolitinib is an effective option, but counseling patients to expect slow improvement is important so that patients stick with it, he noted.

Documenting what treatments patients with vitiligo have used before is important, he said, as is counseling patients that ruxolitinib is approved only for use on up to 10% of a person’s body surface area. (Product labeling recommends that a thin layer be applied twice a day to affected areas up to 10% of body surface area.)

Ruxolitinib has brought a “louder voice” to vitiligo and has opened up options for patients with the disease, Dr. Chovatiya said. “Having the ability to topically treat people who have very extensive disease really gives us a lot more flexibility than we have had before.”
 

Good experiences with payers at safety-net hospital

Candrice R. Heath, MD, assistant professor of dermatology at Temple University, Philadelphia, said that real-world experience with topical ruxolitinib will be more evident after its been on the market for 18-24 months.

Dr. Heath said she, too, encourages use of narrow-band UVB phototherapy in conjunction with the treatment.

From an insurance reimbursement standpoint, she said that she is glad that there have been fewer hurdles in getting ruxolitinib to patients than she has experienced with other medications.

In her safety-net hospital, she told this news organization, she sees patients with many types of insurance, but most have Medicaid. “So, I’m always expecting the step therapies, denials, pushbacks, etc.,” she said. But the path has been smoother for ruxolitinib coverage, she noted.

Her colleagues are committed to documenting everything the patient has tried, she added, and that helps with prior authorization.

Dr. Heath said that pointing out to insurers that ruxolitinib is the only approved treatment for repigmentation helps facilitate coverage.

“The science is advancing, and I’m happy to be practicing during a time when we actually have something approved for vitiligo,” she said. But she pointed out that phototherapy often is not covered for vitiligo, “which is horrible, when it is readily approved for psoriasis and atopic dermatitis.”

To document progress, Dr. Heath said that she always takes photographs of her patients with vitiligo because “the pictures remind us how far we have come.”
 

Data spotlight success in adolescents

Data from two trials give a clinical picture of the drug’s safety and efficacy in younger patients.

Adolescents had particularly good results in the first year with ruxolitinib, according to pooled phase 3 data from TRuE-V1 and TRuE-V2, this news organization reported.

The findings, presented at the 25th World Congress of Dermatology in Singapore, indicate that more than half of the participants achieved at least a 50% improvement from baseline in the total Vitiligo Area Scoring Index (T-VASI50) at 52 weeks.

The percentages of young patients aged 12-17 years taking twice-daily ruxolitinib who achieved T-VASI 50 at weeks 12, 24, and 52 were 11.5%, 26.9%, and 57.7%, respectively. The corresponding percentages for all in the study population were 10.7%, 22.7%, and 44.4%, respectively.

At the meeting, the presenter, Julien Seneschal, MD, PhD, professor of dermatology and head of the vitiligo and pigmentary disorders clinic at the University of Bordeaux, France, said, “This suggests that younger patients can respond better to the treatment.” He noted, however, that there were few adolescents in the studies.
 

New excitement in the field

Daniel Gutierrez, MD, assistant professor of dermatology at New York University, said the treatment has brought new excitement to the field.

“Patients with vitiligo are very motivated to treat their disease,” he said, because it typically is on the face and other highly visual areas, which can affect their overall perception of self.

NYU Langone Health

Previously, he noted in an interview, the only FDA-approved treatment was monobenzone, but that was for depigmentation rather than repigmentation.

Otherwise, treatments were being used off label, and patients were receiving compounded formulations that often weren’t covered by insurance and often had shorter shelf life.

He said that he still occasionally gets denials from payers who consider vitiligo a cosmetic condition.

“I’ve had more luck with insurance, at least in the New York State area.” He added that sometimes payers require use of a topical calcineurin inhibitor for about 12 weeks before they will cover ruxolitinib.

Dr. Gutierrez also recommends using phototherapy with topical ruxolitinib “because they work on slightly different pathways.”

When he starts patients on a new therapy such as ruxolitinib, he asks them to come back in 3 months, and often by then, progress is evident. Facial areas show the most response, he said, while hands and feet are less likely to show significant improvement.

He said that it’s important for physicians and patients to know that improvements can take weeks or months to be noticeable. “I tell patients not to give up,” he added.

Showing the patients pictures from the current appointment and comparing them with pictures from previous appointments can help them better understand their progress, he said.
 

Lead investigator adds observations

David Rosmarin, MD, chair of the department of dermatology at Indiana University, Indianapolis, was the lead investigator of the pivotal TruE-V1 and TruE-V2 trials for vitiligo. In that role, he has been treating vitiligo patients with topical ruxolitinib since 2015.

In an interview, he said that many patients “don’t hit their optimal results at 3 months, 6 months, even the year mark. With continued use, many can see continued benefit.”

Other patients, he said, don’t respond within the first 6 months but with continued use may eventually respond, he said.

“Unfortunately, we have no way of knowing, based on clinical characteristics or baseline demographics, whether a patient will be a delayed responder or not or an early responder,” Dr. Rosmarin added.

He provided several observations about people who have stopped taking the medication.

“When people stop,” he said, “some maintain their response, but some start to depigment again. Again, we have no way of predicting who will be in which category.”

He said that once patients have hit their desired response, he usually advises them to taper down to maybe twice a week or to stop treatment, but if they see any recurrence, they should start reusing the medicine.

“We have some patients who have gone 6 or 7 years now before they had a recurrence, but others may start to depigment again in 2 to 3 months,” Dr. Rosmarin said.

As for phototherapy, he said, the combination with topical ruxolitinib is being studied.

“We think the combination is synergistic and better than either alone, but we’re still waiting for data to prove that,” he said.

In his practice, he offers patients the option either to use just ruxolitinib cream or the combination early on. Many patients, because of convenience, say they’ll first try the cream to see if that works.

“The challenge with light [therapy] is that it can be very inconvenient,” he said. Patients have to live close to a phototherapy unit to receive therapy 2-3 times a week or have a phototherapy product in their home.
 

Next in the pipeline

Experts say the progress doesn’t stop with ruxolitinib cream. Current trials of several medications show there’s more to come for patients with vitiligo.

Dr. Chovatiya said that next up may be oral ritlecitinib (Litfulo), a JAK inhibitor that was approved for severe alopecia areata in June for people aged 12 years and older. Phase 2 results have been published for its use with vitiligo.

“This would be an oral medication that may be able to help people with much more extensive disease as far as vitiligo goes,” he said, adding that he expects approval for a vitiligo indication within a few years.

He pointed out that longer-term safety data will be available because it is already on the market for alopecia.

Upadacitinib (Rinvoq), an oral JAK inhibitor, is approved for atopic dermatitis but is being studied for vitiligo as well, he noted. “I’m very excited to see what that holds for patients as well,” Dr. Chovatiya said.

Dr. Gutierrez said that he is excited about oral JAK inhibitors but sees potential in finding new ways to transplant melanocytes into areas where there are none.

The pigmentation field has seen new energy since last year’s approval, he said, particularly among people of color.

“We have new options for vitiligo that were lacking compared with other conditions, such as atopic dermatitis and psoriasis,” he said. “Hopefully, there will be more promising breakthroughs.”

Dr. Rosmarin is the chief investigator for the pivotal trials that led to FDA approval of ruxolitinib. He disclosed ties with AbbVie, Abcuro, AltruBio, Amgen, Arena, Boehringer Ingelheim, Bristol-Meyers Squibb, Celgene, Concert, CSL Behring, Dermavant, Dermira, Galderma, Incyte, Janssen, Kyowa Kirin, Lilly, Merck, Novartis, Pfizer, Regeneron, Revolo Biotherapeutics, Sanofi, Sun Pharmaceuticals, UCB, and Viela Bio. Dr. Chovatiya disclosed ties with AbbVie, Arcutis, Arena, Argenx, Beiersdorf, Bristol-Myers Squibb, Dermavant, Eli Lilly, EPI Health, Incyte, LEO Pharma, L’Oréal, National Eczema Association, Pfizer, Regeneron, Sanofi, and UCB. Dr. Heath and Dr. Gutierrez report no relevant financial relationships.

A version of this article appeared on Medscape.com.

A year after celebrating the approval of the first treatment for repigmentation of vitiligo, dermatologists describe how topical ruxolitinib has advanced the outlook for patients with the disease and what’s next in the pipeline.

The Food and Drug Administration approved the cream formulation of ruxolitinib (Opzelura), a JAK inhibitor, for repigmentation of nonsegmental vitiligo in July 2022 for people aged 12 years and older.

Raj Chovatiya, MD, PhD, assistant professor of dermatology at Northwestern University, Chicago, said that he likes to use ruxolitinib cream in combination with other treatments.

Dr. Chovatiya

“In the real world with vitiligo patients, we’re oftentimes doing combinatorial therapy anyway. So phototherapy, specifically, narrow-band UVB, is something that we have a lot of clinical evidence for over the years, and it’s a modality that can combine with topical steroids and topical calcineurin inhibitors.”

He said trials to study combinations will yield better guidance on optimal use of ruxolitinib cream. “In general, vitiligo patients can really benefit from phototherapy,” he said in an interview. (Labeling recommends against combination with other JAK inhibitors, biologics, or potent immunosuppressants, such as azathioprine or cyclosporine.)

This first year has shown that ruxolitinib is an effective option, but counseling patients to expect slow improvement is important so that patients stick with it, he noted.

Documenting what treatments patients with vitiligo have used before is important, he said, as is counseling patients that ruxolitinib is approved only for use on up to 10% of a person’s body surface area. (Product labeling recommends that a thin layer be applied twice a day to affected areas up to 10% of body surface area.)

Ruxolitinib has brought a “louder voice” to vitiligo and has opened up options for patients with the disease, Dr. Chovatiya said. “Having the ability to topically treat people who have very extensive disease really gives us a lot more flexibility than we have had before.”
 

Good experiences with payers at safety-net hospital

Candrice R. Heath, MD, assistant professor of dermatology at Temple University, Philadelphia, said that real-world experience with topical ruxolitinib will be more evident after its been on the market for 18-24 months.

Dr. Heath said she, too, encourages use of narrow-band UVB phototherapy in conjunction with the treatment.

From an insurance reimbursement standpoint, she said that she is glad that there have been fewer hurdles in getting ruxolitinib to patients than she has experienced with other medications.

In her safety-net hospital, she told this news organization, she sees patients with many types of insurance, but most have Medicaid. “So, I’m always expecting the step therapies, denials, pushbacks, etc.,” she said. But the path has been smoother for ruxolitinib coverage, she noted.

Her colleagues are committed to documenting everything the patient has tried, she added, and that helps with prior authorization.

Dr. Heath said that pointing out to insurers that ruxolitinib is the only approved treatment for repigmentation helps facilitate coverage.

“The science is advancing, and I’m happy to be practicing during a time when we actually have something approved for vitiligo,” she said. But she pointed out that phototherapy often is not covered for vitiligo, “which is horrible, when it is readily approved for psoriasis and atopic dermatitis.”

To document progress, Dr. Heath said that she always takes photographs of her patients with vitiligo because “the pictures remind us how far we have come.”
 

Data spotlight success in adolescents

Data from two trials give a clinical picture of the drug’s safety and efficacy in younger patients.

Adolescents had particularly good results in the first year with ruxolitinib, according to pooled phase 3 data from TRuE-V1 and TRuE-V2, this news organization reported.

The findings, presented at the 25th World Congress of Dermatology in Singapore, indicate that more than half of the participants achieved at least a 50% improvement from baseline in the total Vitiligo Area Scoring Index (T-VASI50) at 52 weeks.

The percentages of young patients aged 12-17 years taking twice-daily ruxolitinib who achieved T-VASI 50 at weeks 12, 24, and 52 were 11.5%, 26.9%, and 57.7%, respectively. The corresponding percentages for all in the study population were 10.7%, 22.7%, and 44.4%, respectively.

At the meeting, the presenter, Julien Seneschal, MD, PhD, professor of dermatology and head of the vitiligo and pigmentary disorders clinic at the University of Bordeaux, France, said, “This suggests that younger patients can respond better to the treatment.” He noted, however, that there were few adolescents in the studies.
 

New excitement in the field

Daniel Gutierrez, MD, assistant professor of dermatology at New York University, said the treatment has brought new excitement to the field.

“Patients with vitiligo are very motivated to treat their disease,” he said, because it typically is on the face and other highly visual areas, which can affect their overall perception of self.

NYU Langone Health

Previously, he noted in an interview, the only FDA-approved treatment was monobenzone, but that was for depigmentation rather than repigmentation.

Otherwise, treatments were being used off label, and patients were receiving compounded formulations that often weren’t covered by insurance and often had shorter shelf life.

He said that he still occasionally gets denials from payers who consider vitiligo a cosmetic condition.

“I’ve had more luck with insurance, at least in the New York State area.” He added that sometimes payers require use of a topical calcineurin inhibitor for about 12 weeks before they will cover ruxolitinib.

Dr. Gutierrez also recommends using phototherapy with topical ruxolitinib “because they work on slightly different pathways.”

When he starts patients on a new therapy such as ruxolitinib, he asks them to come back in 3 months, and often by then, progress is evident. Facial areas show the most response, he said, while hands and feet are less likely to show significant improvement.

He said that it’s important for physicians and patients to know that improvements can take weeks or months to be noticeable. “I tell patients not to give up,” he added.

Showing the patients pictures from the current appointment and comparing them with pictures from previous appointments can help them better understand their progress, he said.
 

Lead investigator adds observations

David Rosmarin, MD, chair of the department of dermatology at Indiana University, Indianapolis, was the lead investigator of the pivotal TruE-V1 and TruE-V2 trials for vitiligo. In that role, he has been treating vitiligo patients with topical ruxolitinib since 2015.

In an interview, he said that many patients “don’t hit their optimal results at 3 months, 6 months, even the year mark. With continued use, many can see continued benefit.”

Other patients, he said, don’t respond within the first 6 months but with continued use may eventually respond, he said.

“Unfortunately, we have no way of knowing, based on clinical characteristics or baseline demographics, whether a patient will be a delayed responder or not or an early responder,” Dr. Rosmarin added.

He provided several observations about people who have stopped taking the medication.

“When people stop,” he said, “some maintain their response, but some start to depigment again. Again, we have no way of predicting who will be in which category.”

He said that once patients have hit their desired response, he usually advises them to taper down to maybe twice a week or to stop treatment, but if they see any recurrence, they should start reusing the medicine.

“We have some patients who have gone 6 or 7 years now before they had a recurrence, but others may start to depigment again in 2 to 3 months,” Dr. Rosmarin said.

As for phototherapy, he said, the combination with topical ruxolitinib is being studied.

“We think the combination is synergistic and better than either alone, but we’re still waiting for data to prove that,” he said.

In his practice, he offers patients the option either to use just ruxolitinib cream or the combination early on. Many patients, because of convenience, say they’ll first try the cream to see if that works.

“The challenge with light [therapy] is that it can be very inconvenient,” he said. Patients have to live close to a phototherapy unit to receive therapy 2-3 times a week or have a phototherapy product in their home.
 

Next in the pipeline

Experts say the progress doesn’t stop with ruxolitinib cream. Current trials of several medications show there’s more to come for patients with vitiligo.

Dr. Chovatiya said that next up may be oral ritlecitinib (Litfulo), a JAK inhibitor that was approved for severe alopecia areata in June for people aged 12 years and older. Phase 2 results have been published for its use with vitiligo.

“This would be an oral medication that may be able to help people with much more extensive disease as far as vitiligo goes,” he said, adding that he expects approval for a vitiligo indication within a few years.

He pointed out that longer-term safety data will be available because it is already on the market for alopecia.

Upadacitinib (Rinvoq), an oral JAK inhibitor, is approved for atopic dermatitis but is being studied for vitiligo as well, he noted. “I’m very excited to see what that holds for patients as well,” Dr. Chovatiya said.

Dr. Gutierrez said that he is excited about oral JAK inhibitors but sees potential in finding new ways to transplant melanocytes into areas where there are none.

The pigmentation field has seen new energy since last year’s approval, he said, particularly among people of color.

“We have new options for vitiligo that were lacking compared with other conditions, such as atopic dermatitis and psoriasis,” he said. “Hopefully, there will be more promising breakthroughs.”

Dr. Rosmarin is the chief investigator for the pivotal trials that led to FDA approval of ruxolitinib. He disclosed ties with AbbVie, Abcuro, AltruBio, Amgen, Arena, Boehringer Ingelheim, Bristol-Meyers Squibb, Celgene, Concert, CSL Behring, Dermavant, Dermira, Galderma, Incyte, Janssen, Kyowa Kirin, Lilly, Merck, Novartis, Pfizer, Regeneron, Revolo Biotherapeutics, Sanofi, Sun Pharmaceuticals, UCB, and Viela Bio. Dr. Chovatiya disclosed ties with AbbVie, Arcutis, Arena, Argenx, Beiersdorf, Bristol-Myers Squibb, Dermavant, Eli Lilly, EPI Health, Incyte, LEO Pharma, L’Oréal, National Eczema Association, Pfizer, Regeneron, Sanofi, and UCB. Dr. Heath and Dr. Gutierrez report no relevant financial relationships.

A version of this article appeared on Medscape.com.

A year after celebrating the approval of the first treatment for repigmentation of vitiligo, dermatologists describe how topical ruxolitinib has advanced the outlook for patients with the disease and what’s next in the pipeline.

The Food and Drug Administration approved the cream formulation of ruxolitinib (Opzelura), a JAK inhibitor, for repigmentation of nonsegmental vitiligo in July 2022 for people aged 12 years and older.

Raj Chovatiya, MD, PhD, assistant professor of dermatology at Northwestern University, Chicago, said that he likes to use ruxolitinib cream in combination with other treatments.

Dr. Chovatiya

“In the real world with vitiligo patients, we’re oftentimes doing combinatorial therapy anyway. So phototherapy, specifically, narrow-band UVB, is something that we have a lot of clinical evidence for over the years, and it’s a modality that can combine with topical steroids and topical calcineurin inhibitors.”

He said trials to study combinations will yield better guidance on optimal use of ruxolitinib cream. “In general, vitiligo patients can really benefit from phototherapy,” he said in an interview. (Labeling recommends against combination with other JAK inhibitors, biologics, or potent immunosuppressants, such as azathioprine or cyclosporine.)

This first year has shown that ruxolitinib is an effective option, but counseling patients to expect slow improvement is important so that patients stick with it, he noted.

Documenting what treatments patients with vitiligo have used before is important, he said, as is counseling patients that ruxolitinib is approved only for use on up to 10% of a person’s body surface area. (Product labeling recommends that a thin layer be applied twice a day to affected areas up to 10% of body surface area.)

Ruxolitinib has brought a “louder voice” to vitiligo and has opened up options for patients with the disease, Dr. Chovatiya said. “Having the ability to topically treat people who have very extensive disease really gives us a lot more flexibility than we have had before.”
 

Good experiences with payers at safety-net hospital

Candrice R. Heath, MD, assistant professor of dermatology at Temple University, Philadelphia, said that real-world experience with topical ruxolitinib will be more evident after its been on the market for 18-24 months.

Dr. Heath said she, too, encourages use of narrow-band UVB phototherapy in conjunction with the treatment.

From an insurance reimbursement standpoint, she said that she is glad that there have been fewer hurdles in getting ruxolitinib to patients than she has experienced with other medications.

In her safety-net hospital, she told this news organization, she sees patients with many types of insurance, but most have Medicaid. “So, I’m always expecting the step therapies, denials, pushbacks, etc.,” she said. But the path has been smoother for ruxolitinib coverage, she noted.

Her colleagues are committed to documenting everything the patient has tried, she added, and that helps with prior authorization.

Dr. Heath said that pointing out to insurers that ruxolitinib is the only approved treatment for repigmentation helps facilitate coverage.

“The science is advancing, and I’m happy to be practicing during a time when we actually have something approved for vitiligo,” she said. But she pointed out that phototherapy often is not covered for vitiligo, “which is horrible, when it is readily approved for psoriasis and atopic dermatitis.”

To document progress, Dr. Heath said that she always takes photographs of her patients with vitiligo because “the pictures remind us how far we have come.”
 

Data spotlight success in adolescents

Data from two trials give a clinical picture of the drug’s safety and efficacy in younger patients.

Adolescents had particularly good results in the first year with ruxolitinib, according to pooled phase 3 data from TRuE-V1 and TRuE-V2, this news organization reported.

The findings, presented at the 25th World Congress of Dermatology in Singapore, indicate that more than half of the participants achieved at least a 50% improvement from baseline in the total Vitiligo Area Scoring Index (T-VASI50) at 52 weeks.

The percentages of young patients aged 12-17 years taking twice-daily ruxolitinib who achieved T-VASI 50 at weeks 12, 24, and 52 were 11.5%, 26.9%, and 57.7%, respectively. The corresponding percentages for all in the study population were 10.7%, 22.7%, and 44.4%, respectively.

At the meeting, the presenter, Julien Seneschal, MD, PhD, professor of dermatology and head of the vitiligo and pigmentary disorders clinic at the University of Bordeaux, France, said, “This suggests that younger patients can respond better to the treatment.” He noted, however, that there were few adolescents in the studies.
 

New excitement in the field

Daniel Gutierrez, MD, assistant professor of dermatology at New York University, said the treatment has brought new excitement to the field.

“Patients with vitiligo are very motivated to treat their disease,” he said, because it typically is on the face and other highly visual areas, which can affect their overall perception of self.

NYU Langone Health

Previously, he noted in an interview, the only FDA-approved treatment was monobenzone, but that was for depigmentation rather than repigmentation.

Otherwise, treatments were being used off label, and patients were receiving compounded formulations that often weren’t covered by insurance and often had shorter shelf life.

He said that he still occasionally gets denials from payers who consider vitiligo a cosmetic condition.

“I’ve had more luck with insurance, at least in the New York State area.” He added that sometimes payers require use of a topical calcineurin inhibitor for about 12 weeks before they will cover ruxolitinib.

Dr. Gutierrez also recommends using phototherapy with topical ruxolitinib “because they work on slightly different pathways.”

When he starts patients on a new therapy such as ruxolitinib, he asks them to come back in 3 months, and often by then, progress is evident. Facial areas show the most response, he said, while hands and feet are less likely to show significant improvement.

He said that it’s important for physicians and patients to know that improvements can take weeks or months to be noticeable. “I tell patients not to give up,” he added.

Showing the patients pictures from the current appointment and comparing them with pictures from previous appointments can help them better understand their progress, he said.
 

Lead investigator adds observations

David Rosmarin, MD, chair of the department of dermatology at Indiana University, Indianapolis, was the lead investigator of the pivotal TruE-V1 and TruE-V2 trials for vitiligo. In that role, he has been treating vitiligo patients with topical ruxolitinib since 2015.

In an interview, he said that many patients “don’t hit their optimal results at 3 months, 6 months, even the year mark. With continued use, many can see continued benefit.”

Other patients, he said, don’t respond within the first 6 months but with continued use may eventually respond, he said.

“Unfortunately, we have no way of knowing, based on clinical characteristics or baseline demographics, whether a patient will be a delayed responder or not or an early responder,” Dr. Rosmarin added.

He provided several observations about people who have stopped taking the medication.

“When people stop,” he said, “some maintain their response, but some start to depigment again. Again, we have no way of predicting who will be in which category.”

He said that once patients have hit their desired response, he usually advises them to taper down to maybe twice a week or to stop treatment, but if they see any recurrence, they should start reusing the medicine.

“We have some patients who have gone 6 or 7 years now before they had a recurrence, but others may start to depigment again in 2 to 3 months,” Dr. Rosmarin said.

As for phototherapy, he said, the combination with topical ruxolitinib is being studied.

“We think the combination is synergistic and better than either alone, but we’re still waiting for data to prove that,” he said.

In his practice, he offers patients the option either to use just ruxolitinib cream or the combination early on. Many patients, because of convenience, say they’ll first try the cream to see if that works.

“The challenge with light [therapy] is that it can be very inconvenient,” he said. Patients have to live close to a phototherapy unit to receive therapy 2-3 times a week or have a phototherapy product in their home.
 

Next in the pipeline

Experts say the progress doesn’t stop with ruxolitinib cream. Current trials of several medications show there’s more to come for patients with vitiligo.

Dr. Chovatiya said that next up may be oral ritlecitinib (Litfulo), a JAK inhibitor that was approved for severe alopecia areata in June for people aged 12 years and older. Phase 2 results have been published for its use with vitiligo.

“This would be an oral medication that may be able to help people with much more extensive disease as far as vitiligo goes,” he said, adding that he expects approval for a vitiligo indication within a few years.

He pointed out that longer-term safety data will be available because it is already on the market for alopecia.

Upadacitinib (Rinvoq), an oral JAK inhibitor, is approved for atopic dermatitis but is being studied for vitiligo as well, he noted. “I’m very excited to see what that holds for patients as well,” Dr. Chovatiya said.

Dr. Gutierrez said that he is excited about oral JAK inhibitors but sees potential in finding new ways to transplant melanocytes into areas where there are none.

The pigmentation field has seen new energy since last year’s approval, he said, particularly among people of color.

“We have new options for vitiligo that were lacking compared with other conditions, such as atopic dermatitis and psoriasis,” he said. “Hopefully, there will be more promising breakthroughs.”

Dr. Rosmarin is the chief investigator for the pivotal trials that led to FDA approval of ruxolitinib. He disclosed ties with AbbVie, Abcuro, AltruBio, Amgen, Arena, Boehringer Ingelheim, Bristol-Meyers Squibb, Celgene, Concert, CSL Behring, Dermavant, Dermira, Galderma, Incyte, Janssen, Kyowa Kirin, Lilly, Merck, Novartis, Pfizer, Regeneron, Revolo Biotherapeutics, Sanofi, Sun Pharmaceuticals, UCB, and Viela Bio. Dr. Chovatiya disclosed ties with AbbVie, Arcutis, Arena, Argenx, Beiersdorf, Bristol-Myers Squibb, Dermavant, Eli Lilly, EPI Health, Incyte, LEO Pharma, L’Oréal, National Eczema Association, Pfizer, Regeneron, Sanofi, and UCB. Dr. Heath and Dr. Gutierrez report no relevant financial relationships.

A version of this article appeared on Medscape.com.

As the summer ends, greater numbers of patients request treatment for poikiloderma. Poikiloderma of Civatte is an acquired, irreversible sun-induced dermatosis and is one of the most frustrating dermatologic problems to treat.

Poikiloderma is an area of mottled pigmentation (hyper and hypo) with telangiectasias and atrophy often present on the V of the chest, lateral neck, and lateral face. It is always present in sun-exposed areas but shaded areas of the neck, such as the area under the chin, are spared. Cumulative UV radiation is the predominant underlying cause; however, postmenopausal hormonal changes and contact sensitization with perfumes and cosmetics can exacerbate the condition.

Courtesy Dr. Lily Talakoub

Breaking down the subtypes will help direct the treatment options. There are two main types of poikiloderma – telangiectatic and hyperpigmented – and of course, an overlap between the two. Choosing which subtype is dominant is based primarily on clinical presentation and dermoscopic findings. Atrophy is ubiquitous, thus collagen remodeling is a necessary treatment for both.

In my clinical practice, the pigmentation component of poikiloderma in all skin types is pretreated and posttreated with topical hydroquinone and/or oral tranexamic acid to avoid recurrence after any laser treatment. In the majority of my patients with poikiloderma, I first treat the pigmentation with hydroquinone and tranexamic acid (if the patient is a candidate) to minimize the pigment as much as possible and then treat the telangiectasias with lasers. I try to avoid laser treatment of the hyperpigmentation if at all possible.

Telangiectatic poikiloderma is characterized by a linear and reticular dilated network of vessels. Laser treatment options include IPL, V-beam, and KTP lasers. Multiple treatments are usually necessary and if the patient has concomitant flushing and burning symptoms associated with poikiloderma, topical rosacea treatments such as topical oxymetazoline, as well as avoidance of fragrance, and strict use of a broad spectrum mineral sunscreen, should be initiated prior to laser treatments.

Hyperpigmented poikiloderma is characterized by mottled hyperpigmentation caused by the increased melanin irregularly distributed in the basal layer of the epidermis and melanophages within the dermis. The best treatment for this is with 1,927-nm fractionated resurfacing modalities. Although IPL has been used in this area and is often recommended in the literature for the lentigines, in my experience, the results are transient and it is much harder to blend the color of the skin with the surrounding area of the neck, lateral chest, shoulders, and arms. The 1,927-nm fractionated laser allows for a smoother transition and blending of the skin and also helps with some collagen remodeling of the dermis.

Atrophy is visualized under dermoscopy as a white polka dot–like print with flattened, atrophic epidermis and an elastotic papillary dermis in between the hyperemic telangiectatic network. With every case of poikiloderma, there is some atrophy present; therefore, I combine platelet rich plasma (PRP), PRP with microneedling, or very light treatments with the Fraxel dual (1927/1550) laser to help improve architectural changes of the dermis.

As with any condition of the chest and neck, there is a very fine line between treatment efficacy and complications. All treatments, particularly lasers, should be used with considerable caution and test spots and with the expectation that the treatment will mitigate, not resolve the condition. Sun avoidance, use of daily mineral SPF, and avoidance of fragrance should be emphasized. If expectations are set properly, patients are often satisfied with small improvements as this condition can be very troubling and difficult to treat.

Dr. Talakoub is in private practice in McLean, Va. Write to her at dermnews@mdedge.com. She had no relevant disclosures.
 

References

Geronemus R. Arch Dermatol. 1990 Apr;126(4):547-8.

Goldman MP and Weiss RA. Plast Reconstr Surg. 2001 May;107(6):1376-81.

Katoulis AC and Stavrianeas NG. Poikiloderma of Civatte. In: Rigopoulos D, Katoulis AC, editors. Hyperpigmentation (Boca Raton, Fla.: CRC Press, 2017). Chapter 12.

As the summer ends, greater numbers of patients request treatment for poikiloderma. Poikiloderma of Civatte is an acquired, irreversible sun-induced dermatosis and is one of the most frustrating dermatologic problems to treat.

Poikiloderma is an area of mottled pigmentation (hyper and hypo) with telangiectasias and atrophy often present on the V of the chest, lateral neck, and lateral face. It is always present in sun-exposed areas but shaded areas of the neck, such as the area under the chin, are spared. Cumulative UV radiation is the predominant underlying cause; however, postmenopausal hormonal changes and contact sensitization with perfumes and cosmetics can exacerbate the condition.

Courtesy Dr. Lily Talakoub

Breaking down the subtypes will help direct the treatment options. There are two main types of poikiloderma – telangiectatic and hyperpigmented – and of course, an overlap between the two. Choosing which subtype is dominant is based primarily on clinical presentation and dermoscopic findings. Atrophy is ubiquitous, thus collagen remodeling is a necessary treatment for both.

In my clinical practice, the pigmentation component of poikiloderma in all skin types is pretreated and posttreated with topical hydroquinone and/or oral tranexamic acid to avoid recurrence after any laser treatment. In the majority of my patients with poikiloderma, I first treat the pigmentation with hydroquinone and tranexamic acid (if the patient is a candidate) to minimize the pigment as much as possible and then treat the telangiectasias with lasers. I try to avoid laser treatment of the hyperpigmentation if at all possible.

Telangiectatic poikiloderma is characterized by a linear and reticular dilated network of vessels. Laser treatment options include IPL, V-beam, and KTP lasers. Multiple treatments are usually necessary and if the patient has concomitant flushing and burning symptoms associated with poikiloderma, topical rosacea treatments such as topical oxymetazoline, as well as avoidance of fragrance, and strict use of a broad spectrum mineral sunscreen, should be initiated prior to laser treatments.

Hyperpigmented poikiloderma is characterized by mottled hyperpigmentation caused by the increased melanin irregularly distributed in the basal layer of the epidermis and melanophages within the dermis. The best treatment for this is with 1,927-nm fractionated resurfacing modalities. Although IPL has been used in this area and is often recommended in the literature for the lentigines, in my experience, the results are transient and it is much harder to blend the color of the skin with the surrounding area of the neck, lateral chest, shoulders, and arms. The 1,927-nm fractionated laser allows for a smoother transition and blending of the skin and also helps with some collagen remodeling of the dermis.

Atrophy is visualized under dermoscopy as a white polka dot–like print with flattened, atrophic epidermis and an elastotic papillary dermis in between the hyperemic telangiectatic network. With every case of poikiloderma, there is some atrophy present; therefore, I combine platelet rich plasma (PRP), PRP with microneedling, or very light treatments with the Fraxel dual (1927/1550) laser to help improve architectural changes of the dermis.

As with any condition of the chest and neck, there is a very fine line between treatment efficacy and complications. All treatments, particularly lasers, should be used with considerable caution and test spots and with the expectation that the treatment will mitigate, not resolve the condition. Sun avoidance, use of daily mineral SPF, and avoidance of fragrance should be emphasized. If expectations are set properly, patients are often satisfied with small improvements as this condition can be very troubling and difficult to treat.

Dr. Talakoub is in private practice in McLean, Va. Write to her at dermnews@mdedge.com. She had no relevant disclosures.
 

References

Geronemus R. Arch Dermatol. 1990 Apr;126(4):547-8.

Goldman MP and Weiss RA. Plast Reconstr Surg. 2001 May;107(6):1376-81.

Katoulis AC and Stavrianeas NG. Poikiloderma of Civatte. In: Rigopoulos D, Katoulis AC, editors. Hyperpigmentation (Boca Raton, Fla.: CRC Press, 2017). Chapter 12.

As the summer ends, greater numbers of patients request treatment for poikiloderma. Poikiloderma of Civatte is an acquired, irreversible sun-induced dermatosis and is one of the most frustrating dermatologic problems to treat.

Poikiloderma is an area of mottled pigmentation (hyper and hypo) with telangiectasias and atrophy often present on the V of the chest, lateral neck, and lateral face. It is always present in sun-exposed areas but shaded areas of the neck, such as the area under the chin, are spared. Cumulative UV radiation is the predominant underlying cause; however, postmenopausal hormonal changes and contact sensitization with perfumes and cosmetics can exacerbate the condition.

Courtesy Dr. Lily Talakoub

Breaking down the subtypes will help direct the treatment options. There are two main types of poikiloderma – telangiectatic and hyperpigmented – and of course, an overlap between the two. Choosing which subtype is dominant is based primarily on clinical presentation and dermoscopic findings. Atrophy is ubiquitous, thus collagen remodeling is a necessary treatment for both.

In my clinical practice, the pigmentation component of poikiloderma in all skin types is pretreated and posttreated with topical hydroquinone and/or oral tranexamic acid to avoid recurrence after any laser treatment. In the majority of my patients with poikiloderma, I first treat the pigmentation with hydroquinone and tranexamic acid (if the patient is a candidate) to minimize the pigment as much as possible and then treat the telangiectasias with lasers. I try to avoid laser treatment of the hyperpigmentation if at all possible.

Telangiectatic poikiloderma is characterized by a linear and reticular dilated network of vessels. Laser treatment options include IPL, V-beam, and KTP lasers. Multiple treatments are usually necessary and if the patient has concomitant flushing and burning symptoms associated with poikiloderma, topical rosacea treatments such as topical oxymetazoline, as well as avoidance of fragrance, and strict use of a broad spectrum mineral sunscreen, should be initiated prior to laser treatments.

Hyperpigmented poikiloderma is characterized by mottled hyperpigmentation caused by the increased melanin irregularly distributed in the basal layer of the epidermis and melanophages within the dermis. The best treatment for this is with 1,927-nm fractionated resurfacing modalities. Although IPL has been used in this area and is often recommended in the literature for the lentigines, in my experience, the results are transient and it is much harder to blend the color of the skin with the surrounding area of the neck, lateral chest, shoulders, and arms. The 1,927-nm fractionated laser allows for a smoother transition and blending of the skin and also helps with some collagen remodeling of the dermis.

Atrophy is visualized under dermoscopy as a white polka dot–like print with flattened, atrophic epidermis and an elastotic papillary dermis in between the hyperemic telangiectatic network. With every case of poikiloderma, there is some atrophy present; therefore, I combine platelet rich plasma (PRP), PRP with microneedling, or very light treatments with the Fraxel dual (1927/1550) laser to help improve architectural changes of the dermis.

As with any condition of the chest and neck, there is a very fine line between treatment efficacy and complications. All treatments, particularly lasers, should be used with considerable caution and test spots and with the expectation that the treatment will mitigate, not resolve the condition. Sun avoidance, use of daily mineral SPF, and avoidance of fragrance should be emphasized. If expectations are set properly, patients are often satisfied with small improvements as this condition can be very troubling and difficult to treat.

Dr. Talakoub is in private practice in McLean, Va. Write to her at dermnews@mdedge.com. She had no relevant disclosures.
 

References

Geronemus R. Arch Dermatol. 1990 Apr;126(4):547-8.

Goldman MP and Weiss RA. Plast Reconstr Surg. 2001 May;107(6):1376-81.

Katoulis AC and Stavrianeas NG. Poikiloderma of Civatte. In: Rigopoulos D, Katoulis AC, editors. Hyperpigmentation (Boca Raton, Fla.: CRC Press, 2017). Chapter 12.