Cutis

The Diagnosis: Necrolytic Migratory Erythema

Necrolytic migratory erythema (NME) is a waxing and waning rash associated with rare pancreatic neuroendocrine tumors called glucagonomas. It is characterized by pruritic and painful, well-demarcated, erythematous plaques that manifest in the intertriginous areas and on the perineum and buttocks.¹ Due to the evolving nature of the rash, the histopathologic findings in NME vary depending on the stage of the cutaneous lesions at the time of biopsy.² Multiple dyskeratotic keratinocytes spanning all epidermal layers may be a diagnostic clue in early lesions of NME.³ Typical features of longstanding lesions include confluent parakeratosis, psoriasiform hyperplasia with mild or absent spongiosis, and upper epidermal necrosis with keratinocyte vacuolization and pallor.⁴ Morphologic features that are present prior to the development of epidermal vacuolation and necrosis frequently are misattributed to psoriasis or eczema. Long-standing lesions also may develop a neutrophilic infiltrate with subcorneal and intraepidermal pustules.² Other common features include a discrete perivascular lymphocytic infiltrate and an erosive or encrusted epidermis.⁵ Although direct immunofluorescence typically is negative, nonspecific findings can be seen, including apoptotic keratinocytes labeling with fibrinogen and C3, as well as scattered, clumped, IgM-positive cytoid bodies present at the dermal-epidermal junction (DEJ).⁶ Biopsies also have shown scattered, clumped, IgM-positive cytoid bodies present at the DEJ.⁵

Psoriasis is a chronic relapsing papulosquamous disorder characterized by scaly erythematous plaques often overlying the extensor surfaces of the extremities. Histopathology shows a psoriasiform pattern of inflammation with thinning of the suprapapillary plates and elongation of the rete ridges. Further diagnostic clues of psoriasis include regular acanthosis, characteristic Munro microabscesses with neutrophils in a hyperkeratotic stratum corneum (Figure 1), hypogranulosis, and neutrophilic spongiform pustules of Kogoj in the stratum spinosum. Generally, there is a lack of the epidermal necrosis seen with NME.^7,8

Lichen simplex chronicus manifests as pruritic, often hyperpigmented, well-defined, lichenified plaques with excoriation following repetitive mechanical trauma, commonly on the lower lateral legs, posterior neck, and flexural areas.⁹ The histologic landscape is marked by well-developed lesions evolving to show compact orthokeratosis, hypergranulosis, irregularly elongated rete ridges (ie, irregular acanthosis), and papillary dermal fibrosis with vertical streaking of collagen (Figure 2).^9,10

Subacute cutaneous lupus erythematosus (SCLE) is recognized clinically by scaly/psoriasiform and annular lesions with mild or absent systemic involvement. Common histopathologic findings include epidermal atrophy, vacuolar interface dermatitis with hydropic degeneration of the basal layer, a subepidermal lymphocytic infiltrate, and a periadnexal and perivascular infiltrate (Figure 3).¹¹ Upper dermal edema, spotty necrosis of individual cells in the epidermis, dermal-epidermal separation caused by prominent basal cell degeneration, and accumulation of acid mucopolysaccharides (mucin) are other histologic features associated with SCLE.^12,13

The immunofluorescence pattern in SCLE features dustlike particles of IgG deposition in the epidermis, subepidermal region, and dermal cellular infiltrate. Lesions also may have granular deposition of immunoreactions at the DEJ.^11,13

The manifestation of drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome (also known as drug-induced hypersensitivity syndrome) is variable, with a morbilliform rash that spreads from the face to the entire body, urticaria, atypical target lesions, purpuriform lesions, lymphadenopathy, and exfoliative dermatitis.¹⁴ The nonspecific morphologic features of DRESS syndrome lesions are associated with variable histologic features, which include focal interface changes with vacuolar alteration of the basal layer; atypical lymphocytes with hyperchromic nuclei; and a superficial, inconsistently dense, perivascular lymphocytic infiltrate. Other relatively common histopathologic patterns include an upper dermis with dilated blood vessels, spongiosis with exocytosis of lymphocytes (Figure 4), and necrotic keratinocytes. Although peripheral eosinophilia is an important diagnostic criterion and is observed consistently, eosinophils are variably present on skin biopsy.^15,16 Given the histopathologic variability and nonspecific findings, clinical correlation is required when diagnosing DRESS syndrome.

The Diagnosis: Necrolytic Migratory Erythema

Necrolytic migratory erythema (NME) is a waxing and waning rash associated with rare pancreatic neuroendocrine tumors called glucagonomas. It is characterized by pruritic and painful, well-demarcated, erythematous plaques that manifest in the intertriginous areas and on the perineum and buttocks.¹ Due to the evolving nature of the rash, the histopathologic findings in NME vary depending on the stage of the cutaneous lesions at the time of biopsy.² Multiple dyskeratotic keratinocytes spanning all epidermal layers may be a diagnostic clue in early lesions of NME.³ Typical features of longstanding lesions include confluent parakeratosis, psoriasiform hyperplasia with mild or absent spongiosis, and upper epidermal necrosis with keratinocyte vacuolization and pallor.⁴ Morphologic features that are present prior to the development of epidermal vacuolation and necrosis frequently are misattributed to psoriasis or eczema. Long-standing lesions also may develop a neutrophilic infiltrate with subcorneal and intraepidermal pustules.² Other common features include a discrete perivascular lymphocytic infiltrate and an erosive or encrusted epidermis.⁵ Although direct immunofluorescence typically is negative, nonspecific findings can be seen, including apoptotic keratinocytes labeling with fibrinogen and C3, as well as scattered, clumped, IgM-positive cytoid bodies present at the dermal-epidermal junction (DEJ).⁶ Biopsies also have shown scattered, clumped, IgM-positive cytoid bodies present at the DEJ.⁵

Psoriasis is a chronic relapsing papulosquamous disorder characterized by scaly erythematous plaques often overlying the extensor surfaces of the extremities. Histopathology shows a psoriasiform pattern of inflammation with thinning of the suprapapillary plates and elongation of the rete ridges. Further diagnostic clues of psoriasis include regular acanthosis, characteristic Munro microabscesses with neutrophils in a hyperkeratotic stratum corneum (Figure 1), hypogranulosis, and neutrophilic spongiform pustules of Kogoj in the stratum spinosum. Generally, there is a lack of the epidermal necrosis seen with NME.^7,8

Lichen simplex chronicus manifests as pruritic, often hyperpigmented, well-defined, lichenified plaques with excoriation following repetitive mechanical trauma, commonly on the lower lateral legs, posterior neck, and flexural areas.⁹ The histologic landscape is marked by well-developed lesions evolving to show compact orthokeratosis, hypergranulosis, irregularly elongated rete ridges (ie, irregular acanthosis), and papillary dermal fibrosis with vertical streaking of collagen (Figure 2).^9,10

Subacute cutaneous lupus erythematosus (SCLE) is recognized clinically by scaly/psoriasiform and annular lesions with mild or absent systemic involvement. Common histopathologic findings include epidermal atrophy, vacuolar interface dermatitis with hydropic degeneration of the basal layer, a subepidermal lymphocytic infiltrate, and a periadnexal and perivascular infiltrate (Figure 3).¹¹ Upper dermal edema, spotty necrosis of individual cells in the epidermis, dermal-epidermal separation caused by prominent basal cell degeneration, and accumulation of acid mucopolysaccharides (mucin) are other histologic features associated with SCLE.^12,13

The immunofluorescence pattern in SCLE features dustlike particles of IgG deposition in the epidermis, subepidermal region, and dermal cellular infiltrate. Lesions also may have granular deposition of immunoreactions at the DEJ.^11,13

The manifestation of drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome (also known as drug-induced hypersensitivity syndrome) is variable, with a morbilliform rash that spreads from the face to the entire body, urticaria, atypical target lesions, purpuriform lesions, lymphadenopathy, and exfoliative dermatitis.¹⁴ The nonspecific morphologic features of DRESS syndrome lesions are associated with variable histologic features, which include focal interface changes with vacuolar alteration of the basal layer; atypical lymphocytes with hyperchromic nuclei; and a superficial, inconsistently dense, perivascular lymphocytic infiltrate. Other relatively common histopathologic patterns include an upper dermis with dilated blood vessels, spongiosis with exocytosis of lymphocytes (Figure 4), and necrotic keratinocytes. Although peripheral eosinophilia is an important diagnostic criterion and is observed consistently, eosinophils are variably present on skin biopsy.^15,16 Given the histopathologic variability and nonspecific findings, clinical correlation is required when diagnosing DRESS syndrome.

The Diagnosis: Necrolytic Migratory Erythema

Necrolytic migratory erythema (NME) is a waxing and waning rash associated with rare pancreatic neuroendocrine tumors called glucagonomas. It is characterized by pruritic and painful, well-demarcated, erythematous plaques that manifest in the intertriginous areas and on the perineum and buttocks.¹ Due to the evolving nature of the rash, the histopathologic findings in NME vary depending on the stage of the cutaneous lesions at the time of biopsy.² Multiple dyskeratotic keratinocytes spanning all epidermal layers may be a diagnostic clue in early lesions of NME.³ Typical features of longstanding lesions include confluent parakeratosis, psoriasiform hyperplasia with mild or absent spongiosis, and upper epidermal necrosis with keratinocyte vacuolization and pallor.⁴ Morphologic features that are present prior to the development of epidermal vacuolation and necrosis frequently are misattributed to psoriasis or eczema. Long-standing lesions also may develop a neutrophilic infiltrate with subcorneal and intraepidermal pustules.² Other common features include a discrete perivascular lymphocytic infiltrate and an erosive or encrusted epidermis.⁵ Although direct immunofluorescence typically is negative, nonspecific findings can be seen, including apoptotic keratinocytes labeling with fibrinogen and C3, as well as scattered, clumped, IgM-positive cytoid bodies present at the dermal-epidermal junction (DEJ).⁶ Biopsies also have shown scattered, clumped, IgM-positive cytoid bodies present at the DEJ.⁵

Psoriasis is a chronic relapsing papulosquamous disorder characterized by scaly erythematous plaques often overlying the extensor surfaces of the extremities. Histopathology shows a psoriasiform pattern of inflammation with thinning of the suprapapillary plates and elongation of the rete ridges. Further diagnostic clues of psoriasis include regular acanthosis, characteristic Munro microabscesses with neutrophils in a hyperkeratotic stratum corneum (Figure 1), hypogranulosis, and neutrophilic spongiform pustules of Kogoj in the stratum spinosum. Generally, there is a lack of the epidermal necrosis seen with NME.^7,8

Lichen simplex chronicus manifests as pruritic, often hyperpigmented, well-defined, lichenified plaques with excoriation following repetitive mechanical trauma, commonly on the lower lateral legs, posterior neck, and flexural areas.⁹ The histologic landscape is marked by well-developed lesions evolving to show compact orthokeratosis, hypergranulosis, irregularly elongated rete ridges (ie, irregular acanthosis), and papillary dermal fibrosis with vertical streaking of collagen (Figure 2).^9,10

Subacute cutaneous lupus erythematosus (SCLE) is recognized clinically by scaly/psoriasiform and annular lesions with mild or absent systemic involvement. Common histopathologic findings include epidermal atrophy, vacuolar interface dermatitis with hydropic degeneration of the basal layer, a subepidermal lymphocytic infiltrate, and a periadnexal and perivascular infiltrate (Figure 3).¹¹ Upper dermal edema, spotty necrosis of individual cells in the epidermis, dermal-epidermal separation caused by prominent basal cell degeneration, and accumulation of acid mucopolysaccharides (mucin) are other histologic features associated with SCLE.^12,13

The immunofluorescence pattern in SCLE features dustlike particles of IgG deposition in the epidermis, subepidermal region, and dermal cellular infiltrate. Lesions also may have granular deposition of immunoreactions at the DEJ.^11,13

The manifestation of drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome (also known as drug-induced hypersensitivity syndrome) is variable, with a morbilliform rash that spreads from the face to the entire body, urticaria, atypical target lesions, purpuriform lesions, lymphadenopathy, and exfoliative dermatitis.¹⁴ The nonspecific morphologic features of DRESS syndrome lesions are associated with variable histologic features, which include focal interface changes with vacuolar alteration of the basal layer; atypical lymphocytes with hyperchromic nuclei; and a superficial, inconsistently dense, perivascular lymphocytic infiltrate. Other relatively common histopathologic patterns include an upper dermis with dilated blood vessels, spongiosis with exocytosis of lymphocytes (Figure 4), and necrotic keratinocytes. Although peripheral eosinophilia is an important diagnostic criterion and is observed consistently, eosinophils are variably present on skin biopsy.^15,16 Given the histopathologic variability and nonspecific findings, clinical correlation is required when diagnosing DRESS syndrome.

Molluscum contagiosum (ie, molluscum) is a ubiquitous infection caused by the poxvirus molluscum contagiosum virus (MCV). Although skin deep, molluscum shares many factors with the more virulent poxviridae. Moisture and trauma can cause viral material to be released from the pearly papules through a small opening, which also allows entry of bacteria and medications into the lesion. The MCV is transmitted by direct contact with skin or via fomites.¹

Molluscum can affect children of any age, with MCV type 1 peaking in toddlers and school-aged children and MCV type 2 after the sexual debut. The prevalence of molluscum has increased since the 1980s. It is stressful for children and caregivers and poses challenges in schools as well as sports such as swimming, wrestling, and karate.^1,2

For the first time, we have US Food and Drug Administration (FDA)–approved products to treat MCV infections. Previously, only off-label agents were used. Therefore, we have to contemplate why treatment is important to our patients.

What type of care is required for molluscum?

Counseling is the first and only mandatory treatment, which consists of 3 parts: natural history, risk factors for spread, and options for therapy. The natural history of molluscum in children is early spread, contagion to oneself and others (as high as 60% of sibling co-bathers³), triggering of dermatitis, eventual onset of the beginning-of-the-end (BOTE) sign, and eventually clearance. The natural history in adults is poorly understood.

Early clearance is uncommon; reports have suggested 45.6% to 48.4% of affected patients are clear at 1 year and 69.5% to 72.6% at 1.5 years.⁴ For many children, especially those with atopic dermatitis (AD), lesions linger and often spread, with many experiencing disease for 3 to 4 years. Fomites such as towels, washcloths, and sponges can transfer the virus and spread lesions; therefore, I advise patients to gently pat their skin dry, wash towels frequently, and avoid sharing bathing equipment.^1,3,5 Children and adults with immunosuppression may have a greater number of lesions and more prolonged course of disease, including those with HIV as well as DOC8 and CARD11 mutations.⁶ The American Academy of Pediatrics (AAP) emphasizes that children should not be excluded from attending child care/school or from swimming in public pools but lesions should be covered.⁶ Lesions, especially those in the antecubital region, can trigger new-onset AD or AD flares.³ In response, gentle skin care including fragrance-free cleansers and periodic application of moisturizers may ward off AD. Topical corticosteroids are preferred.

Dermatitis in MCV is a great mimicker and can resemble erythema multiforme, Gianotti-Crosti syndrome, impetigo, and AD.¹ Superinfection recently has been reported; however, in a retrospective analysis of 56 patients with inflamed lesions secondary to molluscum infection, only 7 had positive bacterial cultures, which supports the idea of the swelling and redness of inflammation as a mimic for infection.⁷ When true infection does occur, tender, swollen, pus-filled lesions should be lanced and cultured.^1,7,8

When should we consider therapy?

Therapy is highly dependent on the child, the caregiver, and the social circumstances.¹ More than 80% of parents are anxious about molluscum, and countless children are embarrassed or ashamed.¹ Ultimately, an unhappy child merits care. The AAP cites the following as reasons to treat: “(1) alleviate discomfort, including itching; (2) reduce autoinoculation; (3) limit transmission of the virus to close contacts; (4) reduce cosmetic concerns; and (5) prevent secondary infection.”⁶ For adults, we should consider limitations to intimacy and reduction of sexual transmission risk.⁶

Treatment can be based on the number of lesions. With a few lesions (<3), therapy is worthwhile if they are unsightly; appear on exposed skin causing embarrassment; and/or are itchy, uncomfortable, or large. In a report of 300 children with molluscum treated with cantharidin, most patients choosing therapy had 10 to 20 lesions, but this was over multiple visits.⁸ Looking at a 2018 data set of 50 patients (all-comers) with molluscum,³ the mean number of lesions was 10 (median, 7); 3 lesions were 1 SD below, while 14, 17, and 45 were 1, 2, and 3 SDs above, respectively. This data set shows that patients can develop more lesions rapidly, and most children have many visible lesions (N.B. Silverberg, MD, unpublished data).

Because each lesion contains infectious viral particles and patients scratch, more lesions are equated to greater autoinoculation and contagion. In addition to the AAP criteria, treatment can be considered for households with immunocompromised individuals, children at risk for new-onset AD, or those with AD at risk for flare. For patients with 45 lesions or more (3 SDs), clearance is harder to achieve with 2 sessions of in-office therapy, and multiple methods or the addition of immunomodulatory therapeutics should be considered.

Do we have to clear every lesion?

New molluscum lesions may arise until a patient achieves immunity, and they may appear more than a month after inoculation, making it difficult to keep up with the rapid spread. Latency between exposure and lesion development usually is 2 to 7 weeks but may be as long as 6 months, making it difficult to prevent spread.⁶ Therefore, when we treat, we should not promise full clearance to patients and parents. Rather, we should inform them that new lesions may develop later, and therapy is only effective on visible lesions. In a recent study, a 50% clearance of lesions was the satisfactory threshold for parents, demonstrating that satisfaction is possible with partial clearance.⁹

What is new in therapeutics for molluscum?

Molluscum therapies are either destructive, immunomodulatory, or antiviral. Two agents now are approved by the FDA for the treatment of molluscum infections.

Berdazimer gel 10.3% is approved for patients 1 year or older, but it is not yet available. This agent has both immunomodulatory and antiviral properties.¹⁰ It features a home therapy that is mixed on a small palette, then painted on by the patient or parent once daily for 12 weeks. Study outcomes demonstrated more than 50% lesional clearance.^11,12 Complete clearance was achieved in at least 30% of patients.¹²A proprietary topical version of cantharidin 0.7% in flexible collodion is now FDA approved for patients 2 years and older. This vesicant-triggering iatrogenic is targeted at creating blisters overlying molluscum lesions. It is conceptually similar to older versions but with some enhanced features.^5,13,14 This version was used for therapy every 3 weeks for up to 4 sessions in clinical trials. Safety is similar across all body sites treated (nonmucosal and not near the mucosal surfaces) but not for mucosa, the mid face, or eyelids.¹³ Complete lesion clearance was 46.3% to 54% and statistically greater than placebo (P<.001).¹⁴Both agents are well tolerated in children with AD; adverse effects include blistering with cantharidin and dermatitislike symptoms with berdazimer.^15,16 These therapies have the advantage of being easy to use.

Final Thoughts

We have entered an era of high-quality molluscum therapy. Patient care involves developing a good knowledge of the agents, incorporating shared decision-making with patients and caregivers, and addressing therapy in the context of comorbid diseases such as AD.

Molluscum contagiosum (ie, molluscum) is a ubiquitous infection caused by the poxvirus molluscum contagiosum virus (MCV). Although skin deep, molluscum shares many factors with the more virulent poxviridae. Moisture and trauma can cause viral material to be released from the pearly papules through a small opening, which also allows entry of bacteria and medications into the lesion. The MCV is transmitted by direct contact with skin or via fomites.¹

Molluscum can affect children of any age, with MCV type 1 peaking in toddlers and school-aged children and MCV type 2 after the sexual debut. The prevalence of molluscum has increased since the 1980s. It is stressful for children and caregivers and poses challenges in schools as well as sports such as swimming, wrestling, and karate.^1,2

For the first time, we have US Food and Drug Administration (FDA)–approved products to treat MCV infections. Previously, only off-label agents were used. Therefore, we have to contemplate why treatment is important to our patients.

What type of care is required for molluscum?

Counseling is the first and only mandatory treatment, which consists of 3 parts: natural history, risk factors for spread, and options for therapy. The natural history of molluscum in children is early spread, contagion to oneself and others (as high as 60% of sibling co-bathers³), triggering of dermatitis, eventual onset of the beginning-of-the-end (BOTE) sign, and eventually clearance. The natural history in adults is poorly understood.

Early clearance is uncommon; reports have suggested 45.6% to 48.4% of affected patients are clear at 1 year and 69.5% to 72.6% at 1.5 years.⁴ For many children, especially those with atopic dermatitis (AD), lesions linger and often spread, with many experiencing disease for 3 to 4 years. Fomites such as towels, washcloths, and sponges can transfer the virus and spread lesions; therefore, I advise patients to gently pat their skin dry, wash towels frequently, and avoid sharing bathing equipment.^1,3,5 Children and adults with immunosuppression may have a greater number of lesions and more prolonged course of disease, including those with HIV as well as DOC8 and CARD11 mutations.⁶ The American Academy of Pediatrics (AAP) emphasizes that children should not be excluded from attending child care/school or from swimming in public pools but lesions should be covered.⁶ Lesions, especially those in the antecubital region, can trigger new-onset AD or AD flares.³ In response, gentle skin care including fragrance-free cleansers and periodic application of moisturizers may ward off AD. Topical corticosteroids are preferred.

Dermatitis in MCV is a great mimicker and can resemble erythema multiforme, Gianotti-Crosti syndrome, impetigo, and AD.¹ Superinfection recently has been reported; however, in a retrospective analysis of 56 patients with inflamed lesions secondary to molluscum infection, only 7 had positive bacterial cultures, which supports the idea of the swelling and redness of inflammation as a mimic for infection.⁷ When true infection does occur, tender, swollen, pus-filled lesions should be lanced and cultured.^1,7,8

When should we consider therapy?

Therapy is highly dependent on the child, the caregiver, and the social circumstances.¹ More than 80% of parents are anxious about molluscum, and countless children are embarrassed or ashamed.¹ Ultimately, an unhappy child merits care. The AAP cites the following as reasons to treat: “(1) alleviate discomfort, including itching; (2) reduce autoinoculation; (3) limit transmission of the virus to close contacts; (4) reduce cosmetic concerns; and (5) prevent secondary infection.”⁶ For adults, we should consider limitations to intimacy and reduction of sexual transmission risk.⁶

Treatment can be based on the number of lesions. With a few lesions (<3), therapy is worthwhile if they are unsightly; appear on exposed skin causing embarrassment; and/or are itchy, uncomfortable, or large. In a report of 300 children with molluscum treated with cantharidin, most patients choosing therapy had 10 to 20 lesions, but this was over multiple visits.⁸ Looking at a 2018 data set of 50 patients (all-comers) with molluscum,³ the mean number of lesions was 10 (median, 7); 3 lesions were 1 SD below, while 14, 17, and 45 were 1, 2, and 3 SDs above, respectively. This data set shows that patients can develop more lesions rapidly, and most children have many visible lesions (N.B. Silverberg, MD, unpublished data).

Because each lesion contains infectious viral particles and patients scratch, more lesions are equated to greater autoinoculation and contagion. In addition to the AAP criteria, treatment can be considered for households with immunocompromised individuals, children at risk for new-onset AD, or those with AD at risk for flare. For patients with 45 lesions or more (3 SDs), clearance is harder to achieve with 2 sessions of in-office therapy, and multiple methods or the addition of immunomodulatory therapeutics should be considered.

Do we have to clear every lesion?

New molluscum lesions may arise until a patient achieves immunity, and they may appear more than a month after inoculation, making it difficult to keep up with the rapid spread. Latency between exposure and lesion development usually is 2 to 7 weeks but may be as long as 6 months, making it difficult to prevent spread.⁶ Therefore, when we treat, we should not promise full clearance to patients and parents. Rather, we should inform them that new lesions may develop later, and therapy is only effective on visible lesions. In a recent study, a 50% clearance of lesions was the satisfactory threshold for parents, demonstrating that satisfaction is possible with partial clearance.⁹

What is new in therapeutics for molluscum?

Molluscum therapies are either destructive, immunomodulatory, or antiviral. Two agents now are approved by the FDA for the treatment of molluscum infections.

Berdazimer gel 10.3% is approved for patients 1 year or older, but it is not yet available. This agent has both immunomodulatory and antiviral properties.¹⁰ It features a home therapy that is mixed on a small palette, then painted on by the patient or parent once daily for 12 weeks. Study outcomes demonstrated more than 50% lesional clearance.^11,12 Complete clearance was achieved in at least 30% of patients.¹²A proprietary topical version of cantharidin 0.7% in flexible collodion is now FDA approved for patients 2 years and older. This vesicant-triggering iatrogenic is targeted at creating blisters overlying molluscum lesions. It is conceptually similar to older versions but with some enhanced features.^5,13,14 This version was used for therapy every 3 weeks for up to 4 sessions in clinical trials. Safety is similar across all body sites treated (nonmucosal and not near the mucosal surfaces) but not for mucosa, the mid face, or eyelids.¹³ Complete lesion clearance was 46.3% to 54% and statistically greater than placebo (P<.001).¹⁴Both agents are well tolerated in children with AD; adverse effects include blistering with cantharidin and dermatitislike symptoms with berdazimer.^15,16 These therapies have the advantage of being easy to use.

Final Thoughts

We have entered an era of high-quality molluscum therapy. Patient care involves developing a good knowledge of the agents, incorporating shared decision-making with patients and caregivers, and addressing therapy in the context of comorbid diseases such as AD.

Molluscum contagiosum (ie, molluscum) is a ubiquitous infection caused by the poxvirus molluscum contagiosum virus (MCV). Although skin deep, molluscum shares many factors with the more virulent poxviridae. Moisture and trauma can cause viral material to be released from the pearly papules through a small opening, which also allows entry of bacteria and medications into the lesion. The MCV is transmitted by direct contact with skin or via fomites.¹

Molluscum can affect children of any age, with MCV type 1 peaking in toddlers and school-aged children and MCV type 2 after the sexual debut. The prevalence of molluscum has increased since the 1980s. It is stressful for children and caregivers and poses challenges in schools as well as sports such as swimming, wrestling, and karate.^1,2

For the first time, we have US Food and Drug Administration (FDA)–approved products to treat MCV infections. Previously, only off-label agents were used. Therefore, we have to contemplate why treatment is important to our patients.

What type of care is required for molluscum?

Counseling is the first and only mandatory treatment, which consists of 3 parts: natural history, risk factors for spread, and options for therapy. The natural history of molluscum in children is early spread, contagion to oneself and others (as high as 60% of sibling co-bathers³), triggering of dermatitis, eventual onset of the beginning-of-the-end (BOTE) sign, and eventually clearance. The natural history in adults is poorly understood.

Early clearance is uncommon; reports have suggested 45.6% to 48.4% of affected patients are clear at 1 year and 69.5% to 72.6% at 1.5 years.⁴ For many children, especially those with atopic dermatitis (AD), lesions linger and often spread, with many experiencing disease for 3 to 4 years. Fomites such as towels, washcloths, and sponges can transfer the virus and spread lesions; therefore, I advise patients to gently pat their skin dry, wash towels frequently, and avoid sharing bathing equipment.^1,3,5 Children and adults with immunosuppression may have a greater number of lesions and more prolonged course of disease, including those with HIV as well as DOC8 and CARD11 mutations.⁶ The American Academy of Pediatrics (AAP) emphasizes that children should not be excluded from attending child care/school or from swimming in public pools but lesions should be covered.⁶ Lesions, especially those in the antecubital region, can trigger new-onset AD or AD flares.³ In response, gentle skin care including fragrance-free cleansers and periodic application of moisturizers may ward off AD. Topical corticosteroids are preferred.

Dermatitis in MCV is a great mimicker and can resemble erythema multiforme, Gianotti-Crosti syndrome, impetigo, and AD.¹ Superinfection recently has been reported; however, in a retrospective analysis of 56 patients with inflamed lesions secondary to molluscum infection, only 7 had positive bacterial cultures, which supports the idea of the swelling and redness of inflammation as a mimic for infection.⁷ When true infection does occur, tender, swollen, pus-filled lesions should be lanced and cultured.^1,7,8

When should we consider therapy?

Therapy is highly dependent on the child, the caregiver, and the social circumstances.¹ More than 80% of parents are anxious about molluscum, and countless children are embarrassed or ashamed.¹ Ultimately, an unhappy child merits care. The AAP cites the following as reasons to treat: “(1) alleviate discomfort, including itching; (2) reduce autoinoculation; (3) limit transmission of the virus to close contacts; (4) reduce cosmetic concerns; and (5) prevent secondary infection.”⁶ For adults, we should consider limitations to intimacy and reduction of sexual transmission risk.⁶

Treatment can be based on the number of lesions. With a few lesions (<3), therapy is worthwhile if they are unsightly; appear on exposed skin causing embarrassment; and/or are itchy, uncomfortable, or large. In a report of 300 children with molluscum treated with cantharidin, most patients choosing therapy had 10 to 20 lesions, but this was over multiple visits.⁸ Looking at a 2018 data set of 50 patients (all-comers) with molluscum,³ the mean number of lesions was 10 (median, 7); 3 lesions were 1 SD below, while 14, 17, and 45 were 1, 2, and 3 SDs above, respectively. This data set shows that patients can develop more lesions rapidly, and most children have many visible lesions (N.B. Silverberg, MD, unpublished data).

Because each lesion contains infectious viral particles and patients scratch, more lesions are equated to greater autoinoculation and contagion. In addition to the AAP criteria, treatment can be considered for households with immunocompromised individuals, children at risk for new-onset AD, or those with AD at risk for flare. For patients with 45 lesions or more (3 SDs), clearance is harder to achieve with 2 sessions of in-office therapy, and multiple methods or the addition of immunomodulatory therapeutics should be considered.

Do we have to clear every lesion?

New molluscum lesions may arise until a patient achieves immunity, and they may appear more than a month after inoculation, making it difficult to keep up with the rapid spread. Latency between exposure and lesion development usually is 2 to 7 weeks but may be as long as 6 months, making it difficult to prevent spread.⁶ Therefore, when we treat, we should not promise full clearance to patients and parents. Rather, we should inform them that new lesions may develop later, and therapy is only effective on visible lesions. In a recent study, a 50% clearance of lesions was the satisfactory threshold for parents, demonstrating that satisfaction is possible with partial clearance.⁹

What is new in therapeutics for molluscum?

Molluscum therapies are either destructive, immunomodulatory, or antiviral. Two agents now are approved by the FDA for the treatment of molluscum infections.

Berdazimer gel 10.3% is approved for patients 1 year or older, but it is not yet available. This agent has both immunomodulatory and antiviral properties.¹⁰ It features a home therapy that is mixed on a small palette, then painted on by the patient or parent once daily for 12 weeks. Study outcomes demonstrated more than 50% lesional clearance.^11,12 Complete clearance was achieved in at least 30% of patients.¹²A proprietary topical version of cantharidin 0.7% in flexible collodion is now FDA approved for patients 2 years and older. This vesicant-triggering iatrogenic is targeted at creating blisters overlying molluscum lesions. It is conceptually similar to older versions but with some enhanced features.^5,13,14 This version was used for therapy every 3 weeks for up to 4 sessions in clinical trials. Safety is similar across all body sites treated (nonmucosal and not near the mucosal surfaces) but not for mucosa, the mid face, or eyelids.¹³ Complete lesion clearance was 46.3% to 54% and statistically greater than placebo (P<.001).¹⁴Both agents are well tolerated in children with AD; adverse effects include blistering with cantharidin and dermatitislike symptoms with berdazimer.^15,16 These therapies have the advantage of being easy to use.

Final Thoughts

We have entered an era of high-quality molluscum therapy. Patient care involves developing a good knowledge of the agents, incorporating shared decision-making with patients and caregivers, and addressing therapy in the context of comorbid diseases such as AD.

Melasma is an acquired hyperpigmentation disorder characterized by irregular brown macules and patches that usually appear on sun-exposed areas of the skin. The term melasma originates from the Greek word melas meaning black.¹ Facial melasma is divided into 2 groups according to its clinical distribution: centrofacial lesions are located in the center of the face (eg, the glabellar, frontal, nasal, zygomatic, upper lip, chin areas), and peripheral lesions manifest on the frontotemporal, preauricular, and mandibular regions.^1,2 There is debate on the categorization of zygomatic (or malar) melasma; some researchers argue it should be categorized independent of other areas, while others include malar melasma in the centrofacial group because of its frequent association with the centrofacial type, especially with glabellar lesions.² Mandibular melasma is rare and occurs mostly in postmenopausal women after intense sun exposure.^1,2 Although the etiopathogenesis of the disease is not clearly known, increased melanogenesis, extracellular matrix alterations, inflammation, and angiogenesis are assumed to play a role.³ Various risk factors such as genetic predisposition, UV radiation (UVR) exposure, pregnancy, thyroid dysfunction, and exogenous hormones (eg, oral contraceptives, hormone replacement therapy) have been identified; phototoxic drugs, anticonvulsants, and some cosmetics also have been implicated.^4,5 Exposure to UVR is thought to be the main triggering environmental factor by inducing both melanin production and oxidative stress.⁵ However, it also has been shown that visible light can induce hyperpigmentation in darker skin types.⁶

The presence of oxidative stress in melasma recently has become an intriguing topic of interest. First, the presence of oxidative stress in the etiopathogenesis of melasma was thought to be based on the effectiveness of antioxidants in treatment. A few studies also have confirmed the presence of oxidative stress in melasma.^7-10 Classically, oxidative stress can be described as a disturbance in the balance between oxidants and antioxidants. Reactive oxygen species (ROS) are highly reactive molecules due to the unpaired electrons in their structure. Although ROS are present at low levels in physiologic conditions and are involved in critical physiologic events, they damage cellular components such as fat, protein, and nucleic acid at high concentrations.⁵

Dynamic thiol/disulfide homeostasis is one of the most important markers of oxidative stress in biological systems. Thiols are organic compounds containing a sulfhydryl (-SH) group. Thiols are considered highly potent antioxidants because they reduce unstable free radicals by donating electrons. They are the first antioxidants to be depleted in an oxidative environment.^11,12 In case of oxidative stress, they transform into reversible forms called disulfide bridges between 2 thiol groups. Disulfide bridges can be reduced back to thiol groups, which is how dynamic thiol/disulfide homeostasis is maintained. Dynamic thiol/disulfide homeostasis is responsible for cellular events such as antioxidant defense, signal transduction, regulation of enzyme function, and apoptosis.^11,12

The aim of this study was to evaluate the presence of oxidative stress in melasma by comparing dynamic thiol/disulfide homeostasis in patients with melasma compared with age- and sex-matched healthy controls.

Materials and Methods

Participants and Eligibility Criteria—We conducted a prospective study in a tertiary-care hospital (Ankara Bilkent City Hospital [Ankara, Turkey]) of patients with melasma who were followed from October 2021 to October 2022 compared with age- and sex-matched healthy volunteers. Ethics committee approval was obtained from Ankara Bilkent City Hospital before the study (E2-21-881)(13.10.2021). Written informed consent was obtained from all participants, and all were older than 18 years. Patients were excluded if there was the presence of any systemic disease or dermatologic disease other than melasma; smoking or alcohol use; any use of vitamins, food supplements, or any medication in the last 3 months; or pregnancy.

Melasma Severity—The modified melasma area and severity index (mMASI) score was used to determine the severity of melasma. The score is calculated from assessments of the darkness of the pigmentation and the percentage of affected area on the face. The mMASI score is the sum of the darkness score (D); area score (A); and separate fixed coefficients for the forehead, as well as the right malar, left malar, and chin regions.¹³ The mMASI score, with a range of 0 to 24, is a reliable and objective marker in the calculation of melasma severity.⁴

Biochemical Analysis of Samples—The 6-cc peripheral fasting venous blood samples obtained from the study participants were centrifuged at 1500 g for 10 minutes, and the separated sera were stored in a freezer at −80 °C until the time of analysis. When the study was completed, the disulfide and thiol values were analyzed. Serum native and total thiol concentrations indicating thiol/disulfide homeostasis were calculated by a new fully automatic colorimetric method developed by Erel and Neselioglu.¹⁴ Using this method, short disulfide bonds are first reduced with sodium borohydride solution to form free-functional thiol groups, and then the unused sodium borohydride is removed using formaldehyde. Finally, all thiol groups are reacted with 5,5’-dithiobis-(2-nitrobenzoic) acid (Ellman reagent), and all thiol groups are detected after reaction with 5,5’-dithiobis-(2-nitrobenzoic) acid. When a disulfide bond (−S−S−) is reduced, 2 thiol groups are formed. For this reason, half of the difference between total thiol (-SH + the amount of thiol formed by the reduction of disulfides) and native thiol (-SH) corresponds to the dynamic disulfide amount (total thiol − native thiol/2).¹⁴

Statistical Analysis—Statistical analysis was performed using SPSS software (version 24.0). Descriptive statistics were presented as numbers and percentages for categorical variables, and numerical variables were presented as mean, SD, median, minimum, maximum, 25th quartile, and 75th quartile. The conformity of the variables to normal distribution was examined using visual (histograms and probability plots) and analytical methods (Kolmogorov-Smirnov/Shapiro-Wilk tests). In pairwise group comparisons for numerical variables, a Mann-Whitney U test was used when normal distribution was not met, and a t test was used when normal distribution was met. The statistical significance level was accepted as P<.05.

Results

Our study included 67 patients with melasma and 41 healthy age- and sex-matched controls. Of the participants with melasma, 60 (89.5%) were female and 7 (10.5%) were male. The control group was similar to the melasma group in terms of sex (87.8% female vs 12.2% male [P=.59]). The mean age (SD) was 33.1 (6.7) years in the melasma group and 31.9 (6.7) years in the control group. Age was similar across both groups (P=.41). All participants were of Asian race, and Fitzpatrick skin types (types II–IV) were similar across both groups.

Fifty-four (80.6%) participants had centrofacial melasma and 13 (19.4%) had mixed-type melasma. The mMASI score ranged from 3 to 20; the mean (SD) mMASI score was 11.28 (3.2). Disease duration ranged from 2 to 72 months; the mean (SD) disease duration was 12.26 (6.3) months. The demographics and clinical characteristics of the study group are shown in eTable 1.

eTable 2 provides a summary of disulfide, native thiol, and total thiol levels, as well as disulfide/native thiol, disulfide/total thiol, and native thiol/total thiol ratios in the study population. Disulfide/native thiol and disulfide/total thiol ratios were higher in melasma patients (Figure 1), whereas the native thiol/total thiol ratio was higher in the control group (P=.025, P=.025, and P=.026, respectively).

All correlations between age, disease duration, and mMASI scores and disulfide, native thiol, and total thiol levels, as well as disulfide/native thiol, disulfide/total thiol, and native thiol/total thiol ratios, are summarized in eTable 3. No significant correlation was observed between age and disease duration and disulfide, native thiol, and total thiol levels or disulfide/native thiol, disulfide/total thiol, and native thiol/total thiol ratios.

We independently assessed whether Fitzpatrick skin types II, III, and IV exhibited distinct levels of oxidative stress in clinical melasma. There were no significant correlations with Fitzpatrick skin type (disulfide/native thiol, P=.25; disulfide/total thiol, P=.19). We further evaluated if the thiol/disulfide parameters were correlated with duration of melasma by dividing the melasma patients into 3 groups (<6 months [n=12], 6–18 months [n=32], >18 months [n=23]), but there was not any significant correlation (disulfide/native thiol, P=.15; disulfide/total thiol, P=.15). We also divided our patients into 3 groups according to age (<27 years [n=14], 27–36 years [n=33], >36 years [n=20]). There was no correlation of the parameters with age (disulfide/native thiol, P=.15; disulfide/total thiol, P=.14).

There was a positive correlation between mMASI score and disulfide, native thiol, and total thiol levels and disulfide/native thiol and disulfide/total thiol ratios, as well as a negative correlation between mMASI score and native thiol/total thiol ratio. The correlations between mMASI scores and disulfide/native thiol and disulfide/total thiol ratios are shown in Figure 2 and eTable 3.

Comment

Melasma is a common condition that may cause psychosocial problems in affected patients and negatively affect quality of life.¹ It occurs in all races but is more common in individuals with darker skin types (eg, Fitzpatrick skin types III and IV). Although melasma is more common in women during reproductive years (50%–70%), it also has been observed in 10% to 30% of men.⁵

Treatment options include topical bleaching agents, chemical peels, and laser therapy, as well as discontinuation of medications that may potentially trigger melasma; use of broad-spectrum sunscreens also is recommended.⁴ Vitamins A, C, and E, as well as niacinamide, are used in the treatment of melasma, especially for their antioxidant properties. The key role of antioxidants in the treatment of melasma supports the importance of oxidative stress in the pathogenesis.⁷ Melasma often is challenging to treat, particularly the mixed or dermal types, due to their stubborn nature. This condition poses a considerable therapeutic challenge for dermatologists.⁴

Oxidative stress and oxidant-antioxidant imbalance previously have been studied in various diseases, but research investigating the presence of oxidative stress in melasma are limited.^7-10 Exposure of the skin to polluted air and intense UVR, as well as some food by-products, cosmetics, and drugs (eg, oral contraceptives), can directly or indirectly cause ROS production in the skin. Reactive oxygen species are thought to be involved in the pathophysiology of melasma by affecting apoptotic pathways and causing cell proliferation. The intermediate heme pathway has pro-oxidant effects and produces ROS and metabolites such as redox-active quinines. Exposure to UVR leads to the generation of ROS, highlighting the role of oxidative stress in the onset of melasma. ⁵

In any cutaneous disease in which oxidative stress plays a role, oxidant and antioxidant levels may be expected to vary both locally and systemically; however, measurement of oxidative stress markers in serum instead of skin is technically and economically more advantageous.⁸ Firstly, serum collection is less invasive and technically simpler than skin biopsies. Drawing blood is a routine procedure that requires minimal specialized equipment and training compared to the extraction and processing of skin samples. Secondly, analyzing serum samples generally is less expensive than processing skin tissue.⁸

In our study, we evaluated dynamic thiol/disulfide homeostasis in serum to investigate the presence of oxidative stress in the setting of melasma. Functional sulfhydryl (-SH) groups in thiols act as substrates for antioxidant enzymes and as free-radical scavengers. They constitute one of the most powerful defense systems against the unwanted effects of ROS. Thiols, which become the main target of ROS under oxidative stress, oxidize with oxidant molecules and form disulfide bridges.¹⁵

Thiol/disulfide homeostasis has been studied many times in dermatologic diseases,^16-19 and the results obtained from these studies are heterogenous depending on the extent of oxidative damage. It has been shown that thiol/disulfide homeostasis plays a role in oxidative stress in conditions such as psoriasis,¹⁷ seborrheic dermatitis,¹¹ atopic dermatitits,¹⁸ and rosacea.¹⁹ In our study, disulfide/native thiol and disulfide/total thiol levels were significantly higher (both P=.025) in the melasma group compared with the control group, which indicates that the thiol/disulfide balance in patients with melasma is shifted to disulfide formation and thiols are oxidized to disulfide bonds in the presence of oxidative stress.

Seçkin et al⁷ evaluated the role of oxidative stress in the pathogenesis of melasma and found that the serum levels of the antioxidants superoxide dismutase and glutathione peroxidase were significantly higher in the patient group compared with the control group (both P<.001). They also found that the levels of nitric oxide (another antioxidant) were increased in the patient group and the levels of protein carbonyl (an oxidative metabolite) were significantly lower (both P<.001). These findings indicated that free-radical damage may be involved in the pathogenesis of melasma.⁷

In a study of 75 patients with melasma, serum levels of the antioxidants melatonin and catalase were significantly (P<.001 and P=.001, respectively) lower in the melasma group compared with the control group, while serum levels of the oxidants protein carbonyl and nitric oxide were significantly higher (P=.002 and P=.001, respectively). No significant correlation was found between oxidative stress parameters and melasma severity.⁸

Choubey et al⁹ found that serum malondialdehyde (an end product of lipid peroxidation), superoxide dismutase, and glutathione peroxidase levels were significantly higher in the melasma group (n=50) compared with the control group (n=50)(all P<.001). In addition, a significant positive correlation (correlation coefficient, +0.307; P<.05) was found between serum malondialdehyde levels and melasma severity. The mean age (SD) of the patients was 32.22 (6.377) years, and the female (n=41) to male (n=9) ratio was 4.55:1. The most common melasma pattern was centrofacial, followed by malar.⁹

In a study with 50 melasma patients and 50 controls, Rahimi et al¹⁰ examined bilirubin and uric acid levels, which are major extracellular antioxidants. The mean age (SD) at disease onset was 32.6 (6.7) years, and the mean MASI score (SD) was 18.1 (9). Serum bilirubin levels were found to be higher in the melasma group than in the control group and were correlated with disease severity. No significant difference in uric acid levels was found between the groups, and no correlation was found between MASI score and bilirubin and uric acid levels.¹⁰

In our study, the melasma group was similar to those in other reportsin the literature regarding gender distribution, mean age, and melasma pattern.^7-10 Additionally, the correlation of mMASI score with disulfide/native thiol and disulfide/total thiol values in the melasma group suggested that oxidative stress also is correlated with melasma severity.

Thiol-based treatments such as n-acetyl cysteine, which contains a thiol compound, may be helpful in melasma.²⁰ In a double-blind, placebo-controlled study, topical n-acetyl cysteine combined with hydroquinone 2% was used in 10 female patients with melasma. Mild to strong bleaching of the skin was observed in 90% (9/10) of the patients.²¹ Systemic use of n-acetyl cysteine in melasma also may be a potential research topic.

Major limitations of our study were the small sample size and lack of measurement of oxidative stress parameters in the skin concurrently with serum.

Conclusion

In our study, the presence of oxidative stress in melasma was demonstrated by evaluating thiol/disulfide homeostasis—one of the strongest markers of oxidative stress. Oxidative stress also correlated with melasma disease severity in our analysis. The data obtained in this study may contribute to understanding the etiopathogenesis of melasma and may open new horizons in treatment; however, more comprehensive studies should be conducted to support our findings.

Melasma is an acquired hyperpigmentation disorder characterized by irregular brown macules and patches that usually appear on sun-exposed areas of the skin. The term melasma originates from the Greek word melas meaning black.¹ Facial melasma is divided into 2 groups according to its clinical distribution: centrofacial lesions are located in the center of the face (eg, the glabellar, frontal, nasal, zygomatic, upper lip, chin areas), and peripheral lesions manifest on the frontotemporal, preauricular, and mandibular regions.^1,2 There is debate on the categorization of zygomatic (or malar) melasma; some researchers argue it should be categorized independent of other areas, while others include malar melasma in the centrofacial group because of its frequent association with the centrofacial type, especially with glabellar lesions.² Mandibular melasma is rare and occurs mostly in postmenopausal women after intense sun exposure.^1,2 Although the etiopathogenesis of the disease is not clearly known, increased melanogenesis, extracellular matrix alterations, inflammation, and angiogenesis are assumed to play a role.³ Various risk factors such as genetic predisposition, UV radiation (UVR) exposure, pregnancy, thyroid dysfunction, and exogenous hormones (eg, oral contraceptives, hormone replacement therapy) have been identified; phototoxic drugs, anticonvulsants, and some cosmetics also have been implicated.^4,5 Exposure to UVR is thought to be the main triggering environmental factor by inducing both melanin production and oxidative stress.⁵ However, it also has been shown that visible light can induce hyperpigmentation in darker skin types.⁶

The presence of oxidative stress in melasma recently has become an intriguing topic of interest. First, the presence of oxidative stress in the etiopathogenesis of melasma was thought to be based on the effectiveness of antioxidants in treatment. A few studies also have confirmed the presence of oxidative stress in melasma.^7-10 Classically, oxidative stress can be described as a disturbance in the balance between oxidants and antioxidants. Reactive oxygen species (ROS) are highly reactive molecules due to the unpaired electrons in their structure. Although ROS are present at low levels in physiologic conditions and are involved in critical physiologic events, they damage cellular components such as fat, protein, and nucleic acid at high concentrations.⁵

Dynamic thiol/disulfide homeostasis is one of the most important markers of oxidative stress in biological systems. Thiols are organic compounds containing a sulfhydryl (-SH) group. Thiols are considered highly potent antioxidants because they reduce unstable free radicals by donating electrons. They are the first antioxidants to be depleted in an oxidative environment.^11,12 In case of oxidative stress, they transform into reversible forms called disulfide bridges between 2 thiol groups. Disulfide bridges can be reduced back to thiol groups, which is how dynamic thiol/disulfide homeostasis is maintained. Dynamic thiol/disulfide homeostasis is responsible for cellular events such as antioxidant defense, signal transduction, regulation of enzyme function, and apoptosis.^11,12

The aim of this study was to evaluate the presence of oxidative stress in melasma by comparing dynamic thiol/disulfide homeostasis in patients with melasma compared with age- and sex-matched healthy controls.

Materials and Methods

Participants and Eligibility Criteria—We conducted a prospective study in a tertiary-care hospital (Ankara Bilkent City Hospital [Ankara, Turkey]) of patients with melasma who were followed from October 2021 to October 2022 compared with age- and sex-matched healthy volunteers. Ethics committee approval was obtained from Ankara Bilkent City Hospital before the study (E2-21-881)(13.10.2021). Written informed consent was obtained from all participants, and all were older than 18 years. Patients were excluded if there was the presence of any systemic disease or dermatologic disease other than melasma; smoking or alcohol use; any use of vitamins, food supplements, or any medication in the last 3 months; or pregnancy.

Melasma Severity—The modified melasma area and severity index (mMASI) score was used to determine the severity of melasma. The score is calculated from assessments of the darkness of the pigmentation and the percentage of affected area on the face. The mMASI score is the sum of the darkness score (D); area score (A); and separate fixed coefficients for the forehead, as well as the right malar, left malar, and chin regions.¹³ The mMASI score, with a range of 0 to 24, is a reliable and objective marker in the calculation of melasma severity.⁴

Biochemical Analysis of Samples—The 6-cc peripheral fasting venous blood samples obtained from the study participants were centrifuged at 1500 g for 10 minutes, and the separated sera were stored in a freezer at −80 °C until the time of analysis. When the study was completed, the disulfide and thiol values were analyzed. Serum native and total thiol concentrations indicating thiol/disulfide homeostasis were calculated by a new fully automatic colorimetric method developed by Erel and Neselioglu.¹⁴ Using this method, short disulfide bonds are first reduced with sodium borohydride solution to form free-functional thiol groups, and then the unused sodium borohydride is removed using formaldehyde. Finally, all thiol groups are reacted with 5,5’-dithiobis-(2-nitrobenzoic) acid (Ellman reagent), and all thiol groups are detected after reaction with 5,5’-dithiobis-(2-nitrobenzoic) acid. When a disulfide bond (−S−S−) is reduced, 2 thiol groups are formed. For this reason, half of the difference between total thiol (-SH + the amount of thiol formed by the reduction of disulfides) and native thiol (-SH) corresponds to the dynamic disulfide amount (total thiol − native thiol/2).¹⁴

Statistical Analysis—Statistical analysis was performed using SPSS software (version 24.0). Descriptive statistics were presented as numbers and percentages for categorical variables, and numerical variables were presented as mean, SD, median, minimum, maximum, 25th quartile, and 75th quartile. The conformity of the variables to normal distribution was examined using visual (histograms and probability plots) and analytical methods (Kolmogorov-Smirnov/Shapiro-Wilk tests). In pairwise group comparisons for numerical variables, a Mann-Whitney U test was used when normal distribution was not met, and a t test was used when normal distribution was met. The statistical significance level was accepted as P<.05.

Results

Our study included 67 patients with melasma and 41 healthy age- and sex-matched controls. Of the participants with melasma, 60 (89.5%) were female and 7 (10.5%) were male. The control group was similar to the melasma group in terms of sex (87.8% female vs 12.2% male [P=.59]). The mean age (SD) was 33.1 (6.7) years in the melasma group and 31.9 (6.7) years in the control group. Age was similar across both groups (P=.41). All participants were of Asian race, and Fitzpatrick skin types (types II–IV) were similar across both groups.

Fifty-four (80.6%) participants had centrofacial melasma and 13 (19.4%) had mixed-type melasma. The mMASI score ranged from 3 to 20; the mean (SD) mMASI score was 11.28 (3.2). Disease duration ranged from 2 to 72 months; the mean (SD) disease duration was 12.26 (6.3) months. The demographics and clinical characteristics of the study group are shown in eTable 1.

eTable 2 provides a summary of disulfide, native thiol, and total thiol levels, as well as disulfide/native thiol, disulfide/total thiol, and native thiol/total thiol ratios in the study population. Disulfide/native thiol and disulfide/total thiol ratios were higher in melasma patients (Figure 1), whereas the native thiol/total thiol ratio was higher in the control group (P=.025, P=.025, and P=.026, respectively).

All correlations between age, disease duration, and mMASI scores and disulfide, native thiol, and total thiol levels, as well as disulfide/native thiol, disulfide/total thiol, and native thiol/total thiol ratios, are summarized in eTable 3. No significant correlation was observed between age and disease duration and disulfide, native thiol, and total thiol levels or disulfide/native thiol, disulfide/total thiol, and native thiol/total thiol ratios.

We independently assessed whether Fitzpatrick skin types II, III, and IV exhibited distinct levels of oxidative stress in clinical melasma. There were no significant correlations with Fitzpatrick skin type (disulfide/native thiol, P=.25; disulfide/total thiol, P=.19). We further evaluated if the thiol/disulfide parameters were correlated with duration of melasma by dividing the melasma patients into 3 groups (<6 months [n=12], 6–18 months [n=32], >18 months [n=23]), but there was not any significant correlation (disulfide/native thiol, P=.15; disulfide/total thiol, P=.15). We also divided our patients into 3 groups according to age (<27 years [n=14], 27–36 years [n=33], >36 years [n=20]). There was no correlation of the parameters with age (disulfide/native thiol, P=.15; disulfide/total thiol, P=.14).

There was a positive correlation between mMASI score and disulfide, native thiol, and total thiol levels and disulfide/native thiol and disulfide/total thiol ratios, as well as a negative correlation between mMASI score and native thiol/total thiol ratio. The correlations between mMASI scores and disulfide/native thiol and disulfide/total thiol ratios are shown in Figure 2 and eTable 3.

Comment

Melasma is a common condition that may cause psychosocial problems in affected patients and negatively affect quality of life.¹ It occurs in all races but is more common in individuals with darker skin types (eg, Fitzpatrick skin types III and IV). Although melasma is more common in women during reproductive years (50%–70%), it also has been observed in 10% to 30% of men.⁵

Treatment options include topical bleaching agents, chemical peels, and laser therapy, as well as discontinuation of medications that may potentially trigger melasma; use of broad-spectrum sunscreens also is recommended.⁴ Vitamins A, C, and E, as well as niacinamide, are used in the treatment of melasma, especially for their antioxidant properties. The key role of antioxidants in the treatment of melasma supports the importance of oxidative stress in the pathogenesis.⁷ Melasma often is challenging to treat, particularly the mixed or dermal types, due to their stubborn nature. This condition poses a considerable therapeutic challenge for dermatologists.⁴

Oxidative stress and oxidant-antioxidant imbalance previously have been studied in various diseases, but research investigating the presence of oxidative stress in melasma are limited.^7-10 Exposure of the skin to polluted air and intense UVR, as well as some food by-products, cosmetics, and drugs (eg, oral contraceptives), can directly or indirectly cause ROS production in the skin. Reactive oxygen species are thought to be involved in the pathophysiology of melasma by affecting apoptotic pathways and causing cell proliferation. The intermediate heme pathway has pro-oxidant effects and produces ROS and metabolites such as redox-active quinines. Exposure to UVR leads to the generation of ROS, highlighting the role of oxidative stress in the onset of melasma. ⁵

In any cutaneous disease in which oxidative stress plays a role, oxidant and antioxidant levels may be expected to vary both locally and systemically; however, measurement of oxidative stress markers in serum instead of skin is technically and economically more advantageous.⁸ Firstly, serum collection is less invasive and technically simpler than skin biopsies. Drawing blood is a routine procedure that requires minimal specialized equipment and training compared to the extraction and processing of skin samples. Secondly, analyzing serum samples generally is less expensive than processing skin tissue.⁸

In our study, we evaluated dynamic thiol/disulfide homeostasis in serum to investigate the presence of oxidative stress in the setting of melasma. Functional sulfhydryl (-SH) groups in thiols act as substrates for antioxidant enzymes and as free-radical scavengers. They constitute one of the most powerful defense systems against the unwanted effects of ROS. Thiols, which become the main target of ROS under oxidative stress, oxidize with oxidant molecules and form disulfide bridges.¹⁵

Thiol/disulfide homeostasis has been studied many times in dermatologic diseases,^16-19 and the results obtained from these studies are heterogenous depending on the extent of oxidative damage. It has been shown that thiol/disulfide homeostasis plays a role in oxidative stress in conditions such as psoriasis,¹⁷ seborrheic dermatitis,¹¹ atopic dermatitits,¹⁸ and rosacea.¹⁹ In our study, disulfide/native thiol and disulfide/total thiol levels were significantly higher (both P=.025) in the melasma group compared with the control group, which indicates that the thiol/disulfide balance in patients with melasma is shifted to disulfide formation and thiols are oxidized to disulfide bonds in the presence of oxidative stress.

Seçkin et al⁷ evaluated the role of oxidative stress in the pathogenesis of melasma and found that the serum levels of the antioxidants superoxide dismutase and glutathione peroxidase were significantly higher in the patient group compared with the control group (both P<.001). They also found that the levels of nitric oxide (another antioxidant) were increased in the patient group and the levels of protein carbonyl (an oxidative metabolite) were significantly lower (both P<.001). These findings indicated that free-radical damage may be involved in the pathogenesis of melasma.⁷

In a study of 75 patients with melasma, serum levels of the antioxidants melatonin and catalase were significantly (P<.001 and P=.001, respectively) lower in the melasma group compared with the control group, while serum levels of the oxidants protein carbonyl and nitric oxide were significantly higher (P=.002 and P=.001, respectively). No significant correlation was found between oxidative stress parameters and melasma severity.⁸

Choubey et al⁹ found that serum malondialdehyde (an end product of lipid peroxidation), superoxide dismutase, and glutathione peroxidase levels were significantly higher in the melasma group (n=50) compared with the control group (n=50)(all P<.001). In addition, a significant positive correlation (correlation coefficient, +0.307; P<.05) was found between serum malondialdehyde levels and melasma severity. The mean age (SD) of the patients was 32.22 (6.377) years, and the female (n=41) to male (n=9) ratio was 4.55:1. The most common melasma pattern was centrofacial, followed by malar.⁹

In a study with 50 melasma patients and 50 controls, Rahimi et al¹⁰ examined bilirubin and uric acid levels, which are major extracellular antioxidants. The mean age (SD) at disease onset was 32.6 (6.7) years, and the mean MASI score (SD) was 18.1 (9). Serum bilirubin levels were found to be higher in the melasma group than in the control group and were correlated with disease severity. No significant difference in uric acid levels was found between the groups, and no correlation was found between MASI score and bilirubin and uric acid levels.¹⁰

In our study, the melasma group was similar to those in other reportsin the literature regarding gender distribution, mean age, and melasma pattern.^7-10 Additionally, the correlation of mMASI score with disulfide/native thiol and disulfide/total thiol values in the melasma group suggested that oxidative stress also is correlated with melasma severity.

Thiol-based treatments such as n-acetyl cysteine, which contains a thiol compound, may be helpful in melasma.²⁰ In a double-blind, placebo-controlled study, topical n-acetyl cysteine combined with hydroquinone 2% was used in 10 female patients with melasma. Mild to strong bleaching of the skin was observed in 90% (9/10) of the patients.²¹ Systemic use of n-acetyl cysteine in melasma also may be a potential research topic.

Major limitations of our study were the small sample size and lack of measurement of oxidative stress parameters in the skin concurrently with serum.

Conclusion

In our study, the presence of oxidative stress in melasma was demonstrated by evaluating thiol/disulfide homeostasis—one of the strongest markers of oxidative stress. Oxidative stress also correlated with melasma disease severity in our analysis. The data obtained in this study may contribute to understanding the etiopathogenesis of melasma and may open new horizons in treatment; however, more comprehensive studies should be conducted to support our findings.

Melasma is an acquired hyperpigmentation disorder characterized by irregular brown macules and patches that usually appear on sun-exposed areas of the skin. The term melasma originates from the Greek word melas meaning black.¹ Facial melasma is divided into 2 groups according to its clinical distribution: centrofacial lesions are located in the center of the face (eg, the glabellar, frontal, nasal, zygomatic, upper lip, chin areas), and peripheral lesions manifest on the frontotemporal, preauricular, and mandibular regions.^1,2 There is debate on the categorization of zygomatic (or malar) melasma; some researchers argue it should be categorized independent of other areas, while others include malar melasma in the centrofacial group because of its frequent association with the centrofacial type, especially with glabellar lesions.² Mandibular melasma is rare and occurs mostly in postmenopausal women after intense sun exposure.^1,2 Although the etiopathogenesis of the disease is not clearly known, increased melanogenesis, extracellular matrix alterations, inflammation, and angiogenesis are assumed to play a role.³ Various risk factors such as genetic predisposition, UV radiation (UVR) exposure, pregnancy, thyroid dysfunction, and exogenous hormones (eg, oral contraceptives, hormone replacement therapy) have been identified; phototoxic drugs, anticonvulsants, and some cosmetics also have been implicated.^4,5 Exposure to UVR is thought to be the main triggering environmental factor by inducing both melanin production and oxidative stress.⁵ However, it also has been shown that visible light can induce hyperpigmentation in darker skin types.⁶

The presence of oxidative stress in melasma recently has become an intriguing topic of interest. First, the presence of oxidative stress in the etiopathogenesis of melasma was thought to be based on the effectiveness of antioxidants in treatment. A few studies also have confirmed the presence of oxidative stress in melasma.^7-10 Classically, oxidative stress can be described as a disturbance in the balance between oxidants and antioxidants. Reactive oxygen species (ROS) are highly reactive molecules due to the unpaired electrons in their structure. Although ROS are present at low levels in physiologic conditions and are involved in critical physiologic events, they damage cellular components such as fat, protein, and nucleic acid at high concentrations.⁵

Dynamic thiol/disulfide homeostasis is one of the most important markers of oxidative stress in biological systems. Thiols are organic compounds containing a sulfhydryl (-SH) group. Thiols are considered highly potent antioxidants because they reduce unstable free radicals by donating electrons. They are the first antioxidants to be depleted in an oxidative environment.^11,12 In case of oxidative stress, they transform into reversible forms called disulfide bridges between 2 thiol groups. Disulfide bridges can be reduced back to thiol groups, which is how dynamic thiol/disulfide homeostasis is maintained. Dynamic thiol/disulfide homeostasis is responsible for cellular events such as antioxidant defense, signal transduction, regulation of enzyme function, and apoptosis.^11,12

The aim of this study was to evaluate the presence of oxidative stress in melasma by comparing dynamic thiol/disulfide homeostasis in patients with melasma compared with age- and sex-matched healthy controls.

Materials and Methods

Participants and Eligibility Criteria—We conducted a prospective study in a tertiary-care hospital (Ankara Bilkent City Hospital [Ankara, Turkey]) of patients with melasma who were followed from October 2021 to October 2022 compared with age- and sex-matched healthy volunteers. Ethics committee approval was obtained from Ankara Bilkent City Hospital before the study (E2-21-881)(13.10.2021). Written informed consent was obtained from all participants, and all were older than 18 years. Patients were excluded if there was the presence of any systemic disease or dermatologic disease other than melasma; smoking or alcohol use; any use of vitamins, food supplements, or any medication in the last 3 months; or pregnancy.

Melasma Severity—The modified melasma area and severity index (mMASI) score was used to determine the severity of melasma. The score is calculated from assessments of the darkness of the pigmentation and the percentage of affected area on the face. The mMASI score is the sum of the darkness score (D); area score (A); and separate fixed coefficients for the forehead, as well as the right malar, left malar, and chin regions.¹³ The mMASI score, with a range of 0 to 24, is a reliable and objective marker in the calculation of melasma severity.⁴

Biochemical Analysis of Samples—The 6-cc peripheral fasting venous blood samples obtained from the study participants were centrifuged at 1500 g for 10 minutes, and the separated sera were stored in a freezer at −80 °C until the time of analysis. When the study was completed, the disulfide and thiol values were analyzed. Serum native and total thiol concentrations indicating thiol/disulfide homeostasis were calculated by a new fully automatic colorimetric method developed by Erel and Neselioglu.¹⁴ Using this method, short disulfide bonds are first reduced with sodium borohydride solution to form free-functional thiol groups, and then the unused sodium borohydride is removed using formaldehyde. Finally, all thiol groups are reacted with 5,5’-dithiobis-(2-nitrobenzoic) acid (Ellman reagent), and all thiol groups are detected after reaction with 5,5’-dithiobis-(2-nitrobenzoic) acid. When a disulfide bond (−S−S−) is reduced, 2 thiol groups are formed. For this reason, half of the difference between total thiol (-SH + the amount of thiol formed by the reduction of disulfides) and native thiol (-SH) corresponds to the dynamic disulfide amount (total thiol − native thiol/2).¹⁴

Statistical Analysis—Statistical analysis was performed using SPSS software (version 24.0). Descriptive statistics were presented as numbers and percentages for categorical variables, and numerical variables were presented as mean, SD, median, minimum, maximum, 25th quartile, and 75th quartile. The conformity of the variables to normal distribution was examined using visual (histograms and probability plots) and analytical methods (Kolmogorov-Smirnov/Shapiro-Wilk tests). In pairwise group comparisons for numerical variables, a Mann-Whitney U test was used when normal distribution was not met, and a t test was used when normal distribution was met. The statistical significance level was accepted as P<.05.

Results

Our study included 67 patients with melasma and 41 healthy age- and sex-matched controls. Of the participants with melasma, 60 (89.5%) were female and 7 (10.5%) were male. The control group was similar to the melasma group in terms of sex (87.8% female vs 12.2% male [P=.59]). The mean age (SD) was 33.1 (6.7) years in the melasma group and 31.9 (6.7) years in the control group. Age was similar across both groups (P=.41). All participants were of Asian race, and Fitzpatrick skin types (types II–IV) were similar across both groups.

Fifty-four (80.6%) participants had centrofacial melasma and 13 (19.4%) had mixed-type melasma. The mMASI score ranged from 3 to 20; the mean (SD) mMASI score was 11.28 (3.2). Disease duration ranged from 2 to 72 months; the mean (SD) disease duration was 12.26 (6.3) months. The demographics and clinical characteristics of the study group are shown in eTable 1.

eTable 2 provides a summary of disulfide, native thiol, and total thiol levels, as well as disulfide/native thiol, disulfide/total thiol, and native thiol/total thiol ratios in the study population. Disulfide/native thiol and disulfide/total thiol ratios were higher in melasma patients (Figure 1), whereas the native thiol/total thiol ratio was higher in the control group (P=.025, P=.025, and P=.026, respectively).

All correlations between age, disease duration, and mMASI scores and disulfide, native thiol, and total thiol levels, as well as disulfide/native thiol, disulfide/total thiol, and native thiol/total thiol ratios, are summarized in eTable 3. No significant correlation was observed between age and disease duration and disulfide, native thiol, and total thiol levels or disulfide/native thiol, disulfide/total thiol, and native thiol/total thiol ratios.

We independently assessed whether Fitzpatrick skin types II, III, and IV exhibited distinct levels of oxidative stress in clinical melasma. There were no significant correlations with Fitzpatrick skin type (disulfide/native thiol, P=.25; disulfide/total thiol, P=.19). We further evaluated if the thiol/disulfide parameters were correlated with duration of melasma by dividing the melasma patients into 3 groups (<6 months [n=12], 6–18 months [n=32], >18 months [n=23]), but there was not any significant correlation (disulfide/native thiol, P=.15; disulfide/total thiol, P=.15). We also divided our patients into 3 groups according to age (<27 years [n=14], 27–36 years [n=33], >36 years [n=20]). There was no correlation of the parameters with age (disulfide/native thiol, P=.15; disulfide/total thiol, P=.14).

There was a positive correlation between mMASI score and disulfide, native thiol, and total thiol levels and disulfide/native thiol and disulfide/total thiol ratios, as well as a negative correlation between mMASI score and native thiol/total thiol ratio. The correlations between mMASI scores and disulfide/native thiol and disulfide/total thiol ratios are shown in Figure 2 and eTable 3.

Comment

Melasma is a common condition that may cause psychosocial problems in affected patients and negatively affect quality of life.¹ It occurs in all races but is more common in individuals with darker skin types (eg, Fitzpatrick skin types III and IV). Although melasma is more common in women during reproductive years (50%–70%), it also has been observed in 10% to 30% of men.⁵

Treatment options include topical bleaching agents, chemical peels, and laser therapy, as well as discontinuation of medications that may potentially trigger melasma; use of broad-spectrum sunscreens also is recommended.⁴ Vitamins A, C, and E, as well as niacinamide, are used in the treatment of melasma, especially for their antioxidant properties. The key role of antioxidants in the treatment of melasma supports the importance of oxidative stress in the pathogenesis.⁷ Melasma often is challenging to treat, particularly the mixed or dermal types, due to their stubborn nature. This condition poses a considerable therapeutic challenge for dermatologists.⁴

Oxidative stress and oxidant-antioxidant imbalance previously have been studied in various diseases, but research investigating the presence of oxidative stress in melasma are limited.^7-10 Exposure of the skin to polluted air and intense UVR, as well as some food by-products, cosmetics, and drugs (eg, oral contraceptives), can directly or indirectly cause ROS production in the skin. Reactive oxygen species are thought to be involved in the pathophysiology of melasma by affecting apoptotic pathways and causing cell proliferation. The intermediate heme pathway has pro-oxidant effects and produces ROS and metabolites such as redox-active quinines. Exposure to UVR leads to the generation of ROS, highlighting the role of oxidative stress in the onset of melasma. ⁵

In any cutaneous disease in which oxidative stress plays a role, oxidant and antioxidant levels may be expected to vary both locally and systemically; however, measurement of oxidative stress markers in serum instead of skin is technically and economically more advantageous.⁸ Firstly, serum collection is less invasive and technically simpler than skin biopsies. Drawing blood is a routine procedure that requires minimal specialized equipment and training compared to the extraction and processing of skin samples. Secondly, analyzing serum samples generally is less expensive than processing skin tissue.⁸

In our study, we evaluated dynamic thiol/disulfide homeostasis in serum to investigate the presence of oxidative stress in the setting of melasma. Functional sulfhydryl (-SH) groups in thiols act as substrates for antioxidant enzymes and as free-radical scavengers. They constitute one of the most powerful defense systems against the unwanted effects of ROS. Thiols, which become the main target of ROS under oxidative stress, oxidize with oxidant molecules and form disulfide bridges.¹⁵

Thiol/disulfide homeostasis has been studied many times in dermatologic diseases,^16-19 and the results obtained from these studies are heterogenous depending on the extent of oxidative damage. It has been shown that thiol/disulfide homeostasis plays a role in oxidative stress in conditions such as psoriasis,¹⁷ seborrheic dermatitis,¹¹ atopic dermatitits,¹⁸ and rosacea.¹⁹ In our study, disulfide/native thiol and disulfide/total thiol levels were significantly higher (both P=.025) in the melasma group compared with the control group, which indicates that the thiol/disulfide balance in patients with melasma is shifted to disulfide formation and thiols are oxidized to disulfide bonds in the presence of oxidative stress.

Seçkin et al⁷ evaluated the role of oxidative stress in the pathogenesis of melasma and found that the serum levels of the antioxidants superoxide dismutase and glutathione peroxidase were significantly higher in the patient group compared with the control group (both P<.001). They also found that the levels of nitric oxide (another antioxidant) were increased in the patient group and the levels of protein carbonyl (an oxidative metabolite) were significantly lower (both P<.001). These findings indicated that free-radical damage may be involved in the pathogenesis of melasma.⁷

In a study of 75 patients with melasma, serum levels of the antioxidants melatonin and catalase were significantly (P<.001 and P=.001, respectively) lower in the melasma group compared with the control group, while serum levels of the oxidants protein carbonyl and nitric oxide were significantly higher (P=.002 and P=.001, respectively). No significant correlation was found between oxidative stress parameters and melasma severity.⁸

Choubey et al⁹ found that serum malondialdehyde (an end product of lipid peroxidation), superoxide dismutase, and glutathione peroxidase levels were significantly higher in the melasma group (n=50) compared with the control group (n=50)(all P<.001). In addition, a significant positive correlation (correlation coefficient, +0.307; P<.05) was found between serum malondialdehyde levels and melasma severity. The mean age (SD) of the patients was 32.22 (6.377) years, and the female (n=41) to male (n=9) ratio was 4.55:1. The most common melasma pattern was centrofacial, followed by malar.⁹

In a study with 50 melasma patients and 50 controls, Rahimi et al¹⁰ examined bilirubin and uric acid levels, which are major extracellular antioxidants. The mean age (SD) at disease onset was 32.6 (6.7) years, and the mean MASI score (SD) was 18.1 (9). Serum bilirubin levels were found to be higher in the melasma group than in the control group and were correlated with disease severity. No significant difference in uric acid levels was found between the groups, and no correlation was found between MASI score and bilirubin and uric acid levels.¹⁰

In our study, the melasma group was similar to those in other reportsin the literature regarding gender distribution, mean age, and melasma pattern.^7-10 Additionally, the correlation of mMASI score with disulfide/native thiol and disulfide/total thiol values in the melasma group suggested that oxidative stress also is correlated with melasma severity.

Thiol-based treatments such as n-acetyl cysteine, which contains a thiol compound, may be helpful in melasma.²⁰ In a double-blind, placebo-controlled study, topical n-acetyl cysteine combined with hydroquinone 2% was used in 10 female patients with melasma. Mild to strong bleaching of the skin was observed in 90% (9/10) of the patients.²¹ Systemic use of n-acetyl cysteine in melasma also may be a potential research topic.

Major limitations of our study were the small sample size and lack of measurement of oxidative stress parameters in the skin concurrently with serum.

Conclusion

In our study, the presence of oxidative stress in melasma was demonstrated by evaluating thiol/disulfide homeostasis—one of the strongest markers of oxidative stress. Oxidative stress also correlated with melasma disease severity in our analysis. The data obtained in this study may contribute to understanding the etiopathogenesis of melasma and may open new horizons in treatment; however, more comprehensive studies should be conducted to support our findings.

Practice Gap

The Wood lamp commonly is used as a diagnostic tool for pigmentary skin conditions (eg, vitiligo) or skin conditions that exhibit fluorescence (eg, erythrasma).¹ Recently, its diagnostic efficacy has extended to scabies, in which it unveils a distinctive wavy, bluish-white, linear fluorescence upon illumination.²

Functionally, the Wood lamp operates by subjecting phosphors to UV light within the wavelength range of 320 to 400 nm, inducing fluorescence in substances such as collagen and elastin. In the context of vitiligo, this process manifests as a preferential chalk white fluorescence in areas lacking melanin.¹

Despite its demonstrated effectiveness, the Wood lamp is not without limitations. It comes with a notable financial investment ranging from $70 to $500, requires periodic maintenance such as light bulb replacements, and can be unwieldy.³ Furthermore, its reliance on a power source poses a challenge in settings where immediate access to convenient power outlets is limited, such as inpatient and rural dermatology clinics. These limitations underscore the need for alternative solutions and innovations to address challenges and ensure accessibility in diverse health care environments.

The Tools

Free smartphone applications (apps), such as Ultraviolet Light-UV Lamp by AppBrain or Blacklight UV Light Simulator by That Smile, can simulate UV light and functionally serve as a Wood lamp.

The Technique

UV light apps use LED or organic LED screen pixels to emit a blue light equivalent at 467 nm.⁴ Although these apps are not designed specifically for dermatologic uses, they are mostly free, widely available for Android and iPhone users, and portable. Importantly, they can demonstrate good performance in visualizing vitiligo, as shown in Figure 1—albeit perhaps not reaching the same level as the Wood lamp (Figure 2).

Because these UV light apps are not regulated and their efficacy for medical use has not been firmly established, the Wood lamp remains the gold standard. Therefore, we propose the use of UV light apps in situations when a Wood lamp is not available or convenient, such as in rural, inpatient, or international health care settings.

Practice Implications

Exploring and adopting these free alternatives can contribute to improved accessibility and diagnostic capabilities in diverse health care environments, particularly for communities facing financial constraints. Continued research and validation of these apps in clinical settings will be essential to establish their reliability and effectiveness in enhancing diagnostic practices.

Practice Gap

The Wood lamp commonly is used as a diagnostic tool for pigmentary skin conditions (eg, vitiligo) or skin conditions that exhibit fluorescence (eg, erythrasma).¹ Recently, its diagnostic efficacy has extended to scabies, in which it unveils a distinctive wavy, bluish-white, linear fluorescence upon illumination.²

Functionally, the Wood lamp operates by subjecting phosphors to UV light within the wavelength range of 320 to 400 nm, inducing fluorescence in substances such as collagen and elastin. In the context of vitiligo, this process manifests as a preferential chalk white fluorescence in areas lacking melanin.¹

Despite its demonstrated effectiveness, the Wood lamp is not without limitations. It comes with a notable financial investment ranging from $70 to $500, requires periodic maintenance such as light bulb replacements, and can be unwieldy.³ Furthermore, its reliance on a power source poses a challenge in settings where immediate access to convenient power outlets is limited, such as inpatient and rural dermatology clinics. These limitations underscore the need for alternative solutions and innovations to address challenges and ensure accessibility in diverse health care environments.

The Tools

Free smartphone applications (apps), such as Ultraviolet Light-UV Lamp by AppBrain or Blacklight UV Light Simulator by That Smile, can simulate UV light and functionally serve as a Wood lamp.

The Technique

UV light apps use LED or organic LED screen pixels to emit a blue light equivalent at 467 nm.⁴ Although these apps are not designed specifically for dermatologic uses, they are mostly free, widely available for Android and iPhone users, and portable. Importantly, they can demonstrate good performance in visualizing vitiligo, as shown in Figure 1—albeit perhaps not reaching the same level as the Wood lamp (Figure 2).

Because these UV light apps are not regulated and their efficacy for medical use has not been firmly established, the Wood lamp remains the gold standard. Therefore, we propose the use of UV light apps in situations when a Wood lamp is not available or convenient, such as in rural, inpatient, or international health care settings.

Practice Implications

Exploring and adopting these free alternatives can contribute to improved accessibility and diagnostic capabilities in diverse health care environments, particularly for communities facing financial constraints. Continued research and validation of these apps in clinical settings will be essential to establish their reliability and effectiveness in enhancing diagnostic practices.

Practice Gap

The Wood lamp commonly is used as a diagnostic tool for pigmentary skin conditions (eg, vitiligo) or skin conditions that exhibit fluorescence (eg, erythrasma).¹ Recently, its diagnostic efficacy has extended to scabies, in which it unveils a distinctive wavy, bluish-white, linear fluorescence upon illumination.²

Functionally, the Wood lamp operates by subjecting phosphors to UV light within the wavelength range of 320 to 400 nm, inducing fluorescence in substances such as collagen and elastin. In the context of vitiligo, this process manifests as a preferential chalk white fluorescence in areas lacking melanin.¹

Despite its demonstrated effectiveness, the Wood lamp is not without limitations. It comes with a notable financial investment ranging from $70 to $500, requires periodic maintenance such as light bulb replacements, and can be unwieldy.³ Furthermore, its reliance on a power source poses a challenge in settings where immediate access to convenient power outlets is limited, such as inpatient and rural dermatology clinics. These limitations underscore the need for alternative solutions and innovations to address challenges and ensure accessibility in diverse health care environments.

The Tools

Free smartphone applications (apps), such as Ultraviolet Light-UV Lamp by AppBrain or Blacklight UV Light Simulator by That Smile, can simulate UV light and functionally serve as a Wood lamp.

The Technique

UV light apps use LED or organic LED screen pixels to emit a blue light equivalent at 467 nm.⁴ Although these apps are not designed specifically for dermatologic uses, they are mostly free, widely available for Android and iPhone users, and portable. Importantly, they can demonstrate good performance in visualizing vitiligo, as shown in Figure 1—albeit perhaps not reaching the same level as the Wood lamp (Figure 2).

Because these UV light apps are not regulated and their efficacy for medical use has not been firmly established, the Wood lamp remains the gold standard. Therefore, we propose the use of UV light apps in situations when a Wood lamp is not available or convenient, such as in rural, inpatient, or international health care settings.

Practice Implications

Exploring and adopting these free alternatives can contribute to improved accessibility and diagnostic capabilities in diverse health care environments, particularly for communities facing financial constraints. Continued research and validation of these apps in clinical settings will be essential to establish their reliability and effectiveness in enhancing diagnostic practices.

Olive oil is obtained by mechanical extraction from the fruit of the Olea europaea tree, which is believed to have originated from ancient Iran and Turkestan, later spreading to Anatolia, Syria, Palestine, and Israel. Mechanical extraction of the oil from the olive fruit involves pressure processing, centrifugation, and adhesion filtering.¹ Refining of olive oil is done via alkali refining or physical refining, with physical refining being useful in removing oxidation by-products and pro-oxidant metals. Olive oil is composed mainly of triacylglycerols, which are glycerol esters attached to various fatty acids, with the most common fatty acid being the monounsaturated oleic acid. Additional fatty acids include palmitic acid, linoleic acid, stearic acid, and palmitoleic acid.² Olive oil contains phenolic compounds, the main ones being oleuropein, hydroxytyrosol, and tyrosol. These phenolic compounds are proposed to be strong antioxidants and radical scavengers.³

Mediterranean countries are responsible for approximately 97% of the world’s olive cultivation.⁴ Olive oil historically was used as lamp fuel, lubricant, body ointment, and later as a source of edible oil.¹ Recently, its potential uses in medicine have called for further exploration into other uses for olive oil.

The skin is the largest organ of the body and serves as a protective barrier against pathogens and harmful substances. Skin damage results in 3 main phases to aid in wound healing: inflammation, proliferation, and maturation. In proper skin healing, inflammation will stop once the harmful microbes are removed. However, an excess and prolongation of inflammation can result in delayed healing. Thus, interventions that can limit the amount of inflammation can help promote wound healing. Olive oil contains several anti-inflammatory molecules (compounds or chemicals), including phenolic compounds and omega-3 fatty acids.⁵ Studies also have shown that olive oil can promote re-epithelialization in tissues.⁶ Thus, use of olive oil in wound therapy has been of great interest.

This article will review studies that have investigated the use of olive oil for wound healing of diabetic foot ulcers, pressure ulcers, perineal ulcers, and chronic ulcers. To conduct a comprehensive scoping review of the literature on the effects of olive oil in wound healing, we utilized the resources of the Galter Health Sciences Library & Learning Center (Chicago, Illinois). Our search strategy was structured to encompass a range of relevant databases accessible through the library, including PubMed, Embase, and Web of Science. We formulated our search terms to be broad yet specific to our topic, combining keywords such as olive oil, wound healing, skin repair, and dermal therapy. The inclusion criteria were set to filter studies conducted from January 2000 to December 2019, focusing on clinical trials, observational studies, and review articles. We limited our search to articles published in English, which yielded a preliminary set of articles that were then screened based on their titles and abstracts. Full-text versions of potentially relevant studies were retrieved and assessed for eligibility. We included studies that specifically evaluated the effects of olive oil in wound healing, excluding those that did not directly relate to our research question or had insufficient data. The data extraction from these studies was conducted using a standardized form, capturing study design, population, intervention details, outcomes, and key findings. The synthesis of these data provided a comprehensive overview of the current evidence on the topic, aiding in the identification of gaps in knowledge and directions for future research.

Diabetic Foot Ulcers

Foot ulcers are common in patients with diabetes mellitus and are associated with notable morbidity and mortality. Foot ulcers can clinically manifest in various forms but are classically described as lesions with a deep sinus in the feet. Patients with diabetic foot ulcers are at risk for infection, and severe forms of the ulcers require amputation.^7,8 Routine care of foot ulcers involves irrigation of the ulcer and surrounding area with normal saline solution daily, followed by a dressing with sterile gauze. Studies investigating the effect of olive oil on foot ulcers suggest that olive oil use for care and healing of foot ulcers is an area of interest.

A double-blind, randomized clinical trial investigated the effects of topical olive oil on diabetic foot ulcers.⁹ A total of 34 patients with foot ulcers of Wagner grades 1 (superficial ulcers that involved the skin but not underlying tissue) or 2 (deeper ulcers penetrating to the ligaments and muscles but not the bone) that had remained open and did not improve for more than 3 months were recruited. The patients were randomly assigned to receive topical olive oil and routine care (intervention group) or to receive routine care (control group). Patients who received olive oil had oil poured on their ulcers with gauze wrapped around the ulcer that was soaked with olive oil. The clinical characteristics of the diabetic ulcer (eg, site, grade, size, status of healing) were assessed. The study revealed that after 4 weeks, olive oil significantly decreased ulcer area (P=.01) and ulcer depth (P=.02) compared with the control. Furthermore, there was a significant difference (P=.003) in complete ulcer healing between the olive oil and control groups: 73.3% (11/15) of patients in the olive oil group had complete ulcer healing, whereas 13.3% (2/15) of patients in the control group had complete ulcer healing.⁹ The positive effect of olive oil on the healing of diabetic foot ulcers encourages further investigation as a possible therapy for foot ulcers.

Another randomized controlled trial of 45 patients with diabetic foot ulcers of Wagner grades 1 or 2 investigated the effect of olive oil.¹⁰ Patients were randomly assigned to 1 of 3 groups for 1 month: the olive oil group, the honey group, or the control group. Patients in the olive oil group had their wounds dressed using gauze with olive oil daily, the patients in the honey group had their wounds dressed using gauze with honey daily, and the control group had routine care consisting of irrigation with saline solution and dressing with a sterile gauze. This study calculated a wound healing score based on a predefined checklist for diabetic foot ulcers through 4 variables: wound grading, color, surrounding tissue status, and drainage. Each variable had a maximum score of 100, contributing to a total possible score of 400, which indicated complete healing. A score of 50 signified ­deterioration. Wound healing was categorized as follows: (1) complete healing is indicated by a total score of 400; (2) partial healing was indicated by an increase of at least 30 points from the initial score; (3) lack of healing occurred when there was no change or less than a 30-point increase from the initial score; and (4) aggravation was noted when the score decreased by at least 10 points from the initial assessment. The study revealed that olive oil and honey treatments resulted in an increase in mean score, which indicated better wound healing. Patients in the olive oil group had a mean score of 253.0 before the intervention and 330.5 after the intervention (P<.0001); patients in the honey group had a mean score of 267.5 before the intervention and 371.5 after the intervention (P<.0001).¹⁰

There also have been case reports on combined olive oil and honey in diabetic foot ulcer management. Haghighian et al¹¹ presented a case of a diabetic foot wound that healed completely within 2 weeks after the combined use of olive oil and honey wax. Zahmatkesh and Rashidi¹² observed the healing of a diabetic foot wound over a month with daily dressings of a mixture of heated honey and olive oil, resulting in granulation tissue formation within 5 days. Microvascular changes, such as capillary basement membrane thickening, pericyte degeneration, and impairment of vasodilation and constriction, may contribute to inflammation in blood vessels, which can delay the healing of diabetic foot ulcers.⁷ Because olive oil and honey contain compounds that have antioxidative, antimicrobial, and anti-inflammatory properties, both may play a role in notably reducing inflammation and promoting the healing of foot ulcers.¹³

Pressure Ulcers

A pressure ulcer is a superficial skin injury that is caused by a prolonged period of pressure on the skin, in which the skin becomes red but there is no rupture. Prolonged periods of immobility resulting in a reduction or pause of blood supply are common causes of pressure ulcers.¹⁴ Studies have suggested that topical olive oil may be effective in prevention of pressure ulcers and should be incorporated as part of standard-of-care measures.

In a randomized, single-blind trial, 72 patients with the first stage of bedsore—which is a pressure ulcer—in the sacral, shoulder, heel, or other areas were randomly assigned to either the intervention or control group.¹⁴ Patients in the intervention group had 15 mL of olive oil rubbed on the wound for 20 minutes daily and then washed with tepid water. The Pressure Ulcer Scale for Healing tool was utilized to assess the healing status of the pressure ulcer. This tool considers wound surface size, exudate rate, and tissue type to provide a score of 0 to 17 (0=healed ulcer; 17=progression of ulcer). The mean score (SD) was lower in the olive oil group at days 4 and 7 compared with the control group (day 4: 7.50 [2.823] vs 9.50 [1.732]; day 7: 5.44 [3.806] vs 8.83 [2.864])(P<.001). Furthermore, between days 1 and 7, there was significant improvement in the olive oil group (mean difference, 3.56; P<.001) but no significant change in the control group (mean difference, 0.75; P=.052).¹⁴ The results indicate that patients in the olive oil group had a better ulcer healing status compared with patients in the control group.

In a noninferiority, randomized, double-blind clinical trial, olive oil was compared to a recommended skin care measure of hyperoxygenated fatty acids (HOFAs) for the prevention of pressure ulcers.¹⁵ The study consisted of 571 residents from several nursing homes who were at risk for pressure ulcers. Either olive oil or HOFA was applied to areas at risk for pressure ulcers, with 2 sprays of 0.2 mL per spray to each area every 12 hours. The participants were followed up for 30 days or until a pressure ulcer developed. Researchers performed skin assessments; the Braden Scale was used to assess the risk for pressure ulcers. The incidence difference of pressure ulcers in the olive oil group and HOFA group did not exceed in the noninferiority margin of 7%. Furthermore, Kaplan-Meier survival curves for the time until pressure ulcer onset showed a nonsignificant difference between the 2 groups.¹⁵ These findings suggest that olive oil is as effective as HOFA for the prevention of pressure ulcers. Although the mechanism of olive oil on prevention of pressure ulcers has not yet been determined, it has been suggested that anti-inflammatory compounds in olive oil, such as polyphenol and oleocanthal compounds, play an anti-inflammatory role.

Perineal Ulcers

Episiotomy is a surgical incision that is made to open the vagina during birth to aid in delivery of the baby. In contrast to spontaneous vaginal tears, an episiotomy allows for easier repair and healing of the laceration.¹⁶ Studies were conducted to investigate the effect of olive oil on women with lacerations after an episiotomy.

A total of 90 primigravid women who had undergone episiotomy were recruited and randomly assigned to 1 of 2 interventions: cold compression with gel packs for 20 minutes within 12 hours after delivery for up to 10 days, if necessary, or topical olive oil twice daily within 12 hours after delivery for up to 10 days.¹⁷ Although there was no significant difference in the structural features of the wound, there was a significant difference in the redness severity. After 10 days, the mean REEDA (redness, edema, ecchymosis, discharge, and apposition) score (SD), which assesses tissue healing, was 0.47 (0.96) in patients who received cold compression with gel packs and 0.20 (0.50) in patients who received topical olive oil (P=.04).¹⁷ This study suggests that there is the potential for olive oil to be used for wound healing after episiotomy.

A double-blind trial consisted of 60 women who had mediolateral episiotomy or perineal tear grades 1 and 2 who were randomly assigned to 1 of 2 groups for 10 days: olive oil sitz bath or distilled water sitz bath (control group). The results showed a significant difference in pain severity after 5 and 10 days (P<.05), wound redness after 5 days (P<.0001), and redness (P<.000) and edema (P<.05) 10 days after delivery.¹⁸ This study encourages further investigation of the benefits of olive oil for care after an episiotomy.

Chronic Ulcers

Chronic ulcers are other persistent wounds that do not respond to standard treatments and pose a notable health burden. Their development is influenced by factors such as oxidative stress, microbial infections, and the body’s immune response. A case series was conducted to investigate the wound healing effects of olive oil on chronic ulcers.¹⁹ Fourteen patients who were diagnosed with 1 or more chronic skin ulcers that had not healed with conventional treatment, such as cleansing, debridement, or infection control, were recruited. The mean (SD) of the patients’ Bates-Jensen Wound Assessment Tool score was 39.05 (4.23), indicating that these ulcers had been challenging to treat. In addition, the wounds in this study were found to be infected with bacteria. An ointment consisting of Ceratothoa oestroides olive oil extract was applied to the wounds after they were cleansed. The results showed that Bates-Jensen Wound Assessment Tool scores decreased by 14.7% to 67.5% (mean, 36%; median, 38%) after 3 months of treatment. Furthermore, 5 patients had a completely healed wound, indicating that C oestroides olive oil extract can regenerate chronic ulcers that do not respond to antibacterial agents.¹⁹ These results encourage further investigation of the role of C oestroides olive oil extract on healing properties and microbial control.

Final Thoughts

This review illuminated several key aspects of research on the role of olive oil in wound healing. Although the studies included in this review offer valuable insights, it is essential to acknowledge the variability in the quality of data presented. Several studies demonstrated robust methodology with clear definitions of outcomes and controlled conditions, providing high-quality evidence. However, other studies exhibited limitations, including small sample sizes and potential biases, which may affect the generalizability of the findings. Despite these limitations, the collective evidence suggests potential for olive oil in wound healing, warranting further investigation. Future research should aim for more standardized methodologies and larger, more diverse patient cohorts to validate these findings and explore the mechanisms underlying the therapeutic effects of olive oil.

Olive oil is obtained by mechanical extraction from the fruit of the Olea europaea tree, which is believed to have originated from ancient Iran and Turkestan, later spreading to Anatolia, Syria, Palestine, and Israel. Mechanical extraction of the oil from the olive fruit involves pressure processing, centrifugation, and adhesion filtering.¹ Refining of olive oil is done via alkali refining or physical refining, with physical refining being useful in removing oxidation by-products and pro-oxidant metals. Olive oil is composed mainly of triacylglycerols, which are glycerol esters attached to various fatty acids, with the most common fatty acid being the monounsaturated oleic acid. Additional fatty acids include palmitic acid, linoleic acid, stearic acid, and palmitoleic acid.² Olive oil contains phenolic compounds, the main ones being oleuropein, hydroxytyrosol, and tyrosol. These phenolic compounds are proposed to be strong antioxidants and radical scavengers.³

Mediterranean countries are responsible for approximately 97% of the world’s olive cultivation.⁴ Olive oil historically was used as lamp fuel, lubricant, body ointment, and later as a source of edible oil.¹ Recently, its potential uses in medicine have called for further exploration into other uses for olive oil.

The skin is the largest organ of the body and serves as a protective barrier against pathogens and harmful substances. Skin damage results in 3 main phases to aid in wound healing: inflammation, proliferation, and maturation. In proper skin healing, inflammation will stop once the harmful microbes are removed. However, an excess and prolongation of inflammation can result in delayed healing. Thus, interventions that can limit the amount of inflammation can help promote wound healing. Olive oil contains several anti-inflammatory molecules (compounds or chemicals), including phenolic compounds and omega-3 fatty acids.⁵ Studies also have shown that olive oil can promote re-epithelialization in tissues.⁶ Thus, use of olive oil in wound therapy has been of great interest.

This article will review studies that have investigated the use of olive oil for wound healing of diabetic foot ulcers, pressure ulcers, perineal ulcers, and chronic ulcers. To conduct a comprehensive scoping review of the literature on the effects of olive oil in wound healing, we utilized the resources of the Galter Health Sciences Library & Learning Center (Chicago, Illinois). Our search strategy was structured to encompass a range of relevant databases accessible through the library, including PubMed, Embase, and Web of Science. We formulated our search terms to be broad yet specific to our topic, combining keywords such as olive oil, wound healing, skin repair, and dermal therapy. The inclusion criteria were set to filter studies conducted from January 2000 to December 2019, focusing on clinical trials, observational studies, and review articles. We limited our search to articles published in English, which yielded a preliminary set of articles that were then screened based on their titles and abstracts. Full-text versions of potentially relevant studies were retrieved and assessed for eligibility. We included studies that specifically evaluated the effects of olive oil in wound healing, excluding those that did not directly relate to our research question or had insufficient data. The data extraction from these studies was conducted using a standardized form, capturing study design, population, intervention details, outcomes, and key findings. The synthesis of these data provided a comprehensive overview of the current evidence on the topic, aiding in the identification of gaps in knowledge and directions for future research.

Diabetic Foot Ulcers

Foot ulcers are common in patients with diabetes mellitus and are associated with notable morbidity and mortality. Foot ulcers can clinically manifest in various forms but are classically described as lesions with a deep sinus in the feet. Patients with diabetic foot ulcers are at risk for infection, and severe forms of the ulcers require amputation.^7,8 Routine care of foot ulcers involves irrigation of the ulcer and surrounding area with normal saline solution daily, followed by a dressing with sterile gauze. Studies investigating the effect of olive oil on foot ulcers suggest that olive oil use for care and healing of foot ulcers is an area of interest.

A double-blind, randomized clinical trial investigated the effects of topical olive oil on diabetic foot ulcers.⁹ A total of 34 patients with foot ulcers of Wagner grades 1 (superficial ulcers that involved the skin but not underlying tissue) or 2 (deeper ulcers penetrating to the ligaments and muscles but not the bone) that had remained open and did not improve for more than 3 months were recruited. The patients were randomly assigned to receive topical olive oil and routine care (intervention group) or to receive routine care (control group). Patients who received olive oil had oil poured on their ulcers with gauze wrapped around the ulcer that was soaked with olive oil. The clinical characteristics of the diabetic ulcer (eg, site, grade, size, status of healing) were assessed. The study revealed that after 4 weeks, olive oil significantly decreased ulcer area (P=.01) and ulcer depth (P=.02) compared with the control. Furthermore, there was a significant difference (P=.003) in complete ulcer healing between the olive oil and control groups: 73.3% (11/15) of patients in the olive oil group had complete ulcer healing, whereas 13.3% (2/15) of patients in the control group had complete ulcer healing.⁹ The positive effect of olive oil on the healing of diabetic foot ulcers encourages further investigation as a possible therapy for foot ulcers.

Another randomized controlled trial of 45 patients with diabetic foot ulcers of Wagner grades 1 or 2 investigated the effect of olive oil.¹⁰ Patients were randomly assigned to 1 of 3 groups for 1 month: the olive oil group, the honey group, or the control group. Patients in the olive oil group had their wounds dressed using gauze with olive oil daily, the patients in the honey group had their wounds dressed using gauze with honey daily, and the control group had routine care consisting of irrigation with saline solution and dressing with a sterile gauze. This study calculated a wound healing score based on a predefined checklist for diabetic foot ulcers through 4 variables: wound grading, color, surrounding tissue status, and drainage. Each variable had a maximum score of 100, contributing to a total possible score of 400, which indicated complete healing. A score of 50 signified ­deterioration. Wound healing was categorized as follows: (1) complete healing is indicated by a total score of 400; (2) partial healing was indicated by an increase of at least 30 points from the initial score; (3) lack of healing occurred when there was no change or less than a 30-point increase from the initial score; and (4) aggravation was noted when the score decreased by at least 10 points from the initial assessment. The study revealed that olive oil and honey treatments resulted in an increase in mean score, which indicated better wound healing. Patients in the olive oil group had a mean score of 253.0 before the intervention and 330.5 after the intervention (P<.0001); patients in the honey group had a mean score of 267.5 before the intervention and 371.5 after the intervention (P<.0001).¹⁰

There also have been case reports on combined olive oil and honey in diabetic foot ulcer management. Haghighian et al¹¹ presented a case of a diabetic foot wound that healed completely within 2 weeks after the combined use of olive oil and honey wax. Zahmatkesh and Rashidi¹² observed the healing of a diabetic foot wound over a month with daily dressings of a mixture of heated honey and olive oil, resulting in granulation tissue formation within 5 days. Microvascular changes, such as capillary basement membrane thickening, pericyte degeneration, and impairment of vasodilation and constriction, may contribute to inflammation in blood vessels, which can delay the healing of diabetic foot ulcers.⁷ Because olive oil and honey contain compounds that have antioxidative, antimicrobial, and anti-inflammatory properties, both may play a role in notably reducing inflammation and promoting the healing of foot ulcers.¹³

Pressure Ulcers

A pressure ulcer is a superficial skin injury that is caused by a prolonged period of pressure on the skin, in which the skin becomes red but there is no rupture. Prolonged periods of immobility resulting in a reduction or pause of blood supply are common causes of pressure ulcers.¹⁴ Studies have suggested that topical olive oil may be effective in prevention of pressure ulcers and should be incorporated as part of standard-of-care measures.

In a randomized, single-blind trial, 72 patients with the first stage of bedsore—which is a pressure ulcer—in the sacral, shoulder, heel, or other areas were randomly assigned to either the intervention or control group.¹⁴ Patients in the intervention group had 15 mL of olive oil rubbed on the wound for 20 minutes daily and then washed with tepid water. The Pressure Ulcer Scale for Healing tool was utilized to assess the healing status of the pressure ulcer. This tool considers wound surface size, exudate rate, and tissue type to provide a score of 0 to 17 (0=healed ulcer; 17=progression of ulcer). The mean score (SD) was lower in the olive oil group at days 4 and 7 compared with the control group (day 4: 7.50 [2.823] vs 9.50 [1.732]; day 7: 5.44 [3.806] vs 8.83 [2.864])(P<.001). Furthermore, between days 1 and 7, there was significant improvement in the olive oil group (mean difference, 3.56; P<.001) but no significant change in the control group (mean difference, 0.75; P=.052).¹⁴ The results indicate that patients in the olive oil group had a better ulcer healing status compared with patients in the control group.

In a noninferiority, randomized, double-blind clinical trial, olive oil was compared to a recommended skin care measure of hyperoxygenated fatty acids (HOFAs) for the prevention of pressure ulcers.¹⁵ The study consisted of 571 residents from several nursing homes who were at risk for pressure ulcers. Either olive oil or HOFA was applied to areas at risk for pressure ulcers, with 2 sprays of 0.2 mL per spray to each area every 12 hours. The participants were followed up for 30 days or until a pressure ulcer developed. Researchers performed skin assessments; the Braden Scale was used to assess the risk for pressure ulcers. The incidence difference of pressure ulcers in the olive oil group and HOFA group did not exceed in the noninferiority margin of 7%. Furthermore, Kaplan-Meier survival curves for the time until pressure ulcer onset showed a nonsignificant difference between the 2 groups.¹⁵ These findings suggest that olive oil is as effective as HOFA for the prevention of pressure ulcers. Although the mechanism of olive oil on prevention of pressure ulcers has not yet been determined, it has been suggested that anti-inflammatory compounds in olive oil, such as polyphenol and oleocanthal compounds, play an anti-inflammatory role.

Perineal Ulcers

Episiotomy is a surgical incision that is made to open the vagina during birth to aid in delivery of the baby. In contrast to spontaneous vaginal tears, an episiotomy allows for easier repair and healing of the laceration.¹⁶ Studies were conducted to investigate the effect of olive oil on women with lacerations after an episiotomy.

A total of 90 primigravid women who had undergone episiotomy were recruited and randomly assigned to 1 of 2 interventions: cold compression with gel packs for 20 minutes within 12 hours after delivery for up to 10 days, if necessary, or topical olive oil twice daily within 12 hours after delivery for up to 10 days.¹⁷ Although there was no significant difference in the structural features of the wound, there was a significant difference in the redness severity. After 10 days, the mean REEDA (redness, edema, ecchymosis, discharge, and apposition) score (SD), which assesses tissue healing, was 0.47 (0.96) in patients who received cold compression with gel packs and 0.20 (0.50) in patients who received topical olive oil (P=.04).¹⁷ This study suggests that there is the potential for olive oil to be used for wound healing after episiotomy.

A double-blind trial consisted of 60 women who had mediolateral episiotomy or perineal tear grades 1 and 2 who were randomly assigned to 1 of 2 groups for 10 days: olive oil sitz bath or distilled water sitz bath (control group). The results showed a significant difference in pain severity after 5 and 10 days (P<.05), wound redness after 5 days (P<.0001), and redness (P<.000) and edema (P<.05) 10 days after delivery.¹⁸ This study encourages further investigation of the benefits of olive oil for care after an episiotomy.

Chronic Ulcers

Chronic ulcers are other persistent wounds that do not respond to standard treatments and pose a notable health burden. Their development is influenced by factors such as oxidative stress, microbial infections, and the body’s immune response. A case series was conducted to investigate the wound healing effects of olive oil on chronic ulcers.¹⁹ Fourteen patients who were diagnosed with 1 or more chronic skin ulcers that had not healed with conventional treatment, such as cleansing, debridement, or infection control, were recruited. The mean (SD) of the patients’ Bates-Jensen Wound Assessment Tool score was 39.05 (4.23), indicating that these ulcers had been challenging to treat. In addition, the wounds in this study were found to be infected with bacteria. An ointment consisting of Ceratothoa oestroides olive oil extract was applied to the wounds after they were cleansed. The results showed that Bates-Jensen Wound Assessment Tool scores decreased by 14.7% to 67.5% (mean, 36%; median, 38%) after 3 months of treatment. Furthermore, 5 patients had a completely healed wound, indicating that C oestroides olive oil extract can regenerate chronic ulcers that do not respond to antibacterial agents.¹⁹ These results encourage further investigation of the role of C oestroides olive oil extract on healing properties and microbial control.

Final Thoughts

This review illuminated several key aspects of research on the role of olive oil in wound healing. Although the studies included in this review offer valuable insights, it is essential to acknowledge the variability in the quality of data presented. Several studies demonstrated robust methodology with clear definitions of outcomes and controlled conditions, providing high-quality evidence. However, other studies exhibited limitations, including small sample sizes and potential biases, which may affect the generalizability of the findings. Despite these limitations, the collective evidence suggests potential for olive oil in wound healing, warranting further investigation. Future research should aim for more standardized methodologies and larger, more diverse patient cohorts to validate these findings and explore the mechanisms underlying the therapeutic effects of olive oil.

Olive oil is obtained by mechanical extraction from the fruit of the Olea europaea tree, which is believed to have originated from ancient Iran and Turkestan, later spreading to Anatolia, Syria, Palestine, and Israel. Mechanical extraction of the oil from the olive fruit involves pressure processing, centrifugation, and adhesion filtering.¹ Refining of olive oil is done via alkali refining or physical refining, with physical refining being useful in removing oxidation by-products and pro-oxidant metals. Olive oil is composed mainly of triacylglycerols, which are glycerol esters attached to various fatty acids, with the most common fatty acid being the monounsaturated oleic acid. Additional fatty acids include palmitic acid, linoleic acid, stearic acid, and palmitoleic acid.² Olive oil contains phenolic compounds, the main ones being oleuropein, hydroxytyrosol, and tyrosol. These phenolic compounds are proposed to be strong antioxidants and radical scavengers.³

Mediterranean countries are responsible for approximately 97% of the world’s olive cultivation.⁴ Olive oil historically was used as lamp fuel, lubricant, body ointment, and later as a source of edible oil.¹ Recently, its potential uses in medicine have called for further exploration into other uses for olive oil.

The skin is the largest organ of the body and serves as a protective barrier against pathogens and harmful substances. Skin damage results in 3 main phases to aid in wound healing: inflammation, proliferation, and maturation. In proper skin healing, inflammation will stop once the harmful microbes are removed. However, an excess and prolongation of inflammation can result in delayed healing. Thus, interventions that can limit the amount of inflammation can help promote wound healing. Olive oil contains several anti-inflammatory molecules (compounds or chemicals), including phenolic compounds and omega-3 fatty acids.⁵ Studies also have shown that olive oil can promote re-epithelialization in tissues.⁶ Thus, use of olive oil in wound therapy has been of great interest.

This article will review studies that have investigated the use of olive oil for wound healing of diabetic foot ulcers, pressure ulcers, perineal ulcers, and chronic ulcers. To conduct a comprehensive scoping review of the literature on the effects of olive oil in wound healing, we utilized the resources of the Galter Health Sciences Library & Learning Center (Chicago, Illinois). Our search strategy was structured to encompass a range of relevant databases accessible through the library, including PubMed, Embase, and Web of Science. We formulated our search terms to be broad yet specific to our topic, combining keywords such as olive oil, wound healing, skin repair, and dermal therapy. The inclusion criteria were set to filter studies conducted from January 2000 to December 2019, focusing on clinical trials, observational studies, and review articles. We limited our search to articles published in English, which yielded a preliminary set of articles that were then screened based on their titles and abstracts. Full-text versions of potentially relevant studies were retrieved and assessed for eligibility. We included studies that specifically evaluated the effects of olive oil in wound healing, excluding those that did not directly relate to our research question or had insufficient data. The data extraction from these studies was conducted using a standardized form, capturing study design, population, intervention details, outcomes, and key findings. The synthesis of these data provided a comprehensive overview of the current evidence on the topic, aiding in the identification of gaps in knowledge and directions for future research.

Diabetic Foot Ulcers

Foot ulcers are common in patients with diabetes mellitus and are associated with notable morbidity and mortality. Foot ulcers can clinically manifest in various forms but are classically described as lesions with a deep sinus in the feet. Patients with diabetic foot ulcers are at risk for infection, and severe forms of the ulcers require amputation.^7,8 Routine care of foot ulcers involves irrigation of the ulcer and surrounding area with normal saline solution daily, followed by a dressing with sterile gauze. Studies investigating the effect of olive oil on foot ulcers suggest that olive oil use for care and healing of foot ulcers is an area of interest.

A double-blind, randomized clinical trial investigated the effects of topical olive oil on diabetic foot ulcers.⁹ A total of 34 patients with foot ulcers of Wagner grades 1 (superficial ulcers that involved the skin but not underlying tissue) or 2 (deeper ulcers penetrating to the ligaments and muscles but not the bone) that had remained open and did not improve for more than 3 months were recruited. The patients were randomly assigned to receive topical olive oil and routine care (intervention group) or to receive routine care (control group). Patients who received olive oil had oil poured on their ulcers with gauze wrapped around the ulcer that was soaked with olive oil. The clinical characteristics of the diabetic ulcer (eg, site, grade, size, status of healing) were assessed. The study revealed that after 4 weeks, olive oil significantly decreased ulcer area (P=.01) and ulcer depth (P=.02) compared with the control. Furthermore, there was a significant difference (P=.003) in complete ulcer healing between the olive oil and control groups: 73.3% (11/15) of patients in the olive oil group had complete ulcer healing, whereas 13.3% (2/15) of patients in the control group had complete ulcer healing.⁹ The positive effect of olive oil on the healing of diabetic foot ulcers encourages further investigation as a possible therapy for foot ulcers.

Another randomized controlled trial of 45 patients with diabetic foot ulcers of Wagner grades 1 or 2 investigated the effect of olive oil.¹⁰ Patients were randomly assigned to 1 of 3 groups for 1 month: the olive oil group, the honey group, or the control group. Patients in the olive oil group had their wounds dressed using gauze with olive oil daily, the patients in the honey group had their wounds dressed using gauze with honey daily, and the control group had routine care consisting of irrigation with saline solution and dressing with a sterile gauze. This study calculated a wound healing score based on a predefined checklist for diabetic foot ulcers through 4 variables: wound grading, color, surrounding tissue status, and drainage. Each variable had a maximum score of 100, contributing to a total possible score of 400, which indicated complete healing. A score of 50 signified ­deterioration. Wound healing was categorized as follows: (1) complete healing is indicated by a total score of 400; (2) partial healing was indicated by an increase of at least 30 points from the initial score; (3) lack of healing occurred when there was no change or less than a 30-point increase from the initial score; and (4) aggravation was noted when the score decreased by at least 10 points from the initial assessment. The study revealed that olive oil and honey treatments resulted in an increase in mean score, which indicated better wound healing. Patients in the olive oil group had a mean score of 253.0 before the intervention and 330.5 after the intervention (P<.0001); patients in the honey group had a mean score of 267.5 before the intervention and 371.5 after the intervention (P<.0001).¹⁰

There also have been case reports on combined olive oil and honey in diabetic foot ulcer management. Haghighian et al¹¹ presented a case of a diabetic foot wound that healed completely within 2 weeks after the combined use of olive oil and honey wax. Zahmatkesh and Rashidi¹² observed the healing of a diabetic foot wound over a month with daily dressings of a mixture of heated honey and olive oil, resulting in granulation tissue formation within 5 days. Microvascular changes, such as capillary basement membrane thickening, pericyte degeneration, and impairment of vasodilation and constriction, may contribute to inflammation in blood vessels, which can delay the healing of diabetic foot ulcers.⁷ Because olive oil and honey contain compounds that have antioxidative, antimicrobial, and anti-inflammatory properties, both may play a role in notably reducing inflammation and promoting the healing of foot ulcers.¹³

Pressure Ulcers

A pressure ulcer is a superficial skin injury that is caused by a prolonged period of pressure on the skin, in which the skin becomes red but there is no rupture. Prolonged periods of immobility resulting in a reduction or pause of blood supply are common causes of pressure ulcers.¹⁴ Studies have suggested that topical olive oil may be effective in prevention of pressure ulcers and should be incorporated as part of standard-of-care measures.

In a randomized, single-blind trial, 72 patients with the first stage of bedsore—which is a pressure ulcer—in the sacral, shoulder, heel, or other areas were randomly assigned to either the intervention or control group.¹⁴ Patients in the intervention group had 15 mL of olive oil rubbed on the wound for 20 minutes daily and then washed with tepid water. The Pressure Ulcer Scale for Healing tool was utilized to assess the healing status of the pressure ulcer. This tool considers wound surface size, exudate rate, and tissue type to provide a score of 0 to 17 (0=healed ulcer; 17=progression of ulcer). The mean score (SD) was lower in the olive oil group at days 4 and 7 compared with the control group (day 4: 7.50 [2.823] vs 9.50 [1.732]; day 7: 5.44 [3.806] vs 8.83 [2.864])(P<.001). Furthermore, between days 1 and 7, there was significant improvement in the olive oil group (mean difference, 3.56; P<.001) but no significant change in the control group (mean difference, 0.75; P=.052).¹⁴ The results indicate that patients in the olive oil group had a better ulcer healing status compared with patients in the control group.

In a noninferiority, randomized, double-blind clinical trial, olive oil was compared to a recommended skin care measure of hyperoxygenated fatty acids (HOFAs) for the prevention of pressure ulcers.¹⁵ The study consisted of 571 residents from several nursing homes who were at risk for pressure ulcers. Either olive oil or HOFA was applied to areas at risk for pressure ulcers, with 2 sprays of 0.2 mL per spray to each area every 12 hours. The participants were followed up for 30 days or until a pressure ulcer developed. Researchers performed skin assessments; the Braden Scale was used to assess the risk for pressure ulcers. The incidence difference of pressure ulcers in the olive oil group and HOFA group did not exceed in the noninferiority margin of 7%. Furthermore, Kaplan-Meier survival curves for the time until pressure ulcer onset showed a nonsignificant difference between the 2 groups.¹⁵ These findings suggest that olive oil is as effective as HOFA for the prevention of pressure ulcers. Although the mechanism of olive oil on prevention of pressure ulcers has not yet been determined, it has been suggested that anti-inflammatory compounds in olive oil, such as polyphenol and oleocanthal compounds, play an anti-inflammatory role.

Perineal Ulcers

Episiotomy is a surgical incision that is made to open the vagina during birth to aid in delivery of the baby. In contrast to spontaneous vaginal tears, an episiotomy allows for easier repair and healing of the laceration.¹⁶ Studies were conducted to investigate the effect of olive oil on women with lacerations after an episiotomy.

A total of 90 primigravid women who had undergone episiotomy were recruited and randomly assigned to 1 of 2 interventions: cold compression with gel packs for 20 minutes within 12 hours after delivery for up to 10 days, if necessary, or topical olive oil twice daily within 12 hours after delivery for up to 10 days.¹⁷ Although there was no significant difference in the structural features of the wound, there was a significant difference in the redness severity. After 10 days, the mean REEDA (redness, edema, ecchymosis, discharge, and apposition) score (SD), which assesses tissue healing, was 0.47 (0.96) in patients who received cold compression with gel packs and 0.20 (0.50) in patients who received topical olive oil (P=.04).¹⁷ This study suggests that there is the potential for olive oil to be used for wound healing after episiotomy.

A double-blind trial consisted of 60 women who had mediolateral episiotomy or perineal tear grades 1 and 2 who were randomly assigned to 1 of 2 groups for 10 days: olive oil sitz bath or distilled water sitz bath (control group). The results showed a significant difference in pain severity after 5 and 10 days (P<.05), wound redness after 5 days (P<.0001), and redness (P<.000) and edema (P<.05) 10 days after delivery.¹⁸ This study encourages further investigation of the benefits of olive oil for care after an episiotomy.

Chronic Ulcers

Chronic ulcers are other persistent wounds that do not respond to standard treatments and pose a notable health burden. Their development is influenced by factors such as oxidative stress, microbial infections, and the body’s immune response. A case series was conducted to investigate the wound healing effects of olive oil on chronic ulcers.¹⁹ Fourteen patients who were diagnosed with 1 or more chronic skin ulcers that had not healed with conventional treatment, such as cleansing, debridement, or infection control, were recruited. The mean (SD) of the patients’ Bates-Jensen Wound Assessment Tool score was 39.05 (4.23), indicating that these ulcers had been challenging to treat. In addition, the wounds in this study were found to be infected with bacteria. An ointment consisting of Ceratothoa oestroides olive oil extract was applied to the wounds after they were cleansed. The results showed that Bates-Jensen Wound Assessment Tool scores decreased by 14.7% to 67.5% (mean, 36%; median, 38%) after 3 months of treatment. Furthermore, 5 patients had a completely healed wound, indicating that C oestroides olive oil extract can regenerate chronic ulcers that do not respond to antibacterial agents.¹⁹ These results encourage further investigation of the role of C oestroides olive oil extract on healing properties and microbial control.

Final Thoughts

This review illuminated several key aspects of research on the role of olive oil in wound healing. Although the studies included in this review offer valuable insights, it is essential to acknowledge the variability in the quality of data presented. Several studies demonstrated robust methodology with clear definitions of outcomes and controlled conditions, providing high-quality evidence. However, other studies exhibited limitations, including small sample sizes and potential biases, which may affect the generalizability of the findings. Despite these limitations, the collective evidence suggests potential for olive oil in wound healing, warranting further investigation. Future research should aim for more standardized methodologies and larger, more diverse patient cohorts to validate these findings and explore the mechanisms underlying the therapeutic effects of olive oil.

The Diagnosis: Subungual Exostosis

Subungual exostosis should be considered as a possible cause of an exophytic subungual nodule in a young active female. In our patient, the involvement of the great toe was a clue, as the hallux is the most common location of subungual exostosis. The patient’s age and sex also were supportive, as subungual exostosis is most common in female children and adolescents— particularly those who are active, as trauma is thought to play a possible role in development of this benign tumor.^1-3 Radiography is the preferred modality for diagnosis; in our case, it showed a trabecular bony overgrowth (Figure 1), which confirmed the diagnosis. Subungual exostosis is a rare, benign, osteocartilaginous tumor of trabecular bone. The etiology is unknown but is hypothesized to be related to trauma, infection, or activation of a cartilaginous cyst.^1,3 The subungual nodule may be asymptomatic or painful. Disruption and elevation of the nail plate is common.⁴ The differential diagnosis includes amelanotic melanoma, fibroma, fibrokeratoma, osteochondroma, pyogenic granuloma, squamous cell carcinoma, glomus tumor, and verruca vulgaris, among others.⁵

Physical examination demonstrates a firm, fixed, subungual nodule, often with an accompanying nail deformity. Further workup is required to confirm the benign nature of the lesion and exclude nail tumors such as melanoma or squamous cell carcinoma. Radiography is the gold standard for diagnosis, demonstrating a trabecular bony overgrowth.⁶ Performing a radiograph as the initial diagnostic test spares the patient from unnecessary procedures such as biopsy or expensive imaging techniques such as magnetic resonance imaging. Early lesions may not demonstrate sufficient bone formation shown on radiography. In these situations, a combination of dermoscopy and histopathologic examination may aid in diagnosis (Figure 2).⁴ Vascular ectasia, hyperkeratosis, onycholysis, and ulceration are the most common findings on dermoscopy (in ascending order).⁷ Histopathology typically demonstrates a base or stalk of normal-appearing trabecular bone with a fibrocartilage cap.⁸ However, initial clinical workup via radiography allows for the least-invasive and highest-yield intervention. Clinical suspicion for this condition is important, as it can be diagnosed with noninvasive inexpensive imaging rather than biopsy or more specialized imaging modalities. Appropriate recognition can save young patients from unnecessary and expensive procedures. Treatment typically involves surgical excision; to prevent regrowth, removal of the lesion at the base of the bone is recommended.²

Although amelanotic melanoma also can manifest as a subungual nail tumor, it would be unusual in a young child and would not be expected to show characteristic changes on radiography. A glomus tumor would be painful, is more common on the fingers than on the toes, and typically has a bluish hue.⁹ Verruca vulgaris can occur subungually but is more common around the nailfold and often has the characteristic dermoscopic finding of thrombosed capillaries. It also would not be expected to show characteristic radiographic findings. Osteochondroma can occur in young patients and can appear clinically similar to subungual exostosis; however, it typically is painful.¹⁰

The Diagnosis: Subungual Exostosis

Subungual exostosis should be considered as a possible cause of an exophytic subungual nodule in a young active female. In our patient, the involvement of the great toe was a clue, as the hallux is the most common location of subungual exostosis. The patient’s age and sex also were supportive, as subungual exostosis is most common in female children and adolescents— particularly those who are active, as trauma is thought to play a possible role in development of this benign tumor.^1-3 Radiography is the preferred modality for diagnosis; in our case, it showed a trabecular bony overgrowth (Figure 1), which confirmed the diagnosis. Subungual exostosis is a rare, benign, osteocartilaginous tumor of trabecular bone. The etiology is unknown but is hypothesized to be related to trauma, infection, or activation of a cartilaginous cyst.^1,3 The subungual nodule may be asymptomatic or painful. Disruption and elevation of the nail plate is common.⁴ The differential diagnosis includes amelanotic melanoma, fibroma, fibrokeratoma, osteochondroma, pyogenic granuloma, squamous cell carcinoma, glomus tumor, and verruca vulgaris, among others.⁵

Physical examination demonstrates a firm, fixed, subungual nodule, often with an accompanying nail deformity. Further workup is required to confirm the benign nature of the lesion and exclude nail tumors such as melanoma or squamous cell carcinoma. Radiography is the gold standard for diagnosis, demonstrating a trabecular bony overgrowth.⁶ Performing a radiograph as the initial diagnostic test spares the patient from unnecessary procedures such as biopsy or expensive imaging techniques such as magnetic resonance imaging. Early lesions may not demonstrate sufficient bone formation shown on radiography. In these situations, a combination of dermoscopy and histopathologic examination may aid in diagnosis (Figure 2).⁴ Vascular ectasia, hyperkeratosis, onycholysis, and ulceration are the most common findings on dermoscopy (in ascending order).⁷ Histopathology typically demonstrates a base or stalk of normal-appearing trabecular bone with a fibrocartilage cap.⁸ However, initial clinical workup via radiography allows for the least-invasive and highest-yield intervention. Clinical suspicion for this condition is important, as it can be diagnosed with noninvasive inexpensive imaging rather than biopsy or more specialized imaging modalities. Appropriate recognition can save young patients from unnecessary and expensive procedures. Treatment typically involves surgical excision; to prevent regrowth, removal of the lesion at the base of the bone is recommended.²

Although amelanotic melanoma also can manifest as a subungual nail tumor, it would be unusual in a young child and would not be expected to show characteristic changes on radiography. A glomus tumor would be painful, is more common on the fingers than on the toes, and typically has a bluish hue.⁹ Verruca vulgaris can occur subungually but is more common around the nailfold and often has the characteristic dermoscopic finding of thrombosed capillaries. It also would not be expected to show characteristic radiographic findings. Osteochondroma can occur in young patients and can appear clinically similar to subungual exostosis; however, it typically is painful.¹⁰

The Diagnosis: Subungual Exostosis

Subungual exostosis should be considered as a possible cause of an exophytic subungual nodule in a young active female. In our patient, the involvement of the great toe was a clue, as the hallux is the most common location of subungual exostosis. The patient’s age and sex also were supportive, as subungual exostosis is most common in female children and adolescents— particularly those who are active, as trauma is thought to play a possible role in development of this benign tumor.^1-3 Radiography is the preferred modality for diagnosis; in our case, it showed a trabecular bony overgrowth (Figure 1), which confirmed the diagnosis. Subungual exostosis is a rare, benign, osteocartilaginous tumor of trabecular bone. The etiology is unknown but is hypothesized to be related to trauma, infection, or activation of a cartilaginous cyst.^1,3 The subungual nodule may be asymptomatic or painful. Disruption and elevation of the nail plate is common.⁴ The differential diagnosis includes amelanotic melanoma, fibroma, fibrokeratoma, osteochondroma, pyogenic granuloma, squamous cell carcinoma, glomus tumor, and verruca vulgaris, among others.⁵

Physical examination demonstrates a firm, fixed, subungual nodule, often with an accompanying nail deformity. Further workup is required to confirm the benign nature of the lesion and exclude nail tumors such as melanoma or squamous cell carcinoma. Radiography is the gold standard for diagnosis, demonstrating a trabecular bony overgrowth.⁶ Performing a radiograph as the initial diagnostic test spares the patient from unnecessary procedures such as biopsy or expensive imaging techniques such as magnetic resonance imaging. Early lesions may not demonstrate sufficient bone formation shown on radiography. In these situations, a combination of dermoscopy and histopathologic examination may aid in diagnosis (Figure 2).⁴ Vascular ectasia, hyperkeratosis, onycholysis, and ulceration are the most common findings on dermoscopy (in ascending order).⁷ Histopathology typically demonstrates a base or stalk of normal-appearing trabecular bone with a fibrocartilage cap.⁸ However, initial clinical workup via radiography allows for the least-invasive and highest-yield intervention. Clinical suspicion for this condition is important, as it can be diagnosed with noninvasive inexpensive imaging rather than biopsy or more specialized imaging modalities. Appropriate recognition can save young patients from unnecessary and expensive procedures. Treatment typically involves surgical excision; to prevent regrowth, removal of the lesion at the base of the bone is recommended.²

Although amelanotic melanoma also can manifest as a subungual nail tumor, it would be unusual in a young child and would not be expected to show characteristic changes on radiography. A glomus tumor would be painful, is more common on the fingers than on the toes, and typically has a bluish hue.⁹ Verruca vulgaris can occur subungually but is more common around the nailfold and often has the characteristic dermoscopic finding of thrombosed capillaries. It also would not be expected to show characteristic radiographic findings. Osteochondroma can occur in young patients and can appear clinically similar to subungual exostosis; however, it typically is painful.¹⁰

The filamentous cyanobacterium Lyngbya majuscula causes irritant contact dermatitis in beachgoers, fishers, and divers in tropical and subtropical marine environments worldwide.¹ If fragments of L majuscula lodge in swimmers’ bathing suits, the toxins can become trapped against the skin and cause seaweed dermatitis.² With climate change resulting in warmer oceans and more extreme storms, L majuscula blooms likely will become more frequent and widespread, thereby increasing the risk for human exposure.^3,4 Herein, we describe the irritants that lead to dermatitis, clinical presentation, and prevention and management of seaweed dermatitis.

Identifying Features and Distribution of Plant

Lyngbya majuscula belongs to the family Oscillatoriaceae; these cyanobacteria grow as filaments and exhibit slow oscillating movements. Commonly referred to as blanketweed or mermaid’s hair due to its appearance, L majuscula grows fine hairlike clumps resembling a mass of olive-colored matted hair.¹ Its thin filaments are 10- to 30-cm long and vary in color from red to white to brown.⁵ Microscopically, a rouleauxlike arrangement of discs provides the structure of each filament.⁶

First identified in Hawaii in 1912, L majuscula was not associated with seaweed dermatitis or dermatotoxicity by the medical community until the first outbreak occurred in Oahu in 1958, though fishermen and beachgoers previously had recognized a relationship between this particular seaweed and skin irritation.^5,7 The first reporting included 125 confirmed cases, with many more mild unreported cases suspected.⁶ Now reported in about 100 locations worldwide, seaweed dermatitis outbreaks have occurred in Australia; Okinawa, Japan; Florida; and the Hawaiian and Marshall islands.^1,2

Exposure to Seaweed

Lyngbya majuscula produces more than 70 biologically active compounds that irritate the skin, eyes, and respiratory system.^2,8 It grows in marine and estuarine environments attached to seagrass, sand, and bedrock at depths of up to 30 m. Warm waters and maximal sunlight provide optimal growth conditions for L majuscula; therefore, the greatest risk for exposure occurs in the Northern and Southern hemispheres in the 1- to 2-month period following their summer solstices.⁵ Runoff during heavy rainfall, which is rich in soil extracts such as phosphorous, iron, and organic carbon, stimulates L majuscula growth and contributes to increased algal blooms.⁴

Dermatitis and Irritants

The dermatoxins Lyngbyatoxin A (LA) and debromoaplysiatoxin (DAT) cause the inflammatory and necrotic appearance of seaweed dermatitis.^1,2,5,8 Lyngbyatoxin A is an indole alkaloid that is closely related to telocidin B, a poisonous compound associated with Streptomyces bacteria.⁹ Sampling of L majuscula and extraction of the dermatoxin, along with human and animal studies, confirmed DAT irritates the skin and induces dermatitis.^5,6Stylocheilus longicauda (sea hare) feeds on L majuscula and contains isolates of DAT in its digestive tract.

Samples of L majuscula taken from several Hawaiian Islands where seaweed dermatitis outbreaks have occurred were examined for differences in toxicities via 6-hour patch tests on human skin.⁶ The samples obtained from the windward side of Oahu contained DAT and aplysiatoxin, while those obtained from the leeward side and Kahala Beach primarily contained LA. Although DAT and LA are vastly different in their molecular structures, testing elicited the same biologic response and induced the same level of skin irritation.⁶ Interestingly, not all strands of L majuscula produced LA and DAT and caused seaweed dermatitis; those that did lead to irritation were more red in color than nontoxic blooms.^5,9

Cutaneous Manifestations

Seaweed dermatitis resembles chemical and thermal burns, ranging from a mild skin rash to severe contact dermatitis with itchy, swollen, ulcerated lesions.^1,7 Patients typically develop a burning or itching sensation beneath their bathing suit or wetsuit that progresses to an erythematous papulovesicular eruption 2 to 24 hours after exposure.^2,6 Within a week, vesicles and bullae desquamate, leaving behind tender erosions.^1,2,6,8 Inframammary lesions are common in females and scrotal swelling in males.^1,6 There is no known association between length of time spent in the water and severity of symptoms.⁵

Most reactions to L majuscula occur from exposure in the water; however, particles that become aerosolized during strong winds or storms can cause seaweed dermatitis on the face. Inhalation of L majuscula may lead to mucous membrane ulceration and pulmonary edema.^1,5,6 Noncutaneous manifestations of seaweed dermatitis include headache, fatigue, and swelling of the eyes, nose, and throat (Figures 1 and 2).^1,5

Prevention and Management

To prevent seaweed dermatitis, avoid swimming in ocean water during L majuscula blooms,¹⁰ which frequently occur following the summer solstices in the Northern and Southern hemispheres.⁵ The National Centers for Coastal Ocean Science Harmful Algae Bloom Monitoring System provides real-time access to algae bloom locations.¹¹ Although this monitoring system is not specific to L majuscula, it may be helpful in determining where potential blooms are. Wearing protective clothing such as coveralls may benefit individuals who enter the water during blooms, but it does not guarantee protection.¹⁰

Currently, there is no treatment for seaweed dermatitis, but symptom management may reduce discomfort and pain. Washing affected skin with soap and water within an hour of exposure may help reduce the severity of seaweed dermatitis, though studies have shown mixed results.^6,7 Application of cool compresses and soothing ointments (eg, calamine) provide symptomatic relief and promote healing.⁷ The dermatitis typically self-resolves within 1 week.

The filamentous cyanobacterium Lyngbya majuscula causes irritant contact dermatitis in beachgoers, fishers, and divers in tropical and subtropical marine environments worldwide.¹ If fragments of L majuscula lodge in swimmers’ bathing suits, the toxins can become trapped against the skin and cause seaweed dermatitis.² With climate change resulting in warmer oceans and more extreme storms, L majuscula blooms likely will become more frequent and widespread, thereby increasing the risk for human exposure.^3,4 Herein, we describe the irritants that lead to dermatitis, clinical presentation, and prevention and management of seaweed dermatitis.

Identifying Features and Distribution of Plant

Lyngbya majuscula belongs to the family Oscillatoriaceae; these cyanobacteria grow as filaments and exhibit slow oscillating movements. Commonly referred to as blanketweed or mermaid’s hair due to its appearance, L majuscula grows fine hairlike clumps resembling a mass of olive-colored matted hair.¹ Its thin filaments are 10- to 30-cm long and vary in color from red to white to brown.⁵ Microscopically, a rouleauxlike arrangement of discs provides the structure of each filament.⁶

First identified in Hawaii in 1912, L majuscula was not associated with seaweed dermatitis or dermatotoxicity by the medical community until the first outbreak occurred in Oahu in 1958, though fishermen and beachgoers previously had recognized a relationship between this particular seaweed and skin irritation.^5,7 The first reporting included 125 confirmed cases, with many more mild unreported cases suspected.⁶ Now reported in about 100 locations worldwide, seaweed dermatitis outbreaks have occurred in Australia; Okinawa, Japan; Florida; and the Hawaiian and Marshall islands.^1,2

Exposure to Seaweed

Lyngbya majuscula produces more than 70 biologically active compounds that irritate the skin, eyes, and respiratory system.^2,8 It grows in marine and estuarine environments attached to seagrass, sand, and bedrock at depths of up to 30 m. Warm waters and maximal sunlight provide optimal growth conditions for L majuscula; therefore, the greatest risk for exposure occurs in the Northern and Southern hemispheres in the 1- to 2-month period following their summer solstices.⁵ Runoff during heavy rainfall, which is rich in soil extracts such as phosphorous, iron, and organic carbon, stimulates L majuscula growth and contributes to increased algal blooms.⁴

Dermatitis and Irritants

The dermatoxins Lyngbyatoxin A (LA) and debromoaplysiatoxin (DAT) cause the inflammatory and necrotic appearance of seaweed dermatitis.^1,2,5,8 Lyngbyatoxin A is an indole alkaloid that is closely related to telocidin B, a poisonous compound associated with Streptomyces bacteria.⁹ Sampling of L majuscula and extraction of the dermatoxin, along with human and animal studies, confirmed DAT irritates the skin and induces dermatitis.^5,6Stylocheilus longicauda (sea hare) feeds on L majuscula and contains isolates of DAT in its digestive tract.

Samples of L majuscula taken from several Hawaiian Islands where seaweed dermatitis outbreaks have occurred were examined for differences in toxicities via 6-hour patch tests on human skin.⁶ The samples obtained from the windward side of Oahu contained DAT and aplysiatoxin, while those obtained from the leeward side and Kahala Beach primarily contained LA. Although DAT and LA are vastly different in their molecular structures, testing elicited the same biologic response and induced the same level of skin irritation.⁶ Interestingly, not all strands of L majuscula produced LA and DAT and caused seaweed dermatitis; those that did lead to irritation were more red in color than nontoxic blooms.^5,9

Cutaneous Manifestations

Seaweed dermatitis resembles chemical and thermal burns, ranging from a mild skin rash to severe contact dermatitis with itchy, swollen, ulcerated lesions.^1,7 Patients typically develop a burning or itching sensation beneath their bathing suit or wetsuit that progresses to an erythematous papulovesicular eruption 2 to 24 hours after exposure.^2,6 Within a week, vesicles and bullae desquamate, leaving behind tender erosions.^1,2,6,8 Inframammary lesions are common in females and scrotal swelling in males.^1,6 There is no known association between length of time spent in the water and severity of symptoms.⁵

Most reactions to L majuscula occur from exposure in the water; however, particles that become aerosolized during strong winds or storms can cause seaweed dermatitis on the face. Inhalation of L majuscula may lead to mucous membrane ulceration and pulmonary edema.^1,5,6 Noncutaneous manifestations of seaweed dermatitis include headache, fatigue, and swelling of the eyes, nose, and throat (Figures 1 and 2).^1,5

Prevention and Management

To prevent seaweed dermatitis, avoid swimming in ocean water during L majuscula blooms,¹⁰ which frequently occur following the summer solstices in the Northern and Southern hemispheres.⁵ The National Centers for Coastal Ocean Science Harmful Algae Bloom Monitoring System provides real-time access to algae bloom locations.¹¹ Although this monitoring system is not specific to L majuscula, it may be helpful in determining where potential blooms are. Wearing protective clothing such as coveralls may benefit individuals who enter the water during blooms, but it does not guarantee protection.¹⁰

Currently, there is no treatment for seaweed dermatitis, but symptom management may reduce discomfort and pain. Washing affected skin with soap and water within an hour of exposure may help reduce the severity of seaweed dermatitis, though studies have shown mixed results.^6,7 Application of cool compresses and soothing ointments (eg, calamine) provide symptomatic relief and promote healing.⁷ The dermatitis typically self-resolves within 1 week.

The filamentous cyanobacterium Lyngbya majuscula causes irritant contact dermatitis in beachgoers, fishers, and divers in tropical and subtropical marine environments worldwide.¹ If fragments of L majuscula lodge in swimmers’ bathing suits, the toxins can become trapped against the skin and cause seaweed dermatitis.² With climate change resulting in warmer oceans and more extreme storms, L majuscula blooms likely will become more frequent and widespread, thereby increasing the risk for human exposure.^3,4 Herein, we describe the irritants that lead to dermatitis, clinical presentation, and prevention and management of seaweed dermatitis.

Identifying Features and Distribution of Plant

Lyngbya majuscula belongs to the family Oscillatoriaceae; these cyanobacteria grow as filaments and exhibit slow oscillating movements. Commonly referred to as blanketweed or mermaid’s hair due to its appearance, L majuscula grows fine hairlike clumps resembling a mass of olive-colored matted hair.¹ Its thin filaments are 10- to 30-cm long and vary in color from red to white to brown.⁵ Microscopically, a rouleauxlike arrangement of discs provides the structure of each filament.⁶

First identified in Hawaii in 1912, L majuscula was not associated with seaweed dermatitis or dermatotoxicity by the medical community until the first outbreak occurred in Oahu in 1958, though fishermen and beachgoers previously had recognized a relationship between this particular seaweed and skin irritation.^5,7 The first reporting included 125 confirmed cases, with many more mild unreported cases suspected.⁶ Now reported in about 100 locations worldwide, seaweed dermatitis outbreaks have occurred in Australia; Okinawa, Japan; Florida; and the Hawaiian and Marshall islands.^1,2

Exposure to Seaweed

Lyngbya majuscula produces more than 70 biologically active compounds that irritate the skin, eyes, and respiratory system.^2,8 It grows in marine and estuarine environments attached to seagrass, sand, and bedrock at depths of up to 30 m. Warm waters and maximal sunlight provide optimal growth conditions for L majuscula; therefore, the greatest risk for exposure occurs in the Northern and Southern hemispheres in the 1- to 2-month period following their summer solstices.⁵ Runoff during heavy rainfall, which is rich in soil extracts such as phosphorous, iron, and organic carbon, stimulates L majuscula growth and contributes to increased algal blooms.⁴

Dermatitis and Irritants

The dermatoxins Lyngbyatoxin A (LA) and debromoaplysiatoxin (DAT) cause the inflammatory and necrotic appearance of seaweed dermatitis.^1,2,5,8 Lyngbyatoxin A is an indole alkaloid that is closely related to telocidin B, a poisonous compound associated with Streptomyces bacteria.⁹ Sampling of L majuscula and extraction of the dermatoxin, along with human and animal studies, confirmed DAT irritates the skin and induces dermatitis.^5,6Stylocheilus longicauda (sea hare) feeds on L majuscula and contains isolates of DAT in its digestive tract.

Samples of L majuscula taken from several Hawaiian Islands where seaweed dermatitis outbreaks have occurred were examined for differences in toxicities via 6-hour patch tests on human skin.⁶ The samples obtained from the windward side of Oahu contained DAT and aplysiatoxin, while those obtained from the leeward side and Kahala Beach primarily contained LA. Although DAT and LA are vastly different in their molecular structures, testing elicited the same biologic response and induced the same level of skin irritation.⁶ Interestingly, not all strands of L majuscula produced LA and DAT and caused seaweed dermatitis; those that did lead to irritation were more red in color than nontoxic blooms.^5,9

Cutaneous Manifestations

Seaweed dermatitis resembles chemical and thermal burns, ranging from a mild skin rash to severe contact dermatitis with itchy, swollen, ulcerated lesions.^1,7 Patients typically develop a burning or itching sensation beneath their bathing suit or wetsuit that progresses to an erythematous papulovesicular eruption 2 to 24 hours after exposure.^2,6 Within a week, vesicles and bullae desquamate, leaving behind tender erosions.^1,2,6,8 Inframammary lesions are common in females and scrotal swelling in males.^1,6 There is no known association between length of time spent in the water and severity of symptoms.⁵

Most reactions to L majuscula occur from exposure in the water; however, particles that become aerosolized during strong winds or storms can cause seaweed dermatitis on the face. Inhalation of L majuscula may lead to mucous membrane ulceration and pulmonary edema.^1,5,6 Noncutaneous manifestations of seaweed dermatitis include headache, fatigue, and swelling of the eyes, nose, and throat (Figures 1 and 2).^1,5

Prevention and Management

To prevent seaweed dermatitis, avoid swimming in ocean water during L majuscula blooms,¹⁰ which frequently occur following the summer solstices in the Northern and Southern hemispheres.⁵ The National Centers for Coastal Ocean Science Harmful Algae Bloom Monitoring System provides real-time access to algae bloom locations.¹¹ Although this monitoring system is not specific to L majuscula, it may be helpful in determining where potential blooms are. Wearing protective clothing such as coveralls may benefit individuals who enter the water during blooms, but it does not guarantee protection.¹⁰

Currently, there is no treatment for seaweed dermatitis, but symptom management may reduce discomfort and pain. Washing affected skin with soap and water within an hour of exposure may help reduce the severity of seaweed dermatitis, though studies have shown mixed results.^6,7 Application of cool compresses and soothing ointments (eg, calamine) provide symptomatic relief and promote healing.⁷ The dermatitis typically self-resolves within 1 week.

Folliculitis decalvans (FD) is classified as a rare primary neutrophilic cicatricial alopecia occurring predominantly in middle-aged adults. Although the true etiology is still unknown, the pathogenesis behind the inflammatory follicular lesions stems from possible Staphylococcus aureus infection and an impaired host immune system in response to released superantigens. ¹ The clinical severity of this inflammatory scalp disorder can range from mild to severe and debilitating. Multiple treatment regimens have been developed with the goal of maintaining full remission. We provide a summary of tumor necrosis factor (TNF) inhibitors, Janus kinase (JAK) inhibitors, phosphodiesterase 4 (PDE4) inhibitors, and monoclonal antibodies being utilized for patients with therapy-recalcitrant FD.

Methods

We conducted a PubMed, Medline, and Google Scholar search for the terms refractory FD, recalcitrant FD, or therapy-resistant FD to identify articles published in English from 1998 to 2022. Articles that reported recalcitrant cases and subsequent therapy with TNF inhibitors, JAK inhibitors, PDE4 inhibitors, and monoclonal antibodies were included. Articles were excluded if recalcitrant cases were not clearly defined. Remission was defined as no recurrence in lesions or pustules or as a reduction in the inflammatory process with stabilization upon continuation or discontinuation of the therapy regimen. Two reviewers (T.F. and K.U.) independently searched for and screened each report.

Results 

Treatment of recalcitrant FD with biologics or small molecule inhibitors was discussed in 9 studies with a combined total of 35 patients.^2-10 The treatment regimens included TNF inhibitors, JAK inhibitors, PDE4 inhibitors, and monoclonal antibodies (Table).

The TNF inhibitors were utilized in 6 reports with a combined total of 29 patients. Treatments included adalimumab or biosimilar adalimumab (27/29 patients), infliximab (1/29 patients), and certolizumab pegol (1/29 patients). Remission was reported in 26 of 29 cases. There were 2 nonresponders to adalimumab and marked improvement with certolizumab pegol without complete resolution. The use of the JAK inhibitor baricitinib in 4 patients resulted in remission. In all 4 patients, baricitinib was used with concurrent treatments, and remission was achieved in an average of 2.25 months. The use of a PDE4 inhibitor, apremilast, was reported in 1 case; remission was achieved in 3 weeks. Secukinumab, a monoclonal antibody that targets IL-17, was utilized in 1 patient. Marked improvement was seen after 2 months, with complete remission in 7 months. 

Comment

Traditional treatment regimens for FD most often include a combination of topical and oral antibiotics; isotretinoin; and oral, topical, or intralesional corticosteroids. In the past, interventions typically were suppressive as opposed to curative; however, recent treatment advancements have shown promise in achieving lasting remission.

Most reports targeting treatment-resistant FD involved the use of TNF inhibitors, including adalimumab, biosimilar adalimumab, infliximab, and certolizumab pegol.  Adalimumab was the most frequently used TNF inhibitor, with 24 of 26 treated patients achieving remission. Adalimumab may have been used the most in the treatment of FD because TNF is pronounced in other neutrophilic dermatoses that have been successfully treated with TNF inhibitors. It has been reported that adalimumab needs to be continued, as stoppage or interruption led to relapse.³

Although there are few reports of the use of JAK inhibitors, PDE4 inhibitors, and monoclonal antibodies for FD, these treatment modalities show promise, as their use led to marked improvement or lasting remission with ongoing treatment. The use of the PDE4 inhibitor apremilast displayed the most rapid improvement of any of the reviewed treatments, with remission achieved in just 3 weeks.⁹ The rapid success of apremilast may be attributed to the inhibitory effect on neutrophils.

Miguel-Gómez et al¹¹ provided a therapeutic protocol for FD based on the severity of disease (N=60). The protocol included rifampicin plus clindamycin for the treatment of severe disease, as 90.5% (19/21) of resistant cases showed clinical response, with remission of 5 months’ duration. Although this may be acceptable for some patients, others may require an alternative approach. Tietze et al¹² showed that rifampicin and clindamycin had the lowest success rate for long-term remission, with 8 of 10 patients relapsing within 2 to 4 months. In addition, the emergence of antimicrobial resistance remains a major concern in the treatment of FD. Upon the review of the most recent reports of successful treatment of ­therapy-resistant FD, biologics and small molecule inhibitors have shown remission extending through a 12-month follow-up period. We suggest considering the addition of biologics and small molecule inhibitors to the treatment protocol for severe or resistant disease.

Limitations—In the articles reviewed, the definition of remission was inconsistent among authors—some characterized it as no recurrence in lesions or pustules and some as a reduction in the inflammatory process. True duration of remission was difficult to assess from case reports, as follow-up periods varied prior to publication. The studies included in this review consisted mainly of small sample sizes owing to the rarity of FD, and consequently, strength of evidence is lacking. Inherent to the nature of systematic reviews, publication bias may have occurred. Lastly, several studies were impacted by difficulty in obtaining optimal treatment due to financial hardship, and regimens were adjusted accordingly.

Conclusion

The relapsing nature of FD leads to frustration and poor quality of life for patients. There is a paucity of data to guide treatment when FD remains recalcitrant to traditional therapy. Therapies such as TNF inhibitors, JAK inhibitors, PDE4 inhibitors, and monoclonal antibodies have shown success in the treatment of this often ­difficult-to-treat disease. Small sample sizes in reports discussing treatment for resistant cases as well as conflicting results make it challenging to draw conclusions about treatment efficacy. Larger studies are needed to understand the long-term outcomes of treatment options. Regardless, disease severity, patient history, patient preferences, and treatment goals can guide the selection of therapeutic options.

Folliculitis decalvans (FD) is classified as a rare primary neutrophilic cicatricial alopecia occurring predominantly in middle-aged adults. Although the true etiology is still unknown, the pathogenesis behind the inflammatory follicular lesions stems from possible Staphylococcus aureus infection and an impaired host immune system in response to released superantigens. ¹ The clinical severity of this inflammatory scalp disorder can range from mild to severe and debilitating. Multiple treatment regimens have been developed with the goal of maintaining full remission. We provide a summary of tumor necrosis factor (TNF) inhibitors, Janus kinase (JAK) inhibitors, phosphodiesterase 4 (PDE4) inhibitors, and monoclonal antibodies being utilized for patients with therapy-recalcitrant FD.

Methods

We conducted a PubMed, Medline, and Google Scholar search for the terms refractory FD, recalcitrant FD, or therapy-resistant FD to identify articles published in English from 1998 to 2022. Articles that reported recalcitrant cases and subsequent therapy with TNF inhibitors, JAK inhibitors, PDE4 inhibitors, and monoclonal antibodies were included. Articles were excluded if recalcitrant cases were not clearly defined. Remission was defined as no recurrence in lesions or pustules or as a reduction in the inflammatory process with stabilization upon continuation or discontinuation of the therapy regimen. Two reviewers (T.F. and K.U.) independently searched for and screened each report.

Results 

Treatment of recalcitrant FD with biologics or small molecule inhibitors was discussed in 9 studies with a combined total of 35 patients.^2-10 The treatment regimens included TNF inhibitors, JAK inhibitors, PDE4 inhibitors, and monoclonal antibodies (Table).

The TNF inhibitors were utilized in 6 reports with a combined total of 29 patients. Treatments included adalimumab or biosimilar adalimumab (27/29 patients), infliximab (1/29 patients), and certolizumab pegol (1/29 patients). Remission was reported in 26 of 29 cases. There were 2 nonresponders to adalimumab and marked improvement with certolizumab pegol without complete resolution. The use of the JAK inhibitor baricitinib in 4 patients resulted in remission. In all 4 patients, baricitinib was used with concurrent treatments, and remission was achieved in an average of 2.25 months. The use of a PDE4 inhibitor, apremilast, was reported in 1 case; remission was achieved in 3 weeks. Secukinumab, a monoclonal antibody that targets IL-17, was utilized in 1 patient. Marked improvement was seen after 2 months, with complete remission in 7 months. 

Comment

Traditional treatment regimens for FD most often include a combination of topical and oral antibiotics; isotretinoin; and oral, topical, or intralesional corticosteroids. In the past, interventions typically were suppressive as opposed to curative; however, recent treatment advancements have shown promise in achieving lasting remission.

Most reports targeting treatment-resistant FD involved the use of TNF inhibitors, including adalimumab, biosimilar adalimumab, infliximab, and certolizumab pegol.  Adalimumab was the most frequently used TNF inhibitor, with 24 of 26 treated patients achieving remission. Adalimumab may have been used the most in the treatment of FD because TNF is pronounced in other neutrophilic dermatoses that have been successfully treated with TNF inhibitors. It has been reported that adalimumab needs to be continued, as stoppage or interruption led to relapse.³

Although there are few reports of the use of JAK inhibitors, PDE4 inhibitors, and monoclonal antibodies for FD, these treatment modalities show promise, as their use led to marked improvement or lasting remission with ongoing treatment. The use of the PDE4 inhibitor apremilast displayed the most rapid improvement of any of the reviewed treatments, with remission achieved in just 3 weeks.⁹ The rapid success of apremilast may be attributed to the inhibitory effect on neutrophils.

Miguel-Gómez et al¹¹ provided a therapeutic protocol for FD based on the severity of disease (N=60). The protocol included rifampicin plus clindamycin for the treatment of severe disease, as 90.5% (19/21) of resistant cases showed clinical response, with remission of 5 months’ duration. Although this may be acceptable for some patients, others may require an alternative approach. Tietze et al¹² showed that rifampicin and clindamycin had the lowest success rate for long-term remission, with 8 of 10 patients relapsing within 2 to 4 months. In addition, the emergence of antimicrobial resistance remains a major concern in the treatment of FD. Upon the review of the most recent reports of successful treatment of ­therapy-resistant FD, biologics and small molecule inhibitors have shown remission extending through a 12-month follow-up period. We suggest considering the addition of biologics and small molecule inhibitors to the treatment protocol for severe or resistant disease.

Limitations—In the articles reviewed, the definition of remission was inconsistent among authors—some characterized it as no recurrence in lesions or pustules and some as a reduction in the inflammatory process. True duration of remission was difficult to assess from case reports, as follow-up periods varied prior to publication. The studies included in this review consisted mainly of small sample sizes owing to the rarity of FD, and consequently, strength of evidence is lacking. Inherent to the nature of systematic reviews, publication bias may have occurred. Lastly, several studies were impacted by difficulty in obtaining optimal treatment due to financial hardship, and regimens were adjusted accordingly.

Conclusion

The relapsing nature of FD leads to frustration and poor quality of life for patients. There is a paucity of data to guide treatment when FD remains recalcitrant to traditional therapy. Therapies such as TNF inhibitors, JAK inhibitors, PDE4 inhibitors, and monoclonal antibodies have shown success in the treatment of this often ­difficult-to-treat disease. Small sample sizes in reports discussing treatment for resistant cases as well as conflicting results make it challenging to draw conclusions about treatment efficacy. Larger studies are needed to understand the long-term outcomes of treatment options. Regardless, disease severity, patient history, patient preferences, and treatment goals can guide the selection of therapeutic options.

Folliculitis decalvans (FD) is classified as a rare primary neutrophilic cicatricial alopecia occurring predominantly in middle-aged adults. Although the true etiology is still unknown, the pathogenesis behind the inflammatory follicular lesions stems from possible Staphylococcus aureus infection and an impaired host immune system in response to released superantigens. ¹ The clinical severity of this inflammatory scalp disorder can range from mild to severe and debilitating. Multiple treatment regimens have been developed with the goal of maintaining full remission. We provide a summary of tumor necrosis factor (TNF) inhibitors, Janus kinase (JAK) inhibitors, phosphodiesterase 4 (PDE4) inhibitors, and monoclonal antibodies being utilized for patients with therapy-recalcitrant FD.

Methods

We conducted a PubMed, Medline, and Google Scholar search for the terms refractory FD, recalcitrant FD, or therapy-resistant FD to identify articles published in English from 1998 to 2022. Articles that reported recalcitrant cases and subsequent therapy with TNF inhibitors, JAK inhibitors, PDE4 inhibitors, and monoclonal antibodies were included. Articles were excluded if recalcitrant cases were not clearly defined. Remission was defined as no recurrence in lesions or pustules or as a reduction in the inflammatory process with stabilization upon continuation or discontinuation of the therapy regimen. Two reviewers (T.F. and K.U.) independently searched for and screened each report.

Results 

Treatment of recalcitrant FD with biologics or small molecule inhibitors was discussed in 9 studies with a combined total of 35 patients.^2-10 The treatment regimens included TNF inhibitors, JAK inhibitors, PDE4 inhibitors, and monoclonal antibodies (Table).

The TNF inhibitors were utilized in 6 reports with a combined total of 29 patients. Treatments included adalimumab or biosimilar adalimumab (27/29 patients), infliximab (1/29 patients), and certolizumab pegol (1/29 patients). Remission was reported in 26 of 29 cases. There were 2 nonresponders to adalimumab and marked improvement with certolizumab pegol without complete resolution. The use of the JAK inhibitor baricitinib in 4 patients resulted in remission. In all 4 patients, baricitinib was used with concurrent treatments, and remission was achieved in an average of 2.25 months. The use of a PDE4 inhibitor, apremilast, was reported in 1 case; remission was achieved in 3 weeks. Secukinumab, a monoclonal antibody that targets IL-17, was utilized in 1 patient. Marked improvement was seen after 2 months, with complete remission in 7 months. 

Comment

Traditional treatment regimens for FD most often include a combination of topical and oral antibiotics; isotretinoin; and oral, topical, or intralesional corticosteroids. In the past, interventions typically were suppressive as opposed to curative; however, recent treatment advancements have shown promise in achieving lasting remission.

Most reports targeting treatment-resistant FD involved the use of TNF inhibitors, including adalimumab, biosimilar adalimumab, infliximab, and certolizumab pegol.  Adalimumab was the most frequently used TNF inhibitor, with 24 of 26 treated patients achieving remission. Adalimumab may have been used the most in the treatment of FD because TNF is pronounced in other neutrophilic dermatoses that have been successfully treated with TNF inhibitors. It has been reported that adalimumab needs to be continued, as stoppage or interruption led to relapse.³

Although there are few reports of the use of JAK inhibitors, PDE4 inhibitors, and monoclonal antibodies for FD, these treatment modalities show promise, as their use led to marked improvement or lasting remission with ongoing treatment. The use of the PDE4 inhibitor apremilast displayed the most rapid improvement of any of the reviewed treatments, with remission achieved in just 3 weeks.⁹ The rapid success of apremilast may be attributed to the inhibitory effect on neutrophils.

Miguel-Gómez et al¹¹ provided a therapeutic protocol for FD based on the severity of disease (N=60). The protocol included rifampicin plus clindamycin for the treatment of severe disease, as 90.5% (19/21) of resistant cases showed clinical response, with remission of 5 months’ duration. Although this may be acceptable for some patients, others may require an alternative approach. Tietze et al¹² showed that rifampicin and clindamycin had the lowest success rate for long-term remission, with 8 of 10 patients relapsing within 2 to 4 months. In addition, the emergence of antimicrobial resistance remains a major concern in the treatment of FD. Upon the review of the most recent reports of successful treatment of ­therapy-resistant FD, biologics and small molecule inhibitors have shown remission extending through a 12-month follow-up period. We suggest considering the addition of biologics and small molecule inhibitors to the treatment protocol for severe or resistant disease.

Limitations—In the articles reviewed, the definition of remission was inconsistent among authors—some characterized it as no recurrence in lesions or pustules and some as a reduction in the inflammatory process. True duration of remission was difficult to assess from case reports, as follow-up periods varied prior to publication. The studies included in this review consisted mainly of small sample sizes owing to the rarity of FD, and consequently, strength of evidence is lacking. Inherent to the nature of systematic reviews, publication bias may have occurred. Lastly, several studies were impacted by difficulty in obtaining optimal treatment due to financial hardship, and regimens were adjusted accordingly.

Conclusion

The relapsing nature of FD leads to frustration and poor quality of life for patients. There is a paucity of data to guide treatment when FD remains recalcitrant to traditional therapy. Therapies such as TNF inhibitors, JAK inhibitors, PDE4 inhibitors, and monoclonal antibodies have shown success in the treatment of this often ­difficult-to-treat disease. Small sample sizes in reports discussing treatment for resistant cases as well as conflicting results make it challenging to draw conclusions about treatment efficacy. Larger studies are needed to understand the long-term outcomes of treatment options. Regardless, disease severity, patient history, patient preferences, and treatment goals can guide the selection of therapeutic options.

Attendees of the 2024 American Academy of Dermatology annual meeting in San Diego, California, were eager to delve into the latest trends and advancements in dermatology and dermatologic surgery. This article provides a few key takeaways for residents from a range of engaging sessions, with an emphasis on procedural dermatology and physician health and well-being.

Practical Applications of Surgical Enhancements

In an informative session dedicated to dermatologic surgeons and their patients, “Simple Tricks and Practical Tips to Optimize the Surgical Experience for You and Your Patients,” attendees learned practical tips for enhancing the surgical experience. The discussion spanned various aspects of surgery, from managing preoperative anxiety with anxiolytics such as midazolam to the strategic use of skin hooks for delicate tissue manipulation. Midazolam is fast acting and its use is tailored to patient factors such as weight, hepatic function, and prior use. An innovative anxiety management algorithm combining “talkesethesia” with other methods such as anodynes and benzodiazepines underscored the importance of a calm patient in successful surgical outcomes. Talkesthesia involves engaging patients in soothing and distracting conversation throughout the procedure. This technique can include discussing nonmedical topics of interest with the patient—such as their hobbies, family, or favorite movies—to divert their attention from the surgical process and reduce anxiety. By creating a friendly and reassuring atmosphere, talkesthesia helps to establish trust between the patient and the medical team, ultimately contributing to a more relaxed and cooperative patient.¹

The utility of skin hooks also was discussed, with an emphasis on their role in ensuring gentle tissue handling. The modified buried vertical mattress technique was discussed for its added benefits in wound approximation and strength. Emphasis was placed on the importance of maintaining a clear surgical field by electrocautery to ensure optimal visibility.

Focusing on the treatment of skin cancer, curettage alone was touted as a viable alternative to electrodesiccation and curettage, especially in reducing postoperative hypopigmentation while maintaining high cure rates. This method was shown to be effective in treating basal cell carcinoma and well-differentiated squamous cell carcinoma.^2,3

Suturing techniques such as pulley, purse-string, and buried sutures offer efficiencies in time, cost, and improved healing in high-tension areas. These methods can contribute to postsurgical aesthetic and functional outcomes. Additionally, Dr. Desiree Ratner shared her tips for painless local anesthesia techniques, emphasizing the importance of patient comfort through methods such as slow injection and buffering of lidocaine. The next time you give a local anesthetic, try this technique to minimize pain: using a 30-gauge needle, hold the syringe with the bevel up, insert only the bevel into the skin (needle tip goes into the papillary dermis), and numb superficially around the periphery using as little volume as possible. Keep pressure slow and steady without moving the needle, then insert the needle only in previously anesthetized areas, numbing deeply only after the entire periphery has been anesthetized.

The session concluded with the recommendation to provide patients with a goody bag containing postoperative supplies. This thoughtful gesture not only enhances patient satisfaction but also addresses the practical aspect of postsurgery care, offering an inexpensive yet impactful way to ensure patients have the necessary supplies for their recovery.

Take-Home Point—This session distilled essential surgical enhancements into practical applications, emphasizing the importance of anxiety management, delicate tissue handling, innovative suturing techniques, and thoughtful patient care postsurgery. The overarching message highlighted the synergy between technical skill and patient-centric approaches in optimizing surgical outcomes, underscoring the significance of attention to detail in every aspect of patient care, from preoperative preparation to postoperative recovery.

Optimizing Safety and Ergonomics in Surgical Practices

Understanding the dynamics of surgical plume is crucial to safety in the operating room. The carcinogenic risk associated with surgical smoke is not trivial: exposure to the plume generated by monopolar electrocautery in a single day can be equivalent to smoking approximately 30 cigarettes, and a surgeon’s lifetime cancer risk from polycyclic aromatic hydrocarbons exposure is alarmingly high.⁴ To mitigate these risks, several strategies were recommended, including using lower-energy settings, choosing indirect or bipolar cautery, and ensuring efficient room ventilation with HEPA (high-efficiency particulate absorbing) filters to turn over air frequently. Additionally, employing the use of smoke evacuators and suction devices with proper filters can reduce particulate matter in the operating room.

The importance of the surgeon’s posture during procedures also was emphasized for ergonomic benefits and to minimize fatigue. Maintaining a neutral stance with the core and glutes engaged, standing on the balls of the feet, and aligning the table height to keep the hands at the lower chest level were recommended; this not only helps in reducing strain but also in maintaining precision during surgical tasks.

The surgeons on the panel also highlighted the novel use of hydrocolloid dressings with tattoo lasers, electrodesiccation and curettage for treating rhinophyma, and purse-string closure for chest defects as evolving practices to enhance outcomes and safety.

The session offered valuable insights into suturing techniques, advocating for the use of deep sutures—­ideally Monocryl (Ethicon US, LLC)—for superficial closures and fast-absorbing gut sutures for patients who are not expected to return for suture removal. Keith LeBlanc Jr, MD, shared one of his favorite tricks for suturing fragile, sun-damaged skin on the forearm in elderly patients: apply adhesive skin closures aligned parallel to the suture line, then suture through them for extra support. This can help ensure a more secure closure.

In situations when no deep sutures are required, such as on the hair-bearing scalp, large bites through the galea using monofilament nonabsorbable sutures for up to 14 days or staples can offer favorable closures and enhanced hemostasis. Tranexamic acid has emerged as a versatile hemostatic agent—available in multiple forms ranging from direct injection to topical applications—and is cost-effective, enhancing its accessibility in various surgical settings.

A high proportion of patients are taken aback by the length of the scar following removal of what they perceive as a small skin cancer. Leslie Storey, MD, cleverly recommended using the back of a glove to mark surgical ­planning, giving the patient a visual guide for anticipating the size of the excision. This is a simple yet effective approach to enhance patient understanding and informed consent. 

Lastly, the notion that “patients remember you if you don’t cause them pain” resonated deeply, underlining the importance of gentle techniques such as pinching the suture rather than pushing the wound edges together and asking assistants to maintain tension without obstructing the field. In the words of Seth Matarasso, MD: “If you pain ‘em, you won’t retain ‘em!”

Take-Home Point—The take-home message from the session was a comprehensive approach to surgical excellence that aligns technical proficiency with a strong emphasis on safety, patient comfort, and operative efficiency. Surgeons were advised to adopt practices that reduce the risks associated with surgical plume, maintain ergonomic discipline, and apply innovative suturing techniques to enhance patient outcomes. Compassionate patient care, innovative use of materials and methods, and a commitment to continual learning and adaptation of new evidence-based practices are paramount for the modern surgeon.

Approaches for Facial Reconstruction

The intricacies of multisubunit facial reconstruction were explored in a session that blended the pursuit of aesthetic harmony with functional restoration, “Simplifying the Complex: Reconstructing Multisubunit Defects.” The session began with an introduction to flap design principles, emphasizing the importance of thorough defect analysis and the strategic design of flaps. A key objective within this framework is the integration of the flap within existing cosmetic subunits to avoid unwanted effects such as unintended eyebrow elevation.

The concept of tissue reservoirs was discussed,focusing on regions such as the glabella as potential sources for skin recruitment. This then transitioned into a nuanced discussion on incision planning, underscoring the significance of aligning incision lines with relaxed skin tension lines to enhance healing and minimize scarring.

The topic of delayed reconstruction also was introduced as a deliberate tactic for high-risk tumor management. This approach allows for an in-depth pathologic examination and provides patients with more time for psychological adjustment, which may be particularly important for those with complex medical histories or those who require staged surgical interventions.

In a thorough examination of flap design techniques, the session highlighted the bilobed transposition flap as a versatile choice for nasal reconstruction, particularly apt for the distal third of the nose due to its design that harnesses skin from nonadjacent areas. Accompanying this was an exploration of Zitelli modifications, which enhance the bilobed flap by reducing issues such as pincushioning through a moderated rotation angle and the strategic incorporation of a Burow triangle.

Finally, the interpolated paranasal flap was discussed. This technique is designed to reduce the risk for cheek asymmetry and is suitable for patients with generous donor sites; however, this method requires diligent evaluation to avoid complications such as external nasal valve collapse.

Take-Home Point—This session highlighted approaches in facial reconstruction, emphasizing the necessity of strategic flap design and meticulous incision planning to maintain aesthetic harmony and functional integrity.

Strategies for Improving Physician Well-Being

Evidence-based recommendations to support physicians’ well-being are crucial as the health care system becomes increasingly demanding. Instead of focusing on aspects of the health care system that frequently are outside of physicians’ control, the session “A Realistic and Evidence-Based Roadmap for Thriving in Life and Career” discussed many practical, self-empowering tools and strategies to lead a happier and healthier life—both personally and professionally.

The speakers cautioned against the concept of an “unlimited ceiling” for achieving a certain goal, where an unlimited amount of time and energy is allowed to be dedicated to a given task over a period of time. They highlighted the potential consequences of this approach, such as stress, dissatisfaction, and ultimately burnout. The speakers explored the concept of well-being as a continuous journey rather than a destination, emphasizing that it is not the opposite of burnout. To promote well-being, the speakers advocated for utilizing concepts rooted in positive psychology to empower the individual rather than longing for a different environment. They hypothesized that changing one’s life can be accomplished by changing one’s mind, independent of the environment.

The roadmap for physician well-being, as presented by clinical psychologist Amy MacDonald, PsyD, commenced with urging the audience to introspect on situations and experiences, categorizing them into “feel good” and “feel bad” buckets. For every feel-good event, Dr. MacDonald proposed 5 mental exercises for optimized well-being: (1) control/increase: evaluate whether one can control or increase the frequency of the event; (2) consider: reflect on why this event feels good and explore other aspects to gain any additional joy from the event; (3) share: recognize that some feel goods are more joyous when shared; (4) value: connect the feel-good experiences with personal core values, as research shows value affirmations can buffer neuroendocrine and psychological stress responses; and (5) savor: deliberately relish each small or notable feel-good moment.

Similarly, after labeling an event as a feel-bad experience, Dr. MacDonald encouraged the audience to go through mental exercises to strengthen their well-being journey; however, before proceeding, she highlighted the importance of arming ourselves with self-compassion. The 5 mental exercises to address feel bads include (1) solve: assess whether we have control over the situation and attempt to make changes if possible; (2) reframe: explore new perspectives and assess assumptions without minimizing the situation; (3) connect: embrace the positive impact of safe human connections on our stress response; (4) reflect: search curiously using a compassionate lens for any existing patterns of reactions; and (5) accept and pivot: allow thoughts and feelings to exist and pivot to values-based engagement without waiting for the environment to change. Consistently seeking and appreciating feel goods while addressing rather than suppressing the feel bads can lead to joyful satisfaction and overall well-being.

Additional pearls for optimizing physician well-being included accurately labeling emotions rather than lumping them into an overarching theme (eg, stressed), avoiding comparisons with others, choosing courage over comfort, celebrating vulnerability, and embracing the ability to say no to prioritize engagements aligned with one’s purpose and values. Additional resources were shared for further reading, including Emotional Agility by Susan David, Daring Greatly and Rising Strong by Brené Brown, and Self-Compassion by Kristin Neff.

Take-Home Point—This lecture highlighted key strategies for physicians to improve their well-being, emphasizing self-empowerment and practical tools over external circumstances. It distinguished between productive and destructive influences on satisfaction, and emphasized decision-making aligned with personal values. The concept of well-being as a journey, not a destination, was central, encouraging positive psychology and self-reflection to enhance fulfillment. By focusing on amplifying feel-good experiences and addressing feel-bad experiences with resilience, the lecture advocated for internal over external change, offering a pathway to a balanced and satisfying professional and personal life for physicians.

Final Thoughts

The recent American Academy of Dermatology meeting offered valuable insights and practical pearls to enhance surgical practices and promote physician well-being, in addition to a wide range of topics beyond what is mentioned in this article. From optimizing surgical techniques to prioritizing patient care and safety, the sessions underscored the importance of continuous learning and adaptation in the ever-evolving field of dermatology. As we reflect on the lessons learned and the camaraderie shared during this gathering, let us carry forward these teachings to improve patient outcomes, foster innovation, and cultivate resilience in our pursuit of excellence. Together, we can continue to push the boundaries of dermatologic care while nurturing our own well-being and that of our colleagues, ensuring a brighter future for both patients and practitioners alike.



Acknowledgments—Sultan H. Qiblawi, MD, MBA; Eva Shelton, MD; and Christy T. Behnam, MD (all from Madison, Wisconsin), shared their insights and key takeaways from American Academy of Dermatology lecturers, which enriched the content of this article.

Attendees of the 2024 American Academy of Dermatology annual meeting in San Diego, California, were eager to delve into the latest trends and advancements in dermatology and dermatologic surgery. This article provides a few key takeaways for residents from a range of engaging sessions, with an emphasis on procedural dermatology and physician health and well-being.

Practical Applications of Surgical Enhancements

In an informative session dedicated to dermatologic surgeons and their patients, “Simple Tricks and Practical Tips to Optimize the Surgical Experience for You and Your Patients,” attendees learned practical tips for enhancing the surgical experience. The discussion spanned various aspects of surgery, from managing preoperative anxiety with anxiolytics such as midazolam to the strategic use of skin hooks for delicate tissue manipulation. Midazolam is fast acting and its use is tailored to patient factors such as weight, hepatic function, and prior use. An innovative anxiety management algorithm combining “talkesethesia” with other methods such as anodynes and benzodiazepines underscored the importance of a calm patient in successful surgical outcomes. Talkesthesia involves engaging patients in soothing and distracting conversation throughout the procedure. This technique can include discussing nonmedical topics of interest with the patient—such as their hobbies, family, or favorite movies—to divert their attention from the surgical process and reduce anxiety. By creating a friendly and reassuring atmosphere, talkesthesia helps to establish trust between the patient and the medical team, ultimately contributing to a more relaxed and cooperative patient.¹

The utility of skin hooks also was discussed, with an emphasis on their role in ensuring gentle tissue handling. The modified buried vertical mattress technique was discussed for its added benefits in wound approximation and strength. Emphasis was placed on the importance of maintaining a clear surgical field by electrocautery to ensure optimal visibility.

Focusing on the treatment of skin cancer, curettage alone was touted as a viable alternative to electrodesiccation and curettage, especially in reducing postoperative hypopigmentation while maintaining high cure rates. This method was shown to be effective in treating basal cell carcinoma and well-differentiated squamous cell carcinoma.^2,3

Suturing techniques such as pulley, purse-string, and buried sutures offer efficiencies in time, cost, and improved healing in high-tension areas. These methods can contribute to postsurgical aesthetic and functional outcomes. Additionally, Dr. Desiree Ratner shared her tips for painless local anesthesia techniques, emphasizing the importance of patient comfort through methods such as slow injection and buffering of lidocaine. The next time you give a local anesthetic, try this technique to minimize pain: using a 30-gauge needle, hold the syringe with the bevel up, insert only the bevel into the skin (needle tip goes into the papillary dermis), and numb superficially around the periphery using as little volume as possible. Keep pressure slow and steady without moving the needle, then insert the needle only in previously anesthetized areas, numbing deeply only after the entire periphery has been anesthetized.

The session concluded with the recommendation to provide patients with a goody bag containing postoperative supplies. This thoughtful gesture not only enhances patient satisfaction but also addresses the practical aspect of postsurgery care, offering an inexpensive yet impactful way to ensure patients have the necessary supplies for their recovery.

Take-Home Point—This session distilled essential surgical enhancements into practical applications, emphasizing the importance of anxiety management, delicate tissue handling, innovative suturing techniques, and thoughtful patient care postsurgery. The overarching message highlighted the synergy between technical skill and patient-centric approaches in optimizing surgical outcomes, underscoring the significance of attention to detail in every aspect of patient care, from preoperative preparation to postoperative recovery.

Optimizing Safety and Ergonomics in Surgical Practices

Understanding the dynamics of surgical plume is crucial to safety in the operating room. The carcinogenic risk associated with surgical smoke is not trivial: exposure to the plume generated by monopolar electrocautery in a single day can be equivalent to smoking approximately 30 cigarettes, and a surgeon’s lifetime cancer risk from polycyclic aromatic hydrocarbons exposure is alarmingly high.⁴ To mitigate these risks, several strategies were recommended, including using lower-energy settings, choosing indirect or bipolar cautery, and ensuring efficient room ventilation with HEPA (high-efficiency particulate absorbing) filters to turn over air frequently. Additionally, employing the use of smoke evacuators and suction devices with proper filters can reduce particulate matter in the operating room.

The importance of the surgeon’s posture during procedures also was emphasized for ergonomic benefits and to minimize fatigue. Maintaining a neutral stance with the core and glutes engaged, standing on the balls of the feet, and aligning the table height to keep the hands at the lower chest level were recommended; this not only helps in reducing strain but also in maintaining precision during surgical tasks.

The surgeons on the panel also highlighted the novel use of hydrocolloid dressings with tattoo lasers, electrodesiccation and curettage for treating rhinophyma, and purse-string closure for chest defects as evolving practices to enhance outcomes and safety.

The session offered valuable insights into suturing techniques, advocating for the use of deep sutures—­ideally Monocryl (Ethicon US, LLC)—for superficial closures and fast-absorbing gut sutures for patients who are not expected to return for suture removal. Keith LeBlanc Jr, MD, shared one of his favorite tricks for suturing fragile, sun-damaged skin on the forearm in elderly patients: apply adhesive skin closures aligned parallel to the suture line, then suture through them for extra support. This can help ensure a more secure closure.

In situations when no deep sutures are required, such as on the hair-bearing scalp, large bites through the galea using monofilament nonabsorbable sutures for up to 14 days or staples can offer favorable closures and enhanced hemostasis. Tranexamic acid has emerged as a versatile hemostatic agent—available in multiple forms ranging from direct injection to topical applications—and is cost-effective, enhancing its accessibility in various surgical settings.

A high proportion of patients are taken aback by the length of the scar following removal of what they perceive as a small skin cancer. Leslie Storey, MD, cleverly recommended using the back of a glove to mark surgical ­planning, giving the patient a visual guide for anticipating the size of the excision. This is a simple yet effective approach to enhance patient understanding and informed consent. 

Lastly, the notion that “patients remember you if you don’t cause them pain” resonated deeply, underlining the importance of gentle techniques such as pinching the suture rather than pushing the wound edges together and asking assistants to maintain tension without obstructing the field. In the words of Seth Matarasso, MD: “If you pain ‘em, you won’t retain ‘em!”

Take-Home Point—The take-home message from the session was a comprehensive approach to surgical excellence that aligns technical proficiency with a strong emphasis on safety, patient comfort, and operative efficiency. Surgeons were advised to adopt practices that reduce the risks associated with surgical plume, maintain ergonomic discipline, and apply innovative suturing techniques to enhance patient outcomes. Compassionate patient care, innovative use of materials and methods, and a commitment to continual learning and adaptation of new evidence-based practices are paramount for the modern surgeon.

Approaches for Facial Reconstruction

The intricacies of multisubunit facial reconstruction were explored in a session that blended the pursuit of aesthetic harmony with functional restoration, “Simplifying the Complex: Reconstructing Multisubunit Defects.” The session began with an introduction to flap design principles, emphasizing the importance of thorough defect analysis and the strategic design of flaps. A key objective within this framework is the integration of the flap within existing cosmetic subunits to avoid unwanted effects such as unintended eyebrow elevation.

The concept of tissue reservoirs was discussed,focusing on regions such as the glabella as potential sources for skin recruitment. This then transitioned into a nuanced discussion on incision planning, underscoring the significance of aligning incision lines with relaxed skin tension lines to enhance healing and minimize scarring.

The topic of delayed reconstruction also was introduced as a deliberate tactic for high-risk tumor management. This approach allows for an in-depth pathologic examination and provides patients with more time for psychological adjustment, which may be particularly important for those with complex medical histories or those who require staged surgical interventions.

In a thorough examination of flap design techniques, the session highlighted the bilobed transposition flap as a versatile choice for nasal reconstruction, particularly apt for the distal third of the nose due to its design that harnesses skin from nonadjacent areas. Accompanying this was an exploration of Zitelli modifications, which enhance the bilobed flap by reducing issues such as pincushioning through a moderated rotation angle and the strategic incorporation of a Burow triangle.

Finally, the interpolated paranasal flap was discussed. This technique is designed to reduce the risk for cheek asymmetry and is suitable for patients with generous donor sites; however, this method requires diligent evaluation to avoid complications such as external nasal valve collapse.

Take-Home Point—This session highlighted approaches in facial reconstruction, emphasizing the necessity of strategic flap design and meticulous incision planning to maintain aesthetic harmony and functional integrity.

Strategies for Improving Physician Well-Being

Evidence-based recommendations to support physicians’ well-being are crucial as the health care system becomes increasingly demanding. Instead of focusing on aspects of the health care system that frequently are outside of physicians’ control, the session “A Realistic and Evidence-Based Roadmap for Thriving in Life and Career” discussed many practical, self-empowering tools and strategies to lead a happier and healthier life—both personally and professionally.

The speakers cautioned against the concept of an “unlimited ceiling” for achieving a certain goal, where an unlimited amount of time and energy is allowed to be dedicated to a given task over a period of time. They highlighted the potential consequences of this approach, such as stress, dissatisfaction, and ultimately burnout. The speakers explored the concept of well-being as a continuous journey rather than a destination, emphasizing that it is not the opposite of burnout. To promote well-being, the speakers advocated for utilizing concepts rooted in positive psychology to empower the individual rather than longing for a different environment. They hypothesized that changing one’s life can be accomplished by changing one’s mind, independent of the environment.

The roadmap for physician well-being, as presented by clinical psychologist Amy MacDonald, PsyD, commenced with urging the audience to introspect on situations and experiences, categorizing them into “feel good” and “feel bad” buckets. For every feel-good event, Dr. MacDonald proposed 5 mental exercises for optimized well-being: (1) control/increase: evaluate whether one can control or increase the frequency of the event; (2) consider: reflect on why this event feels good and explore other aspects to gain any additional joy from the event; (3) share: recognize that some feel goods are more joyous when shared; (4) value: connect the feel-good experiences with personal core values, as research shows value affirmations can buffer neuroendocrine and psychological stress responses; and (5) savor: deliberately relish each small or notable feel-good moment.

Similarly, after labeling an event as a feel-bad experience, Dr. MacDonald encouraged the audience to go through mental exercises to strengthen their well-being journey; however, before proceeding, she highlighted the importance of arming ourselves with self-compassion. The 5 mental exercises to address feel bads include (1) solve: assess whether we have control over the situation and attempt to make changes if possible; (2) reframe: explore new perspectives and assess assumptions without minimizing the situation; (3) connect: embrace the positive impact of safe human connections on our stress response; (4) reflect: search curiously using a compassionate lens for any existing patterns of reactions; and (5) accept and pivot: allow thoughts and feelings to exist and pivot to values-based engagement without waiting for the environment to change. Consistently seeking and appreciating feel goods while addressing rather than suppressing the feel bads can lead to joyful satisfaction and overall well-being.

Additional pearls for optimizing physician well-being included accurately labeling emotions rather than lumping them into an overarching theme (eg, stressed), avoiding comparisons with others, choosing courage over comfort, celebrating vulnerability, and embracing the ability to say no to prioritize engagements aligned with one’s purpose and values. Additional resources were shared for further reading, including Emotional Agility by Susan David, Daring Greatly and Rising Strong by Brené Brown, and Self-Compassion by Kristin Neff.

Take-Home Point—This lecture highlighted key strategies for physicians to improve their well-being, emphasizing self-empowerment and practical tools over external circumstances. It distinguished between productive and destructive influences on satisfaction, and emphasized decision-making aligned with personal values. The concept of well-being as a journey, not a destination, was central, encouraging positive psychology and self-reflection to enhance fulfillment. By focusing on amplifying feel-good experiences and addressing feel-bad experiences with resilience, the lecture advocated for internal over external change, offering a pathway to a balanced and satisfying professional and personal life for physicians.

Final Thoughts

The recent American Academy of Dermatology meeting offered valuable insights and practical pearls to enhance surgical practices and promote physician well-being, in addition to a wide range of topics beyond what is mentioned in this article. From optimizing surgical techniques to prioritizing patient care and safety, the sessions underscored the importance of continuous learning and adaptation in the ever-evolving field of dermatology. As we reflect on the lessons learned and the camaraderie shared during this gathering, let us carry forward these teachings to improve patient outcomes, foster innovation, and cultivate resilience in our pursuit of excellence. Together, we can continue to push the boundaries of dermatologic care while nurturing our own well-being and that of our colleagues, ensuring a brighter future for both patients and practitioners alike.



Acknowledgments—Sultan H. Qiblawi, MD, MBA; Eva Shelton, MD; and Christy T. Behnam, MD (all from Madison, Wisconsin), shared their insights and key takeaways from American Academy of Dermatology lecturers, which enriched the content of this article.

Attendees of the 2024 American Academy of Dermatology annual meeting in San Diego, California, were eager to delve into the latest trends and advancements in dermatology and dermatologic surgery. This article provides a few key takeaways for residents from a range of engaging sessions, with an emphasis on procedural dermatology and physician health and well-being.

Practical Applications of Surgical Enhancements

In an informative session dedicated to dermatologic surgeons and their patients, “Simple Tricks and Practical Tips to Optimize the Surgical Experience for You and Your Patients,” attendees learned practical tips for enhancing the surgical experience. The discussion spanned various aspects of surgery, from managing preoperative anxiety with anxiolytics such as midazolam to the strategic use of skin hooks for delicate tissue manipulation. Midazolam is fast acting and its use is tailored to patient factors such as weight, hepatic function, and prior use. An innovative anxiety management algorithm combining “talkesethesia” with other methods such as anodynes and benzodiazepines underscored the importance of a calm patient in successful surgical outcomes. Talkesthesia involves engaging patients in soothing and distracting conversation throughout the procedure. This technique can include discussing nonmedical topics of interest with the patient—such as their hobbies, family, or favorite movies—to divert their attention from the surgical process and reduce anxiety. By creating a friendly and reassuring atmosphere, talkesthesia helps to establish trust between the patient and the medical team, ultimately contributing to a more relaxed and cooperative patient.¹

The utility of skin hooks also was discussed, with an emphasis on their role in ensuring gentle tissue handling. The modified buried vertical mattress technique was discussed for its added benefits in wound approximation and strength. Emphasis was placed on the importance of maintaining a clear surgical field by electrocautery to ensure optimal visibility.

Focusing on the treatment of skin cancer, curettage alone was touted as a viable alternative to electrodesiccation and curettage, especially in reducing postoperative hypopigmentation while maintaining high cure rates. This method was shown to be effective in treating basal cell carcinoma and well-differentiated squamous cell carcinoma.^2,3

Suturing techniques such as pulley, purse-string, and buried sutures offer efficiencies in time, cost, and improved healing in high-tension areas. These methods can contribute to postsurgical aesthetic and functional outcomes. Additionally, Dr. Desiree Ratner shared her tips for painless local anesthesia techniques, emphasizing the importance of patient comfort through methods such as slow injection and buffering of lidocaine. The next time you give a local anesthetic, try this technique to minimize pain: using a 30-gauge needle, hold the syringe with the bevel up, insert only the bevel into the skin (needle tip goes into the papillary dermis), and numb superficially around the periphery using as little volume as possible. Keep pressure slow and steady without moving the needle, then insert the needle only in previously anesthetized areas, numbing deeply only after the entire periphery has been anesthetized.

The session concluded with the recommendation to provide patients with a goody bag containing postoperative supplies. This thoughtful gesture not only enhances patient satisfaction but also addresses the practical aspect of postsurgery care, offering an inexpensive yet impactful way to ensure patients have the necessary supplies for their recovery.

Take-Home Point—This session distilled essential surgical enhancements into practical applications, emphasizing the importance of anxiety management, delicate tissue handling, innovative suturing techniques, and thoughtful patient care postsurgery. The overarching message highlighted the synergy between technical skill and patient-centric approaches in optimizing surgical outcomes, underscoring the significance of attention to detail in every aspect of patient care, from preoperative preparation to postoperative recovery.

Optimizing Safety and Ergonomics in Surgical Practices

Understanding the dynamics of surgical plume is crucial to safety in the operating room. The carcinogenic risk associated with surgical smoke is not trivial: exposure to the plume generated by monopolar electrocautery in a single day can be equivalent to smoking approximately 30 cigarettes, and a surgeon’s lifetime cancer risk from polycyclic aromatic hydrocarbons exposure is alarmingly high.⁴ To mitigate these risks, several strategies were recommended, including using lower-energy settings, choosing indirect or bipolar cautery, and ensuring efficient room ventilation with HEPA (high-efficiency particulate absorbing) filters to turn over air frequently. Additionally, employing the use of smoke evacuators and suction devices with proper filters can reduce particulate matter in the operating room.

The importance of the surgeon’s posture during procedures also was emphasized for ergonomic benefits and to minimize fatigue. Maintaining a neutral stance with the core and glutes engaged, standing on the balls of the feet, and aligning the table height to keep the hands at the lower chest level were recommended; this not only helps in reducing strain but also in maintaining precision during surgical tasks.

The surgeons on the panel also highlighted the novel use of hydrocolloid dressings with tattoo lasers, electrodesiccation and curettage for treating rhinophyma, and purse-string closure for chest defects as evolving practices to enhance outcomes and safety.

The session offered valuable insights into suturing techniques, advocating for the use of deep sutures—­ideally Monocryl (Ethicon US, LLC)—for superficial closures and fast-absorbing gut sutures for patients who are not expected to return for suture removal. Keith LeBlanc Jr, MD, shared one of his favorite tricks for suturing fragile, sun-damaged skin on the forearm in elderly patients: apply adhesive skin closures aligned parallel to the suture line, then suture through them for extra support. This can help ensure a more secure closure.

In situations when no deep sutures are required, such as on the hair-bearing scalp, large bites through the galea using monofilament nonabsorbable sutures for up to 14 days or staples can offer favorable closures and enhanced hemostasis. Tranexamic acid has emerged as a versatile hemostatic agent—available in multiple forms ranging from direct injection to topical applications—and is cost-effective, enhancing its accessibility in various surgical settings.

A high proportion of patients are taken aback by the length of the scar following removal of what they perceive as a small skin cancer. Leslie Storey, MD, cleverly recommended using the back of a glove to mark surgical ­planning, giving the patient a visual guide for anticipating the size of the excision. This is a simple yet effective approach to enhance patient understanding and informed consent. 

Lastly, the notion that “patients remember you if you don’t cause them pain” resonated deeply, underlining the importance of gentle techniques such as pinching the suture rather than pushing the wound edges together and asking assistants to maintain tension without obstructing the field. In the words of Seth Matarasso, MD: “If you pain ‘em, you won’t retain ‘em!”

Take-Home Point—The take-home message from the session was a comprehensive approach to surgical excellence that aligns technical proficiency with a strong emphasis on safety, patient comfort, and operative efficiency. Surgeons were advised to adopt practices that reduce the risks associated with surgical plume, maintain ergonomic discipline, and apply innovative suturing techniques to enhance patient outcomes. Compassionate patient care, innovative use of materials and methods, and a commitment to continual learning and adaptation of new evidence-based practices are paramount for the modern surgeon.

Approaches for Facial Reconstruction

The intricacies of multisubunit facial reconstruction were explored in a session that blended the pursuit of aesthetic harmony with functional restoration, “Simplifying the Complex: Reconstructing Multisubunit Defects.” The session began with an introduction to flap design principles, emphasizing the importance of thorough defect analysis and the strategic design of flaps. A key objective within this framework is the integration of the flap within existing cosmetic subunits to avoid unwanted effects such as unintended eyebrow elevation.

The concept of tissue reservoirs was discussed,focusing on regions such as the glabella as potential sources for skin recruitment. This then transitioned into a nuanced discussion on incision planning, underscoring the significance of aligning incision lines with relaxed skin tension lines to enhance healing and minimize scarring.

The topic of delayed reconstruction also was introduced as a deliberate tactic for high-risk tumor management. This approach allows for an in-depth pathologic examination and provides patients with more time for psychological adjustment, which may be particularly important for those with complex medical histories or those who require staged surgical interventions.

In a thorough examination of flap design techniques, the session highlighted the bilobed transposition flap as a versatile choice for nasal reconstruction, particularly apt for the distal third of the nose due to its design that harnesses skin from nonadjacent areas. Accompanying this was an exploration of Zitelli modifications, which enhance the bilobed flap by reducing issues such as pincushioning through a moderated rotation angle and the strategic incorporation of a Burow triangle.

Finally, the interpolated paranasal flap was discussed. This technique is designed to reduce the risk for cheek asymmetry and is suitable for patients with generous donor sites; however, this method requires diligent evaluation to avoid complications such as external nasal valve collapse.

Take-Home Point—This session highlighted approaches in facial reconstruction, emphasizing the necessity of strategic flap design and meticulous incision planning to maintain aesthetic harmony and functional integrity.

Strategies for Improving Physician Well-Being

Evidence-based recommendations to support physicians’ well-being are crucial as the health care system becomes increasingly demanding. Instead of focusing on aspects of the health care system that frequently are outside of physicians’ control, the session “A Realistic and Evidence-Based Roadmap for Thriving in Life and Career” discussed many practical, self-empowering tools and strategies to lead a happier and healthier life—both personally and professionally.

The speakers cautioned against the concept of an “unlimited ceiling” for achieving a certain goal, where an unlimited amount of time and energy is allowed to be dedicated to a given task over a period of time. They highlighted the potential consequences of this approach, such as stress, dissatisfaction, and ultimately burnout. The speakers explored the concept of well-being as a continuous journey rather than a destination, emphasizing that it is not the opposite of burnout. To promote well-being, the speakers advocated for utilizing concepts rooted in positive psychology to empower the individual rather than longing for a different environment. They hypothesized that changing one’s life can be accomplished by changing one’s mind, independent of the environment.

The roadmap for physician well-being, as presented by clinical psychologist Amy MacDonald, PsyD, commenced with urging the audience to introspect on situations and experiences, categorizing them into “feel good” and “feel bad” buckets. For every feel-good event, Dr. MacDonald proposed 5 mental exercises for optimized well-being: (1) control/increase: evaluate whether one can control or increase the frequency of the event; (2) consider: reflect on why this event feels good and explore other aspects to gain any additional joy from the event; (3) share: recognize that some feel goods are more joyous when shared; (4) value: connect the feel-good experiences with personal core values, as research shows value affirmations can buffer neuroendocrine and psychological stress responses; and (5) savor: deliberately relish each small or notable feel-good moment.

Similarly, after labeling an event as a feel-bad experience, Dr. MacDonald encouraged the audience to go through mental exercises to strengthen their well-being journey; however, before proceeding, she highlighted the importance of arming ourselves with self-compassion. The 5 mental exercises to address feel bads include (1) solve: assess whether we have control over the situation and attempt to make changes if possible; (2) reframe: explore new perspectives and assess assumptions without minimizing the situation; (3) connect: embrace the positive impact of safe human connections on our stress response; (4) reflect: search curiously using a compassionate lens for any existing patterns of reactions; and (5) accept and pivot: allow thoughts and feelings to exist and pivot to values-based engagement without waiting for the environment to change. Consistently seeking and appreciating feel goods while addressing rather than suppressing the feel bads can lead to joyful satisfaction and overall well-being.

Additional pearls for optimizing physician well-being included accurately labeling emotions rather than lumping them into an overarching theme (eg, stressed), avoiding comparisons with others, choosing courage over comfort, celebrating vulnerability, and embracing the ability to say no to prioritize engagements aligned with one’s purpose and values. Additional resources were shared for further reading, including Emotional Agility by Susan David, Daring Greatly and Rising Strong by Brené Brown, and Self-Compassion by Kristin Neff.

Take-Home Point—This lecture highlighted key strategies for physicians to improve their well-being, emphasizing self-empowerment and practical tools over external circumstances. It distinguished between productive and destructive influences on satisfaction, and emphasized decision-making aligned with personal values. The concept of well-being as a journey, not a destination, was central, encouraging positive psychology and self-reflection to enhance fulfillment. By focusing on amplifying feel-good experiences and addressing feel-bad experiences with resilience, the lecture advocated for internal over external change, offering a pathway to a balanced and satisfying professional and personal life for physicians.

Final Thoughts

The recent American Academy of Dermatology meeting offered valuable insights and practical pearls to enhance surgical practices and promote physician well-being, in addition to a wide range of topics beyond what is mentioned in this article. From optimizing surgical techniques to prioritizing patient care and safety, the sessions underscored the importance of continuous learning and adaptation in the ever-evolving field of dermatology. As we reflect on the lessons learned and the camaraderie shared during this gathering, let us carry forward these teachings to improve patient outcomes, foster innovation, and cultivate resilience in our pursuit of excellence. Together, we can continue to push the boundaries of dermatologic care while nurturing our own well-being and that of our colleagues, ensuring a brighter future for both patients and practitioners alike.



Acknowledgments—Sultan H. Qiblawi, MD, MBA; Eva Shelton, MD; and Christy T. Behnam, MD (all from Madison, Wisconsin), shared their insights and key takeaways from American Academy of Dermatology lecturers, which enriched the content of this article.