Acne

The Diagnosis: Syphilis

Histopathology revealed psoriasiform hyperplasia, endothelial cell swelling, and a brisk lichenoid inflammation with plasma cells (Figure, A). There also was pustular folliculitis in association with well-formed granulomatous inflammation and a prominent number of plasma cells (Figure, B). Treponema pallidum immunostaining showed numerous organisms in the epidermal and follicular epithelium. Rapid plasma reagin was found to be positive with a titer of 1:128. Evaluation for neurosyphilis through lumbar puncture was negative; the patient also was HIV negative. All of our patient’s skin lesions cleared after a 3-week course of weekly intramuscular benzathine G injections. Due to his substantial clinical improvement, the patient was subsequently lost to follow-up.

Syphilis, an infectious disease caused by the spirochete bacterium T pallidum, has a well-known natural history defined by various stages classically categorized as primary, secondary, latent, or late (tertiary).¹ The classic lesion in primary syphilis is the chancre, a painless ulcer with raised borders that develops within approximately 3 weeks following the initial inoculation.² Secondary syphilis manifests with mucocutaneous findings in up to 97% of patients, and untreated patients develop secondary syphilis at a rate of approximately 25%.³ Although mucocutaneous findings in secondary syphilis can vary widely, patients most commonly develop a diffuse maculopapular exanthem, and 40% develop mucosal findings including genital ulcers, mucous patches, and condylomata lata.¹ In latent syphilis, there is seroreactivity, but otherwise there are no clinical symptoms. A clear symptomatic history of prior primary or secondary syphilis may be known or unknown. Latent syphilis is divided into early and late phases, and the World Health Organization designates 2 years after the first suspected exposure as the cutoff point for early and late latency.⁴ During the first 4 years of latent syphilis, patients may exhibit mucocutaneous relapses. Our patient denied any sexual activity for more than 3 years prior to presentation. Because of the start of iatrogenic immunosuppression during this period, this case was classified as late latent syphilis with mucocutaneous reactivation.

Behçet disease was included within the differential diagnosis but is characterized by multiorgan systemic vasculitis that causes various mucocutaneous findings including aphthous ulcers, papulopustular lesions, and genital ulcers.⁵ Histopathologic features are nonspecific, and the clinical finding of recurrent genital and oral ulceration should be present for diagnosis. This disease predominantly occurs in East Asian or Mediterranean populations and is otherwise rare in White individuals.

SAPHO (synovitis, acne, pustulosis, hyperostosis, osteitis) syndrome is a rare disorder consisting of skin, joint, and bone manifestations.⁶ Severe acne generally is accompanied by palmoplantar pustulosis along with pain and joint tenderness involving the anterior chest and axial skeleton, both of which were absent in our patient.

Pustular psoriasis can be localized or generalized. Localized presentations frequently are acral and may be associated with a variable degree of nail dystrophy and arthritis. Generalized presentations are characterized by hyperemic, well-defined patches with variable numbers of pustules.⁷ The pustules are the consequence of exuberate neutrophilic exocytosis into the epidermis and are nonfollicular.

Steroid-induced acne may be considered in the proper clinical setting of an acneform eruption with a prior history of systemic steroid treatment. However, additional findings of mucositis would not be expected, and although our patient was prescribed prednisone from his primary care physician prior to presentation to our clinic, this medication was given after the onset of the cutaneous eruption.

Syphilis commonly is referred to as the great mimicker due to its potential diverse morphologic presentations, which can involve acneform eruptions, though rare.⁸ In the setting of mucositis, generalized acneform eruptions should raise suspicion for the possibility of syphilis, even in the absence of other more classic cutaneous features.

The Diagnosis: Syphilis

Histopathology revealed psoriasiform hyperplasia, endothelial cell swelling, and a brisk lichenoid inflammation with plasma cells (Figure, A). There also was pustular folliculitis in association with well-formed granulomatous inflammation and a prominent number of plasma cells (Figure, B). Treponema pallidum immunostaining showed numerous organisms in the epidermal and follicular epithelium. Rapid plasma reagin was found to be positive with a titer of 1:128. Evaluation for neurosyphilis through lumbar puncture was negative; the patient also was HIV negative. All of our patient’s skin lesions cleared after a 3-week course of weekly intramuscular benzathine G injections. Due to his substantial clinical improvement, the patient was subsequently lost to follow-up.

Syphilis, an infectious disease caused by the spirochete bacterium T pallidum, has a well-known natural history defined by various stages classically categorized as primary, secondary, latent, or late (tertiary).¹ The classic lesion in primary syphilis is the chancre, a painless ulcer with raised borders that develops within approximately 3 weeks following the initial inoculation.² Secondary syphilis manifests with mucocutaneous findings in up to 97% of patients, and untreated patients develop secondary syphilis at a rate of approximately 25%.³ Although mucocutaneous findings in secondary syphilis can vary widely, patients most commonly develop a diffuse maculopapular exanthem, and 40% develop mucosal findings including genital ulcers, mucous patches, and condylomata lata.¹ In latent syphilis, there is seroreactivity, but otherwise there are no clinical symptoms. A clear symptomatic history of prior primary or secondary syphilis may be known or unknown. Latent syphilis is divided into early and late phases, and the World Health Organization designates 2 years after the first suspected exposure as the cutoff point for early and late latency.⁴ During the first 4 years of latent syphilis, patients may exhibit mucocutaneous relapses. Our patient denied any sexual activity for more than 3 years prior to presentation. Because of the start of iatrogenic immunosuppression during this period, this case was classified as late latent syphilis with mucocutaneous reactivation.

Behçet disease was included within the differential diagnosis but is characterized by multiorgan systemic vasculitis that causes various mucocutaneous findings including aphthous ulcers, papulopustular lesions, and genital ulcers.⁵ Histopathologic features are nonspecific, and the clinical finding of recurrent genital and oral ulceration should be present for diagnosis. This disease predominantly occurs in East Asian or Mediterranean populations and is otherwise rare in White individuals.

SAPHO (synovitis, acne, pustulosis, hyperostosis, osteitis) syndrome is a rare disorder consisting of skin, joint, and bone manifestations.⁶ Severe acne generally is accompanied by palmoplantar pustulosis along with pain and joint tenderness involving the anterior chest and axial skeleton, both of which were absent in our patient.

Pustular psoriasis can be localized or generalized. Localized presentations frequently are acral and may be associated with a variable degree of nail dystrophy and arthritis. Generalized presentations are characterized by hyperemic, well-defined patches with variable numbers of pustules.⁷ The pustules are the consequence of exuberate neutrophilic exocytosis into the epidermis and are nonfollicular.

Steroid-induced acne may be considered in the proper clinical setting of an acneform eruption with a prior history of systemic steroid treatment. However, additional findings of mucositis would not be expected, and although our patient was prescribed prednisone from his primary care physician prior to presentation to our clinic, this medication was given after the onset of the cutaneous eruption.

Syphilis commonly is referred to as the great mimicker due to its potential diverse morphologic presentations, which can involve acneform eruptions, though rare.⁸ In the setting of mucositis, generalized acneform eruptions should raise suspicion for the possibility of syphilis, even in the absence of other more classic cutaneous features.

The Diagnosis: Syphilis

Histopathology revealed psoriasiform hyperplasia, endothelial cell swelling, and a brisk lichenoid inflammation with plasma cells (Figure, A). There also was pustular folliculitis in association with well-formed granulomatous inflammation and a prominent number of plasma cells (Figure, B). Treponema pallidum immunostaining showed numerous organisms in the epidermal and follicular epithelium. Rapid plasma reagin was found to be positive with a titer of 1:128. Evaluation for neurosyphilis through lumbar puncture was negative; the patient also was HIV negative. All of our patient’s skin lesions cleared after a 3-week course of weekly intramuscular benzathine G injections. Due to his substantial clinical improvement, the patient was subsequently lost to follow-up.

Syphilis, an infectious disease caused by the spirochete bacterium T pallidum, has a well-known natural history defined by various stages classically categorized as primary, secondary, latent, or late (tertiary).¹ The classic lesion in primary syphilis is the chancre, a painless ulcer with raised borders that develops within approximately 3 weeks following the initial inoculation.² Secondary syphilis manifests with mucocutaneous findings in up to 97% of patients, and untreated patients develop secondary syphilis at a rate of approximately 25%.³ Although mucocutaneous findings in secondary syphilis can vary widely, patients most commonly develop a diffuse maculopapular exanthem, and 40% develop mucosal findings including genital ulcers, mucous patches, and condylomata lata.¹ In latent syphilis, there is seroreactivity, but otherwise there are no clinical symptoms. A clear symptomatic history of prior primary or secondary syphilis may be known or unknown. Latent syphilis is divided into early and late phases, and the World Health Organization designates 2 years after the first suspected exposure as the cutoff point for early and late latency.⁴ During the first 4 years of latent syphilis, patients may exhibit mucocutaneous relapses. Our patient denied any sexual activity for more than 3 years prior to presentation. Because of the start of iatrogenic immunosuppression during this period, this case was classified as late latent syphilis with mucocutaneous reactivation.

Behçet disease was included within the differential diagnosis but is characterized by multiorgan systemic vasculitis that causes various mucocutaneous findings including aphthous ulcers, papulopustular lesions, and genital ulcers.⁵ Histopathologic features are nonspecific, and the clinical finding of recurrent genital and oral ulceration should be present for diagnosis. This disease predominantly occurs in East Asian or Mediterranean populations and is otherwise rare in White individuals.

SAPHO (synovitis, acne, pustulosis, hyperostosis, osteitis) syndrome is a rare disorder consisting of skin, joint, and bone manifestations.⁶ Severe acne generally is accompanied by palmoplantar pustulosis along with pain and joint tenderness involving the anterior chest and axial skeleton, both of which were absent in our patient.

Pustular psoriasis can be localized or generalized. Localized presentations frequently are acral and may be associated with a variable degree of nail dystrophy and arthritis. Generalized presentations are characterized by hyperemic, well-defined patches with variable numbers of pustules.⁷ The pustules are the consequence of exuberate neutrophilic exocytosis into the epidermis and are nonfollicular.

Steroid-induced acne may be considered in the proper clinical setting of an acneform eruption with a prior history of systemic steroid treatment. However, additional findings of mucositis would not be expected, and although our patient was prescribed prednisone from his primary care physician prior to presentation to our clinic, this medication was given after the onset of the cutaneous eruption.

Syphilis commonly is referred to as the great mimicker due to its potential diverse morphologic presentations, which can involve acneform eruptions, though rare.⁸ In the setting of mucositis, generalized acneform eruptions should raise suspicion for the possibility of syphilis, even in the absence of other more classic cutaneous features.

The Diagnosis: PASH (Pyoderma Gangrenosum, Acne, Hidradenitis Suppurativa) Syndrome

Obtaining our patient’s history of hidradenitis suppurativa (HS), a hallmark sterile neutrophilic dermatosis, was key to making the correct diagnosis of PASH (pyoderma gangrenosum, acne, HS) syndrome. In our patient, the history of HS increased the consideration of pyoderma gangrenosum (PG) due to the persistent breast and leg wounds. Additionally, it was important to consider a diagnosis of PG in lesions that were not responding to broad-spectrum antimicrobial treatment. In our patient, the concurrent presentation of draining abscesses in the axillae (Figure, A) and inflammatory nodulocystic facial acne (Figure, B) were additional diagnostic clues that suggested the triad of PASH syndrome.

Although SAPHO (synovitis, acne, pustulosis, hyperostosis, osteitis) syndrome also can present with cutaneous features of acne and HS, the lack of bone and joint involvement in our patient made this diagnosis less likely. Calciphylaxis can present as ulcerations on the lower extremities, but it usually presents with a livedolike pattern with overlying black eschar and is unlikely in the absence of underlying metabolic or renal disease. PAPA (pyogenic arthritis, PG, acne) syndrome is characterized by recurrent joint involvement and lacks features of HS. Lastly, our patient was immunocompetent with no risk factors for mycobacterial infection.

PASH syndrome is a rare inherited syndrome, but its constituent inflammatory conditions are ubiquitous. They share a common underlying mechanism consisting of overactivation of the innate immune systems driven by increased production of the inflammatory cytokines IL-1, IL-17, and tumor necrosis factor α, resulting in sterile neutrophilic dermatoses.¹ The diagnosis is based on the clinical presentation, as laboratory investigations are nondiagnostic. Biopsies and cultures can be performed to rule out infectious etiologies. Additionally, PASH syndrome is considered part of a larger spectrum of syndromes including PAPA and PAPASH (pyogenic arthritis, acne, PG, HS) syndromes. The absence of pyogenic arthritis distinguishes PASH syndrome from PAPA and PAPASH syndromes.² Clinically, PASH syndrome and the related sterile neutrophilic dermatoses share the characteristic of pronounced cutaneous involvement that substantially alters the patient’s quality of life. Cigarette smoking is an exacerbating factor and has a well-established association with HS.³ Therefore, smoking cessation should be encouraged in these patients to avoid exacerbation of the disease process.

Maintaining adequate immunosuppression is key to managing the underlying disease processes. Classic immunosuppressive agents such as systemic glucocorticoids and methotrexate may fail to satisfactorily control the disease.⁴ Treatment options currently are somewhat limited and are aimed at targeting the inflammatory cytokines that propagate the disease. The most consistent responses have been observed with anti–tumor necrosis factor α antagonists such as adalimumab, infliximab, and etanercept.⁵ Additionally, there is varied response to anakinra, suggesting the importance of selectively targeting IL-1β.⁶ Unfortunately, misdiagnosis for an infectious etiology is common, and antibiotics and debridement are of limited use for the underlying pathophysiology of PASH syndrome. Importantly, biopsy and debridement often are discouraged due to the risk of pathergy.⁷

Our case demonstrates the importance of maintaining a high clinical suspicion for immune-mediated lesions that are refractory to antimicrobial agents. Additionally, prior history of multiple neutrophilic dermatoses should prompt consideration for the PASH/PAPA/PAPASH disease spectrum. Early and accurate identification of neutrophilic dermatoses such as PG and HS are crucial to initiating proper cytokine-targeting treatment and achieving disease remission.

The Diagnosis: PASH (Pyoderma Gangrenosum, Acne, Hidradenitis Suppurativa) Syndrome

Obtaining our patient’s history of hidradenitis suppurativa (HS), a hallmark sterile neutrophilic dermatosis, was key to making the correct diagnosis of PASH (pyoderma gangrenosum, acne, HS) syndrome. In our patient, the history of HS increased the consideration of pyoderma gangrenosum (PG) due to the persistent breast and leg wounds. Additionally, it was important to consider a diagnosis of PG in lesions that were not responding to broad-spectrum antimicrobial treatment. In our patient, the concurrent presentation of draining abscesses in the axillae (Figure, A) and inflammatory nodulocystic facial acne (Figure, B) were additional diagnostic clues that suggested the triad of PASH syndrome.

Although SAPHO (synovitis, acne, pustulosis, hyperostosis, osteitis) syndrome also can present with cutaneous features of acne and HS, the lack of bone and joint involvement in our patient made this diagnosis less likely. Calciphylaxis can present as ulcerations on the lower extremities, but it usually presents with a livedolike pattern with overlying black eschar and is unlikely in the absence of underlying metabolic or renal disease. PAPA (pyogenic arthritis, PG, acne) syndrome is characterized by recurrent joint involvement and lacks features of HS. Lastly, our patient was immunocompetent with no risk factors for mycobacterial infection.

PASH syndrome is a rare inherited syndrome, but its constituent inflammatory conditions are ubiquitous. They share a common underlying mechanism consisting of overactivation of the innate immune systems driven by increased production of the inflammatory cytokines IL-1, IL-17, and tumor necrosis factor α, resulting in sterile neutrophilic dermatoses.¹ The diagnosis is based on the clinical presentation, as laboratory investigations are nondiagnostic. Biopsies and cultures can be performed to rule out infectious etiologies. Additionally, PASH syndrome is considered part of a larger spectrum of syndromes including PAPA and PAPASH (pyogenic arthritis, acne, PG, HS) syndromes. The absence of pyogenic arthritis distinguishes PASH syndrome from PAPA and PAPASH syndromes.² Clinically, PASH syndrome and the related sterile neutrophilic dermatoses share the characteristic of pronounced cutaneous involvement that substantially alters the patient’s quality of life. Cigarette smoking is an exacerbating factor and has a well-established association with HS.³ Therefore, smoking cessation should be encouraged in these patients to avoid exacerbation of the disease process.

Maintaining adequate immunosuppression is key to managing the underlying disease processes. Classic immunosuppressive agents such as systemic glucocorticoids and methotrexate may fail to satisfactorily control the disease.⁴ Treatment options currently are somewhat limited and are aimed at targeting the inflammatory cytokines that propagate the disease. The most consistent responses have been observed with anti–tumor necrosis factor α antagonists such as adalimumab, infliximab, and etanercept.⁵ Additionally, there is varied response to anakinra, suggesting the importance of selectively targeting IL-1β.⁶ Unfortunately, misdiagnosis for an infectious etiology is common, and antibiotics and debridement are of limited use for the underlying pathophysiology of PASH syndrome. Importantly, biopsy and debridement often are discouraged due to the risk of pathergy.⁷

Our case demonstrates the importance of maintaining a high clinical suspicion for immune-mediated lesions that are refractory to antimicrobial agents. Additionally, prior history of multiple neutrophilic dermatoses should prompt consideration for the PASH/PAPA/PAPASH disease spectrum. Early and accurate identification of neutrophilic dermatoses such as PG and HS are crucial to initiating proper cytokine-targeting treatment and achieving disease remission.

The Diagnosis: PASH (Pyoderma Gangrenosum, Acne, Hidradenitis Suppurativa) Syndrome

Obtaining our patient’s history of hidradenitis suppurativa (HS), a hallmark sterile neutrophilic dermatosis, was key to making the correct diagnosis of PASH (pyoderma gangrenosum, acne, HS) syndrome. In our patient, the history of HS increased the consideration of pyoderma gangrenosum (PG) due to the persistent breast and leg wounds. Additionally, it was important to consider a diagnosis of PG in lesions that were not responding to broad-spectrum antimicrobial treatment. In our patient, the concurrent presentation of draining abscesses in the axillae (Figure, A) and inflammatory nodulocystic facial acne (Figure, B) were additional diagnostic clues that suggested the triad of PASH syndrome.

Although SAPHO (synovitis, acne, pustulosis, hyperostosis, osteitis) syndrome also can present with cutaneous features of acne and HS, the lack of bone and joint involvement in our patient made this diagnosis less likely. Calciphylaxis can present as ulcerations on the lower extremities, but it usually presents with a livedolike pattern with overlying black eschar and is unlikely in the absence of underlying metabolic or renal disease. PAPA (pyogenic arthritis, PG, acne) syndrome is characterized by recurrent joint involvement and lacks features of HS. Lastly, our patient was immunocompetent with no risk factors for mycobacterial infection.

PASH syndrome is a rare inherited syndrome, but its constituent inflammatory conditions are ubiquitous. They share a common underlying mechanism consisting of overactivation of the innate immune systems driven by increased production of the inflammatory cytokines IL-1, IL-17, and tumor necrosis factor α, resulting in sterile neutrophilic dermatoses.¹ The diagnosis is based on the clinical presentation, as laboratory investigations are nondiagnostic. Biopsies and cultures can be performed to rule out infectious etiologies. Additionally, PASH syndrome is considered part of a larger spectrum of syndromes including PAPA and PAPASH (pyogenic arthritis, acne, PG, HS) syndromes. The absence of pyogenic arthritis distinguishes PASH syndrome from PAPA and PAPASH syndromes.² Clinically, PASH syndrome and the related sterile neutrophilic dermatoses share the characteristic of pronounced cutaneous involvement that substantially alters the patient’s quality of life. Cigarette smoking is an exacerbating factor and has a well-established association with HS.³ Therefore, smoking cessation should be encouraged in these patients to avoid exacerbation of the disease process.

Maintaining adequate immunosuppression is key to managing the underlying disease processes. Classic immunosuppressive agents such as systemic glucocorticoids and methotrexate may fail to satisfactorily control the disease.⁴ Treatment options currently are somewhat limited and are aimed at targeting the inflammatory cytokines that propagate the disease. The most consistent responses have been observed with anti–tumor necrosis factor α antagonists such as adalimumab, infliximab, and etanercept.⁵ Additionally, there is varied response to anakinra, suggesting the importance of selectively targeting IL-1β.⁶ Unfortunately, misdiagnosis for an infectious etiology is common, and antibiotics and debridement are of limited use for the underlying pathophysiology of PASH syndrome. Importantly, biopsy and debridement often are discouraged due to the risk of pathergy.⁷

Our case demonstrates the importance of maintaining a high clinical suspicion for immune-mediated lesions that are refractory to antimicrobial agents. Additionally, prior history of multiple neutrophilic dermatoses should prompt consideration for the PASH/PAPA/PAPASH disease spectrum. Early and accurate identification of neutrophilic dermatoses such as PG and HS are crucial to initiating proper cytokine-targeting treatment and achieving disease remission.

PHOENIX – Ever since PicoSure became the first picosecond laser cleared by the Food and Drug Administration for the treatment of unwanted tattoos and pigmented lesions in 2012, new uses for this technology continue to expand.

Now, several different FDA-cleared picosecond devices are used for treating conditions ranging from nevus of Ota, café-au-lait macules, and lentigines to melasma, photoaging, yellow tattoos, and recalcitrant tattoos. These include PicoWay, PicoSure, Enlighten, PicoPlus, PiQo4, and Quanta Pico, among others.

“PicoWay technology has integrated nicely into my practice in Houston, the most ethnically diverse city in the country, with its ability to safely treat a number of various benign, congenital, and acquired epidermal and dermal pigmented lesions with ultrashort pulse duration and low thermal impact, which greatly reduces the risk of postinflammatory hyperpigmentation even in darker skin types,” Paul M. Friedman, MD, director of the Dermatology and Laser Surgery Center, Houston, said at the annual conference of the American Society for Laser Medicine and Surgery.

Dr. Friedman

He emphasized the importance of therapeutic clinical endpoints, noting that with q-switched lasers, “you’re looking for immediate whitening, whereas with picosecond lasers, your endpoint is slight whitening or slight darkening depending on wavelength, indication, and skin type. The ability to fractionate picosecond pulses has also allowed us to utilize this technology for photoaging as well as acne scarring.”

The PicoWay system includes a 730-nm picosecond titanium sapphire handpiece, which is FDA cleared for treatment of benign pigmented lesions and blue and green tattoo removal. Dr. Friedman said that he has seen good clinical results using the handpiece for café-au-lait macules, particularly in skin of color.

In an abstract presented at the ASLMS meeting, he and his colleagues presented a retrospective review of 12 patients with café-au-lait macules with Fitzpatrick skin types III-VI who were treated with the PicoWay 730 nm handpiece between April 2021 and January 2023. Patients received a mean of 3.1 treatments at intervals that ranged from 5 to 40 weeks. Clinical photographs were graded by three board-certified dermatologists using a 5-point visual analogue scale.

Overall, patients were rated to have a mean improvement of 26%-50%. Two patients achieved 100% clearance after four to five treatment sessions. “Café-au-lait macules with smooth borders responded less well to laser treatment, confirming prior studies at our center,” he said. “We often educate parents that café-au-lait macules may recur over time, especially with repeated sun exposure.”
 

Treating melasma

Dr. Friedman’s go-to devices for melasma include the low-density, low-energy 1,927-nm fractional diode laser; the 1,064 nm picosecond Nd:YAG, the low-fluence 1,064 nm Q-switched Nd:YAG with a nanosecond pulse duration, and the 595-nm pulsed dye laser for lesions exhibiting underlying vascularity. He said that combining therapies that target pigment and vasculature may be ideal to prevent relapses. “Melasma is a multifactorial condition so by improving patient education and expectation alongside advances in laser treatment of melasma, we have ultimately improved our ability to treat this condition,” he said.

“We’re approaching it from all angles, with ultraviolet photography and spectrocolorimetry, behavioral modifications, topical skin-lightening agents, broad spectrum sunscreens with protection against visible light, and oral tranexamic acid in advanced cases. Then, we intervene with these energy-based modalities, and the bottom line is, less energy and density is more, with lengthened treatment intervals. In 2023, we’re better than we’ve ever been in terms of our ability to safely and effectively improve melasma.”

Novel lasers

Dr. Friedman also described the UltraClear, a novel ablative fractional 2,910-nm erbium-doped glass fiber laser that delivers a customized blend of ablation and coagulation based on the patient’s condition, skin type, and tolerability for down time. He provided an overview of the versatility of what he described as highly customizable technology for conditions such as photoaging and dyschromia in patients of various skin types, making it a very versatile platform in his practice.

The AVAVA MIRIA system is a “next generation” laser “where you’re able to use a focal point. Basically, you’re treating the skin from the inside out in a 3D manner and you’re able to focus intradermally up to 1 mm with high energy 1,064 nm or 1,550 nm,” he said. “It’s a unique conical geometry that spares the epidermis, combined with sapphire tip cooling and images the skin at the same time with the potential for personalized treatments of dyschromia and photoaging in all skin types. It’s truly remarkable where the technology is heading.”

Dr. Friedman disclosed that he has received consulting fees from Allergan, Galderma, Acclaro, Merz Aesthetics, Solta Medical, and Cytrellis. He has conducted contracted research for Sofwave and is a member of the speakers bureau for Solta Medical and Candela.

PHOENIX – Ever since PicoSure became the first picosecond laser cleared by the Food and Drug Administration for the treatment of unwanted tattoos and pigmented lesions in 2012, new uses for this technology continue to expand.

Now, several different FDA-cleared picosecond devices are used for treating conditions ranging from nevus of Ota, café-au-lait macules, and lentigines to melasma, photoaging, yellow tattoos, and recalcitrant tattoos. These include PicoWay, PicoSure, Enlighten, PicoPlus, PiQo4, and Quanta Pico, among others.

“PicoWay technology has integrated nicely into my practice in Houston, the most ethnically diverse city in the country, with its ability to safely treat a number of various benign, congenital, and acquired epidermal and dermal pigmented lesions with ultrashort pulse duration and low thermal impact, which greatly reduces the risk of postinflammatory hyperpigmentation even in darker skin types,” Paul M. Friedman, MD, director of the Dermatology and Laser Surgery Center, Houston, said at the annual conference of the American Society for Laser Medicine and Surgery.

Dr. Friedman

He emphasized the importance of therapeutic clinical endpoints, noting that with q-switched lasers, “you’re looking for immediate whitening, whereas with picosecond lasers, your endpoint is slight whitening or slight darkening depending on wavelength, indication, and skin type. The ability to fractionate picosecond pulses has also allowed us to utilize this technology for photoaging as well as acne scarring.”

The PicoWay system includes a 730-nm picosecond titanium sapphire handpiece, which is FDA cleared for treatment of benign pigmented lesions and blue and green tattoo removal. Dr. Friedman said that he has seen good clinical results using the handpiece for café-au-lait macules, particularly in skin of color.

In an abstract presented at the ASLMS meeting, he and his colleagues presented a retrospective review of 12 patients with café-au-lait macules with Fitzpatrick skin types III-VI who were treated with the PicoWay 730 nm handpiece between April 2021 and January 2023. Patients received a mean of 3.1 treatments at intervals that ranged from 5 to 40 weeks. Clinical photographs were graded by three board-certified dermatologists using a 5-point visual analogue scale.

Overall, patients were rated to have a mean improvement of 26%-50%. Two patients achieved 100% clearance after four to five treatment sessions. “Café-au-lait macules with smooth borders responded less well to laser treatment, confirming prior studies at our center,” he said. “We often educate parents that café-au-lait macules may recur over time, especially with repeated sun exposure.”
 

Treating melasma

Dr. Friedman’s go-to devices for melasma include the low-density, low-energy 1,927-nm fractional diode laser; the 1,064 nm picosecond Nd:YAG, the low-fluence 1,064 nm Q-switched Nd:YAG with a nanosecond pulse duration, and the 595-nm pulsed dye laser for lesions exhibiting underlying vascularity. He said that combining therapies that target pigment and vasculature may be ideal to prevent relapses. “Melasma is a multifactorial condition so by improving patient education and expectation alongside advances in laser treatment of melasma, we have ultimately improved our ability to treat this condition,” he said.

“We’re approaching it from all angles, with ultraviolet photography and spectrocolorimetry, behavioral modifications, topical skin-lightening agents, broad spectrum sunscreens with protection against visible light, and oral tranexamic acid in advanced cases. Then, we intervene with these energy-based modalities, and the bottom line is, less energy and density is more, with lengthened treatment intervals. In 2023, we’re better than we’ve ever been in terms of our ability to safely and effectively improve melasma.”

Novel lasers

Dr. Friedman also described the UltraClear, a novel ablative fractional 2,910-nm erbium-doped glass fiber laser that delivers a customized blend of ablation and coagulation based on the patient’s condition, skin type, and tolerability for down time. He provided an overview of the versatility of what he described as highly customizable technology for conditions such as photoaging and dyschromia in patients of various skin types, making it a very versatile platform in his practice.

The AVAVA MIRIA system is a “next generation” laser “where you’re able to use a focal point. Basically, you’re treating the skin from the inside out in a 3D manner and you’re able to focus intradermally up to 1 mm with high energy 1,064 nm or 1,550 nm,” he said. “It’s a unique conical geometry that spares the epidermis, combined with sapphire tip cooling and images the skin at the same time with the potential for personalized treatments of dyschromia and photoaging in all skin types. It’s truly remarkable where the technology is heading.”

Dr. Friedman disclosed that he has received consulting fees from Allergan, Galderma, Acclaro, Merz Aesthetics, Solta Medical, and Cytrellis. He has conducted contracted research for Sofwave and is a member of the speakers bureau for Solta Medical and Candela.

PHOENIX – Ever since PicoSure became the first picosecond laser cleared by the Food and Drug Administration for the treatment of unwanted tattoos and pigmented lesions in 2012, new uses for this technology continue to expand.

Now, several different FDA-cleared picosecond devices are used for treating conditions ranging from nevus of Ota, café-au-lait macules, and lentigines to melasma, photoaging, yellow tattoos, and recalcitrant tattoos. These include PicoWay, PicoSure, Enlighten, PicoPlus, PiQo4, and Quanta Pico, among others.

“PicoWay technology has integrated nicely into my practice in Houston, the most ethnically diverse city in the country, with its ability to safely treat a number of various benign, congenital, and acquired epidermal and dermal pigmented lesions with ultrashort pulse duration and low thermal impact, which greatly reduces the risk of postinflammatory hyperpigmentation even in darker skin types,” Paul M. Friedman, MD, director of the Dermatology and Laser Surgery Center, Houston, said at the annual conference of the American Society for Laser Medicine and Surgery.

Dr. Friedman

He emphasized the importance of therapeutic clinical endpoints, noting that with q-switched lasers, “you’re looking for immediate whitening, whereas with picosecond lasers, your endpoint is slight whitening or slight darkening depending on wavelength, indication, and skin type. The ability to fractionate picosecond pulses has also allowed us to utilize this technology for photoaging as well as acne scarring.”

The PicoWay system includes a 730-nm picosecond titanium sapphire handpiece, which is FDA cleared for treatment of benign pigmented lesions and blue and green tattoo removal. Dr. Friedman said that he has seen good clinical results using the handpiece for café-au-lait macules, particularly in skin of color.

In an abstract presented at the ASLMS meeting, he and his colleagues presented a retrospective review of 12 patients with café-au-lait macules with Fitzpatrick skin types III-VI who were treated with the PicoWay 730 nm handpiece between April 2021 and January 2023. Patients received a mean of 3.1 treatments at intervals that ranged from 5 to 40 weeks. Clinical photographs were graded by three board-certified dermatologists using a 5-point visual analogue scale.

Overall, patients were rated to have a mean improvement of 26%-50%. Two patients achieved 100% clearance after four to five treatment sessions. “Café-au-lait macules with smooth borders responded less well to laser treatment, confirming prior studies at our center,” he said. “We often educate parents that café-au-lait macules may recur over time, especially with repeated sun exposure.”
 

Treating melasma

Dr. Friedman’s go-to devices for melasma include the low-density, low-energy 1,927-nm fractional diode laser; the 1,064 nm picosecond Nd:YAG, the low-fluence 1,064 nm Q-switched Nd:YAG with a nanosecond pulse duration, and the 595-nm pulsed dye laser for lesions exhibiting underlying vascularity. He said that combining therapies that target pigment and vasculature may be ideal to prevent relapses. “Melasma is a multifactorial condition so by improving patient education and expectation alongside advances in laser treatment of melasma, we have ultimately improved our ability to treat this condition,” he said.

“We’re approaching it from all angles, with ultraviolet photography and spectrocolorimetry, behavioral modifications, topical skin-lightening agents, broad spectrum sunscreens with protection against visible light, and oral tranexamic acid in advanced cases. Then, we intervene with these energy-based modalities, and the bottom line is, less energy and density is more, with lengthened treatment intervals. In 2023, we’re better than we’ve ever been in terms of our ability to safely and effectively improve melasma.”

Novel lasers

Dr. Friedman also described the UltraClear, a novel ablative fractional 2,910-nm erbium-doped glass fiber laser that delivers a customized blend of ablation and coagulation based on the patient’s condition, skin type, and tolerability for down time. He provided an overview of the versatility of what he described as highly customizable technology for conditions such as photoaging and dyschromia in patients of various skin types, making it a very versatile platform in his practice.

The AVAVA MIRIA system is a “next generation” laser “where you’re able to use a focal point. Basically, you’re treating the skin from the inside out in a 3D manner and you’re able to focus intradermally up to 1 mm with high energy 1,064 nm or 1,550 nm,” he said. “It’s a unique conical geometry that spares the epidermis, combined with sapphire tip cooling and images the skin at the same time with the potential for personalized treatments of dyschromia and photoaging in all skin types. It’s truly remarkable where the technology is heading.”

Dr. Friedman disclosed that he has received consulting fees from Allergan, Galderma, Acclaro, Merz Aesthetics, Solta Medical, and Cytrellis. He has conducted contracted research for Sofwave and is a member of the speakers bureau for Solta Medical and Candela.

PHOENIX – When Jeffrey Dover, MD, addressed audience members gathered for a session on cutting-edge technologies at the annual conference of the American Society for Laser Medicine and Surgery, he reflected on a conversation he had with R. Rox Anderson, MD, almost 40 years ago, about eventually finding a cure for acne.

“Despite the fact that we have over-the-counter therapies, prescription therapies, and all kinds of devices available to treat acne, there are still barriers to care that get in the way of treatment,” said Dr. Dover, director of SkinCare Physicians in Chestnut Hill, Mass. “If we had a device based on innovative light science that could meet the needs of the acne patient to get rid of these barriers, wouldn’t that be something wonderful?”

Dr. Jeffrey Dover

The answer to this question, he said, is now “yes,” because of advances in lasers that target sebaceous glands.

In a seminal paper published in 2012, Fernanda H. Sakamoto, MD, PhD, Dr. Anderson, and colleagues demonstrated the potential for a free electron laser to target sebaceous glands . Following several years of refinement, there are now two 1,726-nm laser devices – the AviClear and the Accure Laser System – cleared by the Food and Drug Administration for the treatment of mild to severe acne, which have “very impressive results,” Dr. Dover said.

“With the 1,726-nm laser, there is some selective absorption in sebum in skin, which beats out absorption in the other chromophores,” he said. “But it’s not a big difference like it is, for example, for pulsed-dye lasers and vascular targets. ... This means that the therapeutic window is relatively small and protecting the rest of the epidermis and dermis is crucial to be able to target these lesions or the sebaceous gland without unnecessary damage. If we can protect the epidermis and heat just the sebaceous glands, we should be able to get Accutane-like results if we get durability [by] shrinking sebaceous glands.”

Effective cooling, whether contact cooling, bulk cooling, or air cooling, is crucial to success, he continued. “It’s got to be robust and highly specific to protect the skin, so you don’t end up with side effects that are worse than the disease.”

The AviClear laser delivers seven 3-mm spots, which takes into account the thermal relaxation times of the sebaceous glands. The algorithm delivers a treatment imprint at roughly 0.3 Hz and a 1.5-mm depth of penetration, and the device relies on contact cooling. In pivotal data submitted to the FDA, 104 individuals with moderate to severe acne received three treatments with the AviClear 1 month apart, with follow-up at 1, 3, 6, and 12 months post treatment. They had no other treatment regimens, and the primary endpoint was the percentage of patients who achieved a 50% reduction in inflammatory lesion count 3 months after the final treatment. The secondary endpoint was an Investigator’s Global Assessment (IGA) improvement of 2 or greater.

Dr. Dover, who helped design the study, said that, at 3 months, 80% of those treated achieved a 50% or greater reduction in inflammatory lesion count (P < .001). As for secondary endpoints, 36% of individuals were assessed as having clear or almost clear skin; 47% achieved a 2-point or greater improvement in IGA score, compared with baseline, and 87% achieved a 1-point or greater improvement in IGA score, compared with baseline. By 6 months, 88% of individuals achieved a 50% or greater reduction in inflammatory lesion count; this improved to 92% by 12 months (P < .001).

“All of these procedures were done with no topical anesthetic, no intralesional anesthetic, and they tolerated these quite well,” he said. “There was no down time that required medical intervention after the treatments. All posttreatment erythema and swelling resolved quickly,” and 75% of the patients were “very satisfied” with the treatments.

The Accure Laser System features a proprietary technology that precisely controls thermal gradient depth. “So instead of guessing whether you are delivering the correct amount of heat, it actually tells you,” said Dr. Dover, a past president of the ASLMS and the American Society for Dermatologic Surgery. “It correlates surface and at-depth temperatures, and there’s an infrared camera for real-time accurate temperature monitoring.” The device features highly controlled air cooling and a pulsing pattern that ensures treatment of sebaceous glands of all sizes and at all depths. The clinical end marker is peak epidermal temperature.

In a study supported by Accure, the manufacturer, researchers evaluated the efficacy of the Accure Laser System in 35 subjects with types I to VI skin, who received four monthly treatments 30-45 minutes each, and were followed 12, 26, 39, and 52 weeks following their last treatment. To date, data out to 52 weeks is available for 17 study participants. According to Dr. Dover, the researchers found 80% clearance at 12 weeks following the last treatment, with continued improvement at 52 weeks. One hundred percent of subjects responded. Side effects included erythema, edema, crusting, blisters, and inflammatory papules. “None of these were medically significant,” he said.

As dermatologists begin to incorporate the AviClear and Accure devices into their practices, Dr. Dover said that he is reminded of the conversation he had some 40 years ago with Dr. Anderson about finding a cure for acne, and he feels a bit awestruck. “These 1,726-nm lasers are effective for treating acne. I personally think they are going to revolutionize the way we treat at least some of our patients with acne. They may both be effective for treating facial acne scars. Time will tell. Further study of both scarring and acne are needed to fully categorize the benefit and to optimize treatments.”

To date no direct clinical comparisons have been made between the AviClear and Accure devices.

Dr. Dover reported that he is a consultant for Cutera, the manufacturer for AviClear. He also performs research for the company.





 

PHOENIX – When Jeffrey Dover, MD, addressed audience members gathered for a session on cutting-edge technologies at the annual conference of the American Society for Laser Medicine and Surgery, he reflected on a conversation he had with R. Rox Anderson, MD, almost 40 years ago, about eventually finding a cure for acne.

“Despite the fact that we have over-the-counter therapies, prescription therapies, and all kinds of devices available to treat acne, there are still barriers to care that get in the way of treatment,” said Dr. Dover, director of SkinCare Physicians in Chestnut Hill, Mass. “If we had a device based on innovative light science that could meet the needs of the acne patient to get rid of these barriers, wouldn’t that be something wonderful?”

Dr. Jeffrey Dover

The answer to this question, he said, is now “yes,” because of advances in lasers that target sebaceous glands.

In a seminal paper published in 2012, Fernanda H. Sakamoto, MD, PhD, Dr. Anderson, and colleagues demonstrated the potential for a free electron laser to target sebaceous glands . Following several years of refinement, there are now two 1,726-nm laser devices – the AviClear and the Accure Laser System – cleared by the Food and Drug Administration for the treatment of mild to severe acne, which have “very impressive results,” Dr. Dover said.

“With the 1,726-nm laser, there is some selective absorption in sebum in skin, which beats out absorption in the other chromophores,” he said. “But it’s not a big difference like it is, for example, for pulsed-dye lasers and vascular targets. ... This means that the therapeutic window is relatively small and protecting the rest of the epidermis and dermis is crucial to be able to target these lesions or the sebaceous gland without unnecessary damage. If we can protect the epidermis and heat just the sebaceous glands, we should be able to get Accutane-like results if we get durability [by] shrinking sebaceous glands.”

Effective cooling, whether contact cooling, bulk cooling, or air cooling, is crucial to success, he continued. “It’s got to be robust and highly specific to protect the skin, so you don’t end up with side effects that are worse than the disease.”

The AviClear laser delivers seven 3-mm spots, which takes into account the thermal relaxation times of the sebaceous glands. The algorithm delivers a treatment imprint at roughly 0.3 Hz and a 1.5-mm depth of penetration, and the device relies on contact cooling. In pivotal data submitted to the FDA, 104 individuals with moderate to severe acne received three treatments with the AviClear 1 month apart, with follow-up at 1, 3, 6, and 12 months post treatment. They had no other treatment regimens, and the primary endpoint was the percentage of patients who achieved a 50% reduction in inflammatory lesion count 3 months after the final treatment. The secondary endpoint was an Investigator’s Global Assessment (IGA) improvement of 2 or greater.

Dr. Dover, who helped design the study, said that, at 3 months, 80% of those treated achieved a 50% or greater reduction in inflammatory lesion count (P < .001). As for secondary endpoints, 36% of individuals were assessed as having clear or almost clear skin; 47% achieved a 2-point or greater improvement in IGA score, compared with baseline, and 87% achieved a 1-point or greater improvement in IGA score, compared with baseline. By 6 months, 88% of individuals achieved a 50% or greater reduction in inflammatory lesion count; this improved to 92% by 12 months (P < .001).

“All of these procedures were done with no topical anesthetic, no intralesional anesthetic, and they tolerated these quite well,” he said. “There was no down time that required medical intervention after the treatments. All posttreatment erythema and swelling resolved quickly,” and 75% of the patients were “very satisfied” with the treatments.

The Accure Laser System features a proprietary technology that precisely controls thermal gradient depth. “So instead of guessing whether you are delivering the correct amount of heat, it actually tells you,” said Dr. Dover, a past president of the ASLMS and the American Society for Dermatologic Surgery. “It correlates surface and at-depth temperatures, and there’s an infrared camera for real-time accurate temperature monitoring.” The device features highly controlled air cooling and a pulsing pattern that ensures treatment of sebaceous glands of all sizes and at all depths. The clinical end marker is peak epidermal temperature.

In a study supported by Accure, the manufacturer, researchers evaluated the efficacy of the Accure Laser System in 35 subjects with types I to VI skin, who received four monthly treatments 30-45 minutes each, and were followed 12, 26, 39, and 52 weeks following their last treatment. To date, data out to 52 weeks is available for 17 study participants. According to Dr. Dover, the researchers found 80% clearance at 12 weeks following the last treatment, with continued improvement at 52 weeks. One hundred percent of subjects responded. Side effects included erythema, edema, crusting, blisters, and inflammatory papules. “None of these were medically significant,” he said.

As dermatologists begin to incorporate the AviClear and Accure devices into their practices, Dr. Dover said that he is reminded of the conversation he had some 40 years ago with Dr. Anderson about finding a cure for acne, and he feels a bit awestruck. “These 1,726-nm lasers are effective for treating acne. I personally think they are going to revolutionize the way we treat at least some of our patients with acne. They may both be effective for treating facial acne scars. Time will tell. Further study of both scarring and acne are needed to fully categorize the benefit and to optimize treatments.”

To date no direct clinical comparisons have been made between the AviClear and Accure devices.

Dr. Dover reported that he is a consultant for Cutera, the manufacturer for AviClear. He also performs research for the company.





 

PHOENIX – When Jeffrey Dover, MD, addressed audience members gathered for a session on cutting-edge technologies at the annual conference of the American Society for Laser Medicine and Surgery, he reflected on a conversation he had with R. Rox Anderson, MD, almost 40 years ago, about eventually finding a cure for acne.

“Despite the fact that we have over-the-counter therapies, prescription therapies, and all kinds of devices available to treat acne, there are still barriers to care that get in the way of treatment,” said Dr. Dover, director of SkinCare Physicians in Chestnut Hill, Mass. “If we had a device based on innovative light science that could meet the needs of the acne patient to get rid of these barriers, wouldn’t that be something wonderful?”

Dr. Jeffrey Dover

The answer to this question, he said, is now “yes,” because of advances in lasers that target sebaceous glands.

In a seminal paper published in 2012, Fernanda H. Sakamoto, MD, PhD, Dr. Anderson, and colleagues demonstrated the potential for a free electron laser to target sebaceous glands . Following several years of refinement, there are now two 1,726-nm laser devices – the AviClear and the Accure Laser System – cleared by the Food and Drug Administration for the treatment of mild to severe acne, which have “very impressive results,” Dr. Dover said.

“With the 1,726-nm laser, there is some selective absorption in sebum in skin, which beats out absorption in the other chromophores,” he said. “But it’s not a big difference like it is, for example, for pulsed-dye lasers and vascular targets. ... This means that the therapeutic window is relatively small and protecting the rest of the epidermis and dermis is crucial to be able to target these lesions or the sebaceous gland without unnecessary damage. If we can protect the epidermis and heat just the sebaceous glands, we should be able to get Accutane-like results if we get durability [by] shrinking sebaceous glands.”

Effective cooling, whether contact cooling, bulk cooling, or air cooling, is crucial to success, he continued. “It’s got to be robust and highly specific to protect the skin, so you don’t end up with side effects that are worse than the disease.”

The AviClear laser delivers seven 3-mm spots, which takes into account the thermal relaxation times of the sebaceous glands. The algorithm delivers a treatment imprint at roughly 0.3 Hz and a 1.5-mm depth of penetration, and the device relies on contact cooling. In pivotal data submitted to the FDA, 104 individuals with moderate to severe acne received three treatments with the AviClear 1 month apart, with follow-up at 1, 3, 6, and 12 months post treatment. They had no other treatment regimens, and the primary endpoint was the percentage of patients who achieved a 50% reduction in inflammatory lesion count 3 months after the final treatment. The secondary endpoint was an Investigator’s Global Assessment (IGA) improvement of 2 or greater.

Dr. Dover, who helped design the study, said that, at 3 months, 80% of those treated achieved a 50% or greater reduction in inflammatory lesion count (P < .001). As for secondary endpoints, 36% of individuals were assessed as having clear or almost clear skin; 47% achieved a 2-point or greater improvement in IGA score, compared with baseline, and 87% achieved a 1-point or greater improvement in IGA score, compared with baseline. By 6 months, 88% of individuals achieved a 50% or greater reduction in inflammatory lesion count; this improved to 92% by 12 months (P < .001).

“All of these procedures were done with no topical anesthetic, no intralesional anesthetic, and they tolerated these quite well,” he said. “There was no down time that required medical intervention after the treatments. All posttreatment erythema and swelling resolved quickly,” and 75% of the patients were “very satisfied” with the treatments.

The Accure Laser System features a proprietary technology that precisely controls thermal gradient depth. “So instead of guessing whether you are delivering the correct amount of heat, it actually tells you,” said Dr. Dover, a past president of the ASLMS and the American Society for Dermatologic Surgery. “It correlates surface and at-depth temperatures, and there’s an infrared camera for real-time accurate temperature monitoring.” The device features highly controlled air cooling and a pulsing pattern that ensures treatment of sebaceous glands of all sizes and at all depths. The clinical end marker is peak epidermal temperature.

In a study supported by Accure, the manufacturer, researchers evaluated the efficacy of the Accure Laser System in 35 subjects with types I to VI skin, who received four monthly treatments 30-45 minutes each, and were followed 12, 26, 39, and 52 weeks following their last treatment. To date, data out to 52 weeks is available for 17 study participants. According to Dr. Dover, the researchers found 80% clearance at 12 weeks following the last treatment, with continued improvement at 52 weeks. One hundred percent of subjects responded. Side effects included erythema, edema, crusting, blisters, and inflammatory papules. “None of these were medically significant,” he said.

As dermatologists begin to incorporate the AviClear and Accure devices into their practices, Dr. Dover said that he is reminded of the conversation he had some 40 years ago with Dr. Anderson about finding a cure for acne, and he feels a bit awestruck. “These 1,726-nm lasers are effective for treating acne. I personally think they are going to revolutionize the way we treat at least some of our patients with acne. They may both be effective for treating facial acne scars. Time will tell. Further study of both scarring and acne are needed to fully categorize the benefit and to optimize treatments.”

To date no direct clinical comparisons have been made between the AviClear and Accure devices.

Dr. Dover reported that he is a consultant for Cutera, the manufacturer for AviClear. He also performs research for the company.





 

PHOENIX – Combining a serum containing silymarin with nonablative laser therapy could serve as a promising solution for decreasing inflammation, postinflammatory erythema (PIE), and postinflammatory hyperpigmentation (PIH) associated with acne lesions, results from a prospective, single-center study showed.

“Acne vulgaris is the most common inflammatory dermatosis worldwide, often resulting in sequelae such as scarring, PIE, and PIH,” presenting author Jamie Hu, MD, said at the annual conference of the American Society for Laser Medicine and Surgery, where the study results were presented during an abstract session. “This dyschromia can cause greater psychological distress than the original acne lesions, and disproportionately affects skin of color patients.”

Blemish-prone skin is known to have higher levels of sebum and lower levels of antioxidants, leading to lipid peroxidation and oxidative stress, resulting in proliferation of Cutibacterium acnes and an inflammatory cascade that has recently been implicated in postinflammatory dyschromia and the development of PIE and PIH, noted Dr. Hu, a dermatology resident at the University of Miami. “Therefore, the use of antioxidants presents an opportunity to disrupt blemish and dyschromia,” she said.

One such antioxidant is silymarin, which is derived from the milk thistle plant. Recent studies have demonstrated that silymarin reduces proinflammatory mediators, prevents lipid peroxidation, and presents a new way to target the treatment of both acne and postinflammatory dyschromia.

Dr. Hu’s mentor, Jill S. Waibel, MD, owner and medical director of the Miami Dermatology and Laser Institute, hypothesized that nonablative laser therapy followed by topical application of silymarin would improve acne-associated postinflammatory dyschromia. To test her hunch, she conducted a 12-week, prospective trial in which 24 patients with PIE and/or PIH were randomized to one of two treatment arms: laser treatment with topical antioxidants or laser treatment with vehicle control. Patients received three laser treatments, each 1 month apart. The topical antioxidant used was Silymarin CF, a serum that contains 0.5% silymarin, 0.5% salicylic acid, 15% L-ascorbic acid, and 0.5% ferulic acid. (The study was sponsored by SkinCeuticals, the manufacturer of the serum.)

Laser selection was made primarily on the type of dyschromia, with PIE patients receiving treatment with the pulsed dye laser and PIH patients receiving treatment with the 1,927-nm thulium laser. Patients were treated on days 0, 28, and 56 of the 12-week study, followed by immediate application of topical antioxidants or vehicle control. They were also instructed to apply the assigned topical twice daily for the duration of the study. Patients ranged in age from 21 to 61 years, and 20 had skin types III-IV.

To evaluate efficacy, the researchers conducted blinded clinical assessments with the postacne hyperpigmentation index (PAHPI) and the Global Aesthetic Improvement Scale (GAIS), instrumentation with the Mexameter, a device that captures erythema and melanin index values, and visual diagnostics with optical coherence tomography (OCT).

Dr. Hu reported that at week 12, the PAHPI in the silymarin-plus-laser treatment group fell from an average of 3.18 to 1.74 (a decrease of 1.44), which suggested an improvement trend, compared with the laser treatment–only group, whose PAHPI fell from an average of 3.25 to 1.97 (a decrease of 1.28).

As for the GAIS, a one-time score assessed at the end of the trial, the average score for all patients was 3.24, which translated to “much improved/very much improved.” Patients in the silymarin-plus-laser treatment group had higher average scores compared with patients in the laser treatment–only group (3.35 vs. 3.10, respectively), but the differences did not reach statistical significance.

According to results of the Mexameter assessment, paired t-tests showed that the levels of intralesional melanin decreased significantly for patients in the silymarin-plus-laser treatment group, compared with the laser treatment–only group (P < .05). OCT assessments demonstrated an increase in dermal brightness in both groups, corresponding to an increase in dermal collagen, as well as an increase in blood vessel density.

In an interview at the meeting, Dr. Waibel, subsection chief of dermatology at Baptist Hospital of Miami, said that future studies will focus on long-term follow-up to determine if acne scars can be prevented by combining silymarin with lasers to prevent PIH and PIE. “That would be priceless,” she said. “I believe that the PIH is what causes damage to the collagen, and that damage to the collagen is what causes the scarring. So, if we can prevent or treat PIH, we may be able to prevent scarring.”

This approach, she added, “would decrease the pharmaceutical cost because I think there are many dermatologists who are treating PEI and PIH as active acne. You really have to have a keen eye for understanding the differences and you really have to be looking, because PIE and PIH are flat, whereas active acne consists of either comedones or nodules.”

She noted that in skin of color patients, she has seen PIH persist for 9 or 10 months after treatment with isotretinoin. “It’s not the isotretinoin causing the scars, or even the acne, it’s the prolonged inflammation,” she said.

Catherine M. DiGiorgio, MD, a Boston-based laser and cosmetic dermatologist who was asked to comment on the study, said that patients and dermatologists frequently seek alternatives to hydroquinone for unwanted hyperpigmentation.

Dr. DiGiorgio

Dr. Jalian

“While the study failed to show statistically significant improvement in postinflammatory erythema with concomitant laser and topical therapy versus laser alone, the promising data supporting concurrent use of topicals and fractional lasers for treatment of PIH, particularly in dark skin phototypes, is a clinically impactful contribution to our daily practice,” he said.

Dr. Waibel disclosed that she has conducted clinical trials for many device and pharmaceutical companies including SkinCeuticals. Dr. Hu, Dr. DiGiorgio, and Dr. Jalian were not involved with the study and reported having no relevant disclosures.

PHOENIX – Combining a serum containing silymarin with nonablative laser therapy could serve as a promising solution for decreasing inflammation, postinflammatory erythema (PIE), and postinflammatory hyperpigmentation (PIH) associated with acne lesions, results from a prospective, single-center study showed.

“Acne vulgaris is the most common inflammatory dermatosis worldwide, often resulting in sequelae such as scarring, PIE, and PIH,” presenting author Jamie Hu, MD, said at the annual conference of the American Society for Laser Medicine and Surgery, where the study results were presented during an abstract session. “This dyschromia can cause greater psychological distress than the original acne lesions, and disproportionately affects skin of color patients.”

Blemish-prone skin is known to have higher levels of sebum and lower levels of antioxidants, leading to lipid peroxidation and oxidative stress, resulting in proliferation of Cutibacterium acnes and an inflammatory cascade that has recently been implicated in postinflammatory dyschromia and the development of PIE and PIH, noted Dr. Hu, a dermatology resident at the University of Miami. “Therefore, the use of antioxidants presents an opportunity to disrupt blemish and dyschromia,” she said.

One such antioxidant is silymarin, which is derived from the milk thistle plant. Recent studies have demonstrated that silymarin reduces proinflammatory mediators, prevents lipid peroxidation, and presents a new way to target the treatment of both acne and postinflammatory dyschromia.

Dr. Hu’s mentor, Jill S. Waibel, MD, owner and medical director of the Miami Dermatology and Laser Institute, hypothesized that nonablative laser therapy followed by topical application of silymarin would improve acne-associated postinflammatory dyschromia. To test her hunch, she conducted a 12-week, prospective trial in which 24 patients with PIE and/or PIH were randomized to one of two treatment arms: laser treatment with topical antioxidants or laser treatment with vehicle control. Patients received three laser treatments, each 1 month apart. The topical antioxidant used was Silymarin CF, a serum that contains 0.5% silymarin, 0.5% salicylic acid, 15% L-ascorbic acid, and 0.5% ferulic acid. (The study was sponsored by SkinCeuticals, the manufacturer of the serum.)

Laser selection was made primarily on the type of dyschromia, with PIE patients receiving treatment with the pulsed dye laser and PIH patients receiving treatment with the 1,927-nm thulium laser. Patients were treated on days 0, 28, and 56 of the 12-week study, followed by immediate application of topical antioxidants or vehicle control. They were also instructed to apply the assigned topical twice daily for the duration of the study. Patients ranged in age from 21 to 61 years, and 20 had skin types III-IV.

To evaluate efficacy, the researchers conducted blinded clinical assessments with the postacne hyperpigmentation index (PAHPI) and the Global Aesthetic Improvement Scale (GAIS), instrumentation with the Mexameter, a device that captures erythema and melanin index values, and visual diagnostics with optical coherence tomography (OCT).

Dr. Hu reported that at week 12, the PAHPI in the silymarin-plus-laser treatment group fell from an average of 3.18 to 1.74 (a decrease of 1.44), which suggested an improvement trend, compared with the laser treatment–only group, whose PAHPI fell from an average of 3.25 to 1.97 (a decrease of 1.28).

As for the GAIS, a one-time score assessed at the end of the trial, the average score for all patients was 3.24, which translated to “much improved/very much improved.” Patients in the silymarin-plus-laser treatment group had higher average scores compared with patients in the laser treatment–only group (3.35 vs. 3.10, respectively), but the differences did not reach statistical significance.

According to results of the Mexameter assessment, paired t-tests showed that the levels of intralesional melanin decreased significantly for patients in the silymarin-plus-laser treatment group, compared with the laser treatment–only group (P < .05). OCT assessments demonstrated an increase in dermal brightness in both groups, corresponding to an increase in dermal collagen, as well as an increase in blood vessel density.

In an interview at the meeting, Dr. Waibel, subsection chief of dermatology at Baptist Hospital of Miami, said that future studies will focus on long-term follow-up to determine if acne scars can be prevented by combining silymarin with lasers to prevent PIH and PIE. “That would be priceless,” she said. “I believe that the PIH is what causes damage to the collagen, and that damage to the collagen is what causes the scarring. So, if we can prevent or treat PIH, we may be able to prevent scarring.”

This approach, she added, “would decrease the pharmaceutical cost because I think there are many dermatologists who are treating PEI and PIH as active acne. You really have to have a keen eye for understanding the differences and you really have to be looking, because PIE and PIH are flat, whereas active acne consists of either comedones or nodules.”

She noted that in skin of color patients, she has seen PIH persist for 9 or 10 months after treatment with isotretinoin. “It’s not the isotretinoin causing the scars, or even the acne, it’s the prolonged inflammation,” she said.

Catherine M. DiGiorgio, MD, a Boston-based laser and cosmetic dermatologist who was asked to comment on the study, said that patients and dermatologists frequently seek alternatives to hydroquinone for unwanted hyperpigmentation.

Dr. DiGiorgio

Dr. Jalian

“While the study failed to show statistically significant improvement in postinflammatory erythema with concomitant laser and topical therapy versus laser alone, the promising data supporting concurrent use of topicals and fractional lasers for treatment of PIH, particularly in dark skin phototypes, is a clinically impactful contribution to our daily practice,” he said.

Dr. Waibel disclosed that she has conducted clinical trials for many device and pharmaceutical companies including SkinCeuticals. Dr. Hu, Dr. DiGiorgio, and Dr. Jalian were not involved with the study and reported having no relevant disclosures.

PHOENIX – Combining a serum containing silymarin with nonablative laser therapy could serve as a promising solution for decreasing inflammation, postinflammatory erythema (PIE), and postinflammatory hyperpigmentation (PIH) associated with acne lesions, results from a prospective, single-center study showed.

“Acne vulgaris is the most common inflammatory dermatosis worldwide, often resulting in sequelae such as scarring, PIE, and PIH,” presenting author Jamie Hu, MD, said at the annual conference of the American Society for Laser Medicine and Surgery, where the study results were presented during an abstract session. “This dyschromia can cause greater psychological distress than the original acne lesions, and disproportionately affects skin of color patients.”

Blemish-prone skin is known to have higher levels of sebum and lower levels of antioxidants, leading to lipid peroxidation and oxidative stress, resulting in proliferation of Cutibacterium acnes and an inflammatory cascade that has recently been implicated in postinflammatory dyschromia and the development of PIE and PIH, noted Dr. Hu, a dermatology resident at the University of Miami. “Therefore, the use of antioxidants presents an opportunity to disrupt blemish and dyschromia,” she said.

One such antioxidant is silymarin, which is derived from the milk thistle plant. Recent studies have demonstrated that silymarin reduces proinflammatory mediators, prevents lipid peroxidation, and presents a new way to target the treatment of both acne and postinflammatory dyschromia.

Dr. Hu’s mentor, Jill S. Waibel, MD, owner and medical director of the Miami Dermatology and Laser Institute, hypothesized that nonablative laser therapy followed by topical application of silymarin would improve acne-associated postinflammatory dyschromia. To test her hunch, she conducted a 12-week, prospective trial in which 24 patients with PIE and/or PIH were randomized to one of two treatment arms: laser treatment with topical antioxidants or laser treatment with vehicle control. Patients received three laser treatments, each 1 month apart. The topical antioxidant used was Silymarin CF, a serum that contains 0.5% silymarin, 0.5% salicylic acid, 15% L-ascorbic acid, and 0.5% ferulic acid. (The study was sponsored by SkinCeuticals, the manufacturer of the serum.)

Laser selection was made primarily on the type of dyschromia, with PIE patients receiving treatment with the pulsed dye laser and PIH patients receiving treatment with the 1,927-nm thulium laser. Patients were treated on days 0, 28, and 56 of the 12-week study, followed by immediate application of topical antioxidants or vehicle control. They were also instructed to apply the assigned topical twice daily for the duration of the study. Patients ranged in age from 21 to 61 years, and 20 had skin types III-IV.

To evaluate efficacy, the researchers conducted blinded clinical assessments with the postacne hyperpigmentation index (PAHPI) and the Global Aesthetic Improvement Scale (GAIS), instrumentation with the Mexameter, a device that captures erythema and melanin index values, and visual diagnostics with optical coherence tomography (OCT).

Dr. Hu reported that at week 12, the PAHPI in the silymarin-plus-laser treatment group fell from an average of 3.18 to 1.74 (a decrease of 1.44), which suggested an improvement trend, compared with the laser treatment–only group, whose PAHPI fell from an average of 3.25 to 1.97 (a decrease of 1.28).

As for the GAIS, a one-time score assessed at the end of the trial, the average score for all patients was 3.24, which translated to “much improved/very much improved.” Patients in the silymarin-plus-laser treatment group had higher average scores compared with patients in the laser treatment–only group (3.35 vs. 3.10, respectively), but the differences did not reach statistical significance.

According to results of the Mexameter assessment, paired t-tests showed that the levels of intralesional melanin decreased significantly for patients in the silymarin-plus-laser treatment group, compared with the laser treatment–only group (P < .05). OCT assessments demonstrated an increase in dermal brightness in both groups, corresponding to an increase in dermal collagen, as well as an increase in blood vessel density.

In an interview at the meeting, Dr. Waibel, subsection chief of dermatology at Baptist Hospital of Miami, said that future studies will focus on long-term follow-up to determine if acne scars can be prevented by combining silymarin with lasers to prevent PIH and PIE. “That would be priceless,” she said. “I believe that the PIH is what causes damage to the collagen, and that damage to the collagen is what causes the scarring. So, if we can prevent or treat PIH, we may be able to prevent scarring.”

This approach, she added, “would decrease the pharmaceutical cost because I think there are many dermatologists who are treating PEI and PIH as active acne. You really have to have a keen eye for understanding the differences and you really have to be looking, because PIE and PIH are flat, whereas active acne consists of either comedones or nodules.”

She noted that in skin of color patients, she has seen PIH persist for 9 or 10 months after treatment with isotretinoin. “It’s not the isotretinoin causing the scars, or even the acne, it’s the prolonged inflammation,” she said.

Catherine M. DiGiorgio, MD, a Boston-based laser and cosmetic dermatologist who was asked to comment on the study, said that patients and dermatologists frequently seek alternatives to hydroquinone for unwanted hyperpigmentation.

Dr. DiGiorgio

Dr. Jalian

“While the study failed to show statistically significant improvement in postinflammatory erythema with concomitant laser and topical therapy versus laser alone, the promising data supporting concurrent use of topicals and fractional lasers for treatment of PIH, particularly in dark skin phototypes, is a clinically impactful contribution to our daily practice,” he said.

Dr. Waibel disclosed that she has conducted clinical trials for many device and pharmaceutical companies including SkinCeuticals. Dr. Hu, Dr. DiGiorgio, and Dr. Jalian were not involved with the study and reported having no relevant disclosures.

Citrus bergamia (bergamot) is a fruit tree thought to originate in the Mediterranean area; its fruit has been a part of the diet in that region since the early 18th century.¹ Bergamot is known to confer antioxidant as well as anti-inflammatory activity, and yields proapoptotic effects in the sebaceous gland.^2,3 The plant contains the natural furocoumarin bergapten, which is also known as 5-methoxypsoralen.⁴

Antibacterial, anti-inflammatory, hypolipemic, and anticancer properties have been associated with bergapten, which is primarily found in bergamot essential oil and used effectively as a photosensitizing agent.⁵ In this capacity, bergamot oil has been used for photodynamic therapy of cutaneous conditions such as vitiligo.⁶ In fact, for several years 5-methoxypsoralen and 8-methoxypsoralen have been used to achieve acceptable clearance rates of psoriasis and vitiligo.⁷ This column focuses on bergapten, as well as the cutaneous conditions for which bergamot has been shown to have some benefits warranting application or further investigation.
 

Bergapten

In a 2021 literature review, Liang et al. cited the anti-inflammatory, antimicrobial, anticancer, and other salutary effects associated with bergapten. Based on numerous citations, they also cautioned about the phototoxicity of the compound combined with ultraviolet (UV) light while noting the photoactivation of bergapten for anticancer uses.⁴

The following year, Quetglas-Llabrés et al. acknowledged, in another literature review, the numerous preclinical and in vitro studies demonstrating the therapeutic activity of bergapten and highlighted clinical trials revealing notable lesion clearance rates of psoriasis or vitiligo imparted by oral or topical bergapten along with UV irradiation. Bergapten was also found to be effective as hypolipemic therapy.⁵

Anti-inflammatory topical uses

In a 2017 study by Han et al. of 10 essential oils, bergamot was among the investigated oils, all of which exhibited significant anti-proliferative activity in a preinflamed human dermal fibroblast system simulating chronic inflammation. Bergamot was among three essential oils that also suppressed protein molecules involved with inflammation, immune responses, and tissue remodeling, indicating anti-inflammatory and wound healing characteristics.⁸

More recently, Cristiano et al. reported that ultradeformable nanocarriers containing bergamot essential oil and ammonium glycyrrhizinate were demonstrated in healthy human volunteers to be characterized by the appropriate mean size, size distribution, surface charge, and long-term stability for topical administration. Topical administration on human volunteers also revealed greater activity of the combined agents as compared with a nanosystem loaded only with ammonium glycyrrhizinate. The researchers concluded that this combination of ingredients in ultradeformable vesicles shows potential as topical anti-inflammatory treatment.³

Acne

In a 2020 study using golden hamsters, Sun et al. assessed the effects of the juice and essential oils of bergamot and sweet orange on acne vulgaris engendered by excessive androgen secretion. Among 80 male hamsters randomly divided into 10 groups ranging from low to high doses, all results demonstrated improvement with treatment as seen by decreased growth rates of sebaceous glands, suppressed triglyceride accumulation, lowered inflammatory cytokine release, and apoptosis promotion in sebaceous glands. The authors noted that the essential oils yielded better dose-dependent effects than the juices.²

Psoriasis

In 2019, Perna et al. conducted a literature review on the effects of bergamot essential oil, extract, juice, and polyphenolic fraction on various health metrics. Thirty-one studies (20 involving humans with 1,709 subjects and 11 in rats and mice) were identified. Animal models indicated that bergamot essential oil (10 mg/kg or 20 mg/kg daily for 20 weeks) reduced psoriatic plaques, increased skin collagen content, and fostered hair growth and that bergamot juice (20 mg/kg) diminished proinflammatory cytokines. Human studies showed that bergamot extract and essential oil may reduce blood pressure and improve mental conditions.⁹

Vitiligo

In 2019, Shaaban et al. prepared elastic nanocarriers (spanlastics) to deliver psoralen-containing bergamot oil along with PUVB with the intention of harnessing melanogenic activity to treat vitiligo. Histopathologic assessment on rat skin was conducted before clinical treatment in patients with vitiligo. The spanlastics were deemed to be of suitable nanosize and deformable, yielding consistent bergamot oil release. The bergamot oil included in the nanocarrier was found to enhance photostability and photodynamic activity, with the researchers concluding that bergamot oil nanospanlastics with psoralen-UVB therapy shows potential as a vitiligo therapy.¹⁰

Two years later, Shaaban evaluated bergamot oil formulated in nanostructured lipid carriers as a photosensitizer for photodynamic treatment of vitiligo. The botanical oil was effectively used in the nanostructured lipid carriers with a gel consistency that delivered sustained release of the oil for 24 hours. Preclinical and clinical results in patients were encouraging for the topical photodynamic treatment of vitiligo, with the nanostructured lipid carriers improving the photostability and photodynamic activity of bergamot oil.⁶

Photoaging, photoprotection, and safety concerns

Three decades ago, an international cooperative study of the photophysical, photomutagenic, and photocarcinogenic characteristics of bergamot oil and the effect of UVA and UVB sunscreens found that UVB and UVA sunscreens at low concentration (0.5%-1%) in perfumes could not inhibit the phototoxicity of bergamot oil on human skin.¹¹

In a 2015 study assessing the impact of 38% bergamot polyphenolic fraction (a highly concentrated Citrus bergamia fruit extract) on UVB-generated photoaging, Nisticò et al. found that the bergamot compound dose-dependently protected HaCaT cells against UVB-caused oxidative stress and photoaging markers. Suggesting that the high-antioxidant bergamot polyphenolic fraction has potential for use in skin care formulations, the researchers added that the extract seems to induce antiproliferative, immune-modulating, and antiaging activity.¹²In 2022, Alexa et al. performed in vitro tests and found that natural preparations containing bergamot, orange, and clove essential oils do not significantly alter physiological skin parameters and were deemed safe for topical use. An emulsion with bergamot essential oil was also found to reduce the viability of oral squamous cell carcinoma cells.¹³

Conclusion

As a photosensitizing agent, bergamot has an established role in skin care. Beyond its niche role in treatments for vitiligo and psoriasis, this botanical product appears to show potential as an anti-inflammatory agent as well as an ingredient to combat photoaging and skin cancer. Much more research is needed to elucidate the possible wider benefits of this Mediterranean staple.

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

References

1. Juber M. Health benefits of bergamot. WebMD. November 29, 2022. Accessed March 21, 2023.

2. Sun P et al. Mediators Inflamm. 2020 Oct 6;2020:8868107.

3. Cristiano MC et al. Biomedicines. 2022 Apr 30;10(5):1039.

4. Liang Y et al. Phytother Res. 2021 Nov;35(11):6131-47.

5. Quetglas-Llabrés MM et al. Oxid Med Cell Longev. 2022 Apr 25;2022:8615242.

6. Shaaban M et al. Expert Opin Drug Deliv. 2021 Jan;18(1):139-50.

7. McNeely W, Goa KL. Drugs. 1998 Oct;56(4):667-90.

8. Han X, Beaumont C, Stevens N. Biochim Open. 2017 Apr 26;5:1-7.

9. Perna S et al. Food Sci Nutr. 2019 Jan 25;7(2):369-84.

10. Shaaban M et al. Drug Deliv Transl Res. 2019 Dec;9(6):1106-16.

11. Dubertret L et al. J Photochem Photobiol B. 1990 Nov;7(2-4):251-9.

12. Nisticò S et al. J Biol Regul Homeost Agents. 2015 Jul-Sep;29(3):723-8.

13. Alexa VT et al. Molecules. 2022 Feb 1;27(3):990.

Citrus bergamia (bergamot) is a fruit tree thought to originate in the Mediterranean area; its fruit has been a part of the diet in that region since the early 18th century.¹ Bergamot is known to confer antioxidant as well as anti-inflammatory activity, and yields proapoptotic effects in the sebaceous gland.^2,3 The plant contains the natural furocoumarin bergapten, which is also known as 5-methoxypsoralen.⁴

Antibacterial, anti-inflammatory, hypolipemic, and anticancer properties have been associated with bergapten, which is primarily found in bergamot essential oil and used effectively as a photosensitizing agent.⁵ In this capacity, bergamot oil has been used for photodynamic therapy of cutaneous conditions such as vitiligo.⁶ In fact, for several years 5-methoxypsoralen and 8-methoxypsoralen have been used to achieve acceptable clearance rates of psoriasis and vitiligo.⁷ This column focuses on bergapten, as well as the cutaneous conditions for which bergamot has been shown to have some benefits warranting application or further investigation.
 

Bergapten

In a 2021 literature review, Liang et al. cited the anti-inflammatory, antimicrobial, anticancer, and other salutary effects associated with bergapten. Based on numerous citations, they also cautioned about the phototoxicity of the compound combined with ultraviolet (UV) light while noting the photoactivation of bergapten for anticancer uses.⁴

The following year, Quetglas-Llabrés et al. acknowledged, in another literature review, the numerous preclinical and in vitro studies demonstrating the therapeutic activity of bergapten and highlighted clinical trials revealing notable lesion clearance rates of psoriasis or vitiligo imparted by oral or topical bergapten along with UV irradiation. Bergapten was also found to be effective as hypolipemic therapy.⁵

Anti-inflammatory topical uses

In a 2017 study by Han et al. of 10 essential oils, bergamot was among the investigated oils, all of which exhibited significant anti-proliferative activity in a preinflamed human dermal fibroblast system simulating chronic inflammation. Bergamot was among three essential oils that also suppressed protein molecules involved with inflammation, immune responses, and tissue remodeling, indicating anti-inflammatory and wound healing characteristics.⁸

More recently, Cristiano et al. reported that ultradeformable nanocarriers containing bergamot essential oil and ammonium glycyrrhizinate were demonstrated in healthy human volunteers to be characterized by the appropriate mean size, size distribution, surface charge, and long-term stability for topical administration. Topical administration on human volunteers also revealed greater activity of the combined agents as compared with a nanosystem loaded only with ammonium glycyrrhizinate. The researchers concluded that this combination of ingredients in ultradeformable vesicles shows potential as topical anti-inflammatory treatment.³

Acne

In a 2020 study using golden hamsters, Sun et al. assessed the effects of the juice and essential oils of bergamot and sweet orange on acne vulgaris engendered by excessive androgen secretion. Among 80 male hamsters randomly divided into 10 groups ranging from low to high doses, all results demonstrated improvement with treatment as seen by decreased growth rates of sebaceous glands, suppressed triglyceride accumulation, lowered inflammatory cytokine release, and apoptosis promotion in sebaceous glands. The authors noted that the essential oils yielded better dose-dependent effects than the juices.²

Psoriasis

In 2019, Perna et al. conducted a literature review on the effects of bergamot essential oil, extract, juice, and polyphenolic fraction on various health metrics. Thirty-one studies (20 involving humans with 1,709 subjects and 11 in rats and mice) were identified. Animal models indicated that bergamot essential oil (10 mg/kg or 20 mg/kg daily for 20 weeks) reduced psoriatic plaques, increased skin collagen content, and fostered hair growth and that bergamot juice (20 mg/kg) diminished proinflammatory cytokines. Human studies showed that bergamot extract and essential oil may reduce blood pressure and improve mental conditions.⁹

Vitiligo

In 2019, Shaaban et al. prepared elastic nanocarriers (spanlastics) to deliver psoralen-containing bergamot oil along with PUVB with the intention of harnessing melanogenic activity to treat vitiligo. Histopathologic assessment on rat skin was conducted before clinical treatment in patients with vitiligo. The spanlastics were deemed to be of suitable nanosize and deformable, yielding consistent bergamot oil release. The bergamot oil included in the nanocarrier was found to enhance photostability and photodynamic activity, with the researchers concluding that bergamot oil nanospanlastics with psoralen-UVB therapy shows potential as a vitiligo therapy.¹⁰

Two years later, Shaaban evaluated bergamot oil formulated in nanostructured lipid carriers as a photosensitizer for photodynamic treatment of vitiligo. The botanical oil was effectively used in the nanostructured lipid carriers with a gel consistency that delivered sustained release of the oil for 24 hours. Preclinical and clinical results in patients were encouraging for the topical photodynamic treatment of vitiligo, with the nanostructured lipid carriers improving the photostability and photodynamic activity of bergamot oil.⁶

Photoaging, photoprotection, and safety concerns

Three decades ago, an international cooperative study of the photophysical, photomutagenic, and photocarcinogenic characteristics of bergamot oil and the effect of UVA and UVB sunscreens found that UVB and UVA sunscreens at low concentration (0.5%-1%) in perfumes could not inhibit the phototoxicity of bergamot oil on human skin.¹¹

In a 2015 study assessing the impact of 38% bergamot polyphenolic fraction (a highly concentrated Citrus bergamia fruit extract) on UVB-generated photoaging, Nisticò et al. found that the bergamot compound dose-dependently protected HaCaT cells against UVB-caused oxidative stress and photoaging markers. Suggesting that the high-antioxidant bergamot polyphenolic fraction has potential for use in skin care formulations, the researchers added that the extract seems to induce antiproliferative, immune-modulating, and antiaging activity.¹²In 2022, Alexa et al. performed in vitro tests and found that natural preparations containing bergamot, orange, and clove essential oils do not significantly alter physiological skin parameters and were deemed safe for topical use. An emulsion with bergamot essential oil was also found to reduce the viability of oral squamous cell carcinoma cells.¹³

Conclusion

As a photosensitizing agent, bergamot has an established role in skin care. Beyond its niche role in treatments for vitiligo and psoriasis, this botanical product appears to show potential as an anti-inflammatory agent as well as an ingredient to combat photoaging and skin cancer. Much more research is needed to elucidate the possible wider benefits of this Mediterranean staple.

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

References

1. Juber M. Health benefits of bergamot. WebMD. November 29, 2022. Accessed March 21, 2023.

2. Sun P et al. Mediators Inflamm. 2020 Oct 6;2020:8868107.

3. Cristiano MC et al. Biomedicines. 2022 Apr 30;10(5):1039.

4. Liang Y et al. Phytother Res. 2021 Nov;35(11):6131-47.

5. Quetglas-Llabrés MM et al. Oxid Med Cell Longev. 2022 Apr 25;2022:8615242.

6. Shaaban M et al. Expert Opin Drug Deliv. 2021 Jan;18(1):139-50.

7. McNeely W, Goa KL. Drugs. 1998 Oct;56(4):667-90.

8. Han X, Beaumont C, Stevens N. Biochim Open. 2017 Apr 26;5:1-7.

9. Perna S et al. Food Sci Nutr. 2019 Jan 25;7(2):369-84.

10. Shaaban M et al. Drug Deliv Transl Res. 2019 Dec;9(6):1106-16.

11. Dubertret L et al. J Photochem Photobiol B. 1990 Nov;7(2-4):251-9.

12. Nisticò S et al. J Biol Regul Homeost Agents. 2015 Jul-Sep;29(3):723-8.

13. Alexa VT et al. Molecules. 2022 Feb 1;27(3):990.

Citrus bergamia (bergamot) is a fruit tree thought to originate in the Mediterranean area; its fruit has been a part of the diet in that region since the early 18th century.¹ Bergamot is known to confer antioxidant as well as anti-inflammatory activity, and yields proapoptotic effects in the sebaceous gland.^2,3 The plant contains the natural furocoumarin bergapten, which is also known as 5-methoxypsoralen.⁴

Antibacterial, anti-inflammatory, hypolipemic, and anticancer properties have been associated with bergapten, which is primarily found in bergamot essential oil and used effectively as a photosensitizing agent.⁵ In this capacity, bergamot oil has been used for photodynamic therapy of cutaneous conditions such as vitiligo.⁶ In fact, for several years 5-methoxypsoralen and 8-methoxypsoralen have been used to achieve acceptable clearance rates of psoriasis and vitiligo.⁷ This column focuses on bergapten, as well as the cutaneous conditions for which bergamot has been shown to have some benefits warranting application or further investigation.
 

Bergapten

In a 2021 literature review, Liang et al. cited the anti-inflammatory, antimicrobial, anticancer, and other salutary effects associated with bergapten. Based on numerous citations, they also cautioned about the phototoxicity of the compound combined with ultraviolet (UV) light while noting the photoactivation of bergapten for anticancer uses.⁴

The following year, Quetglas-Llabrés et al. acknowledged, in another literature review, the numerous preclinical and in vitro studies demonstrating the therapeutic activity of bergapten and highlighted clinical trials revealing notable lesion clearance rates of psoriasis or vitiligo imparted by oral or topical bergapten along with UV irradiation. Bergapten was also found to be effective as hypolipemic therapy.⁵

Anti-inflammatory topical uses

In a 2017 study by Han et al. of 10 essential oils, bergamot was among the investigated oils, all of which exhibited significant anti-proliferative activity in a preinflamed human dermal fibroblast system simulating chronic inflammation. Bergamot was among three essential oils that also suppressed protein molecules involved with inflammation, immune responses, and tissue remodeling, indicating anti-inflammatory and wound healing characteristics.⁸

More recently, Cristiano et al. reported that ultradeformable nanocarriers containing bergamot essential oil and ammonium glycyrrhizinate were demonstrated in healthy human volunteers to be characterized by the appropriate mean size, size distribution, surface charge, and long-term stability for topical administration. Topical administration on human volunteers also revealed greater activity of the combined agents as compared with a nanosystem loaded only with ammonium glycyrrhizinate. The researchers concluded that this combination of ingredients in ultradeformable vesicles shows potential as topical anti-inflammatory treatment.³

Acne

In a 2020 study using golden hamsters, Sun et al. assessed the effects of the juice and essential oils of bergamot and sweet orange on acne vulgaris engendered by excessive androgen secretion. Among 80 male hamsters randomly divided into 10 groups ranging from low to high doses, all results demonstrated improvement with treatment as seen by decreased growth rates of sebaceous glands, suppressed triglyceride accumulation, lowered inflammatory cytokine release, and apoptosis promotion in sebaceous glands. The authors noted that the essential oils yielded better dose-dependent effects than the juices.²

Psoriasis

In 2019, Perna et al. conducted a literature review on the effects of bergamot essential oil, extract, juice, and polyphenolic fraction on various health metrics. Thirty-one studies (20 involving humans with 1,709 subjects and 11 in rats and mice) were identified. Animal models indicated that bergamot essential oil (10 mg/kg or 20 mg/kg daily for 20 weeks) reduced psoriatic plaques, increased skin collagen content, and fostered hair growth and that bergamot juice (20 mg/kg) diminished proinflammatory cytokines. Human studies showed that bergamot extract and essential oil may reduce blood pressure and improve mental conditions.⁹

Vitiligo

In 2019, Shaaban et al. prepared elastic nanocarriers (spanlastics) to deliver psoralen-containing bergamot oil along with PUVB with the intention of harnessing melanogenic activity to treat vitiligo. Histopathologic assessment on rat skin was conducted before clinical treatment in patients with vitiligo. The spanlastics were deemed to be of suitable nanosize and deformable, yielding consistent bergamot oil release. The bergamot oil included in the nanocarrier was found to enhance photostability and photodynamic activity, with the researchers concluding that bergamot oil nanospanlastics with psoralen-UVB therapy shows potential as a vitiligo therapy.¹⁰

Two years later, Shaaban evaluated bergamot oil formulated in nanostructured lipid carriers as a photosensitizer for photodynamic treatment of vitiligo. The botanical oil was effectively used in the nanostructured lipid carriers with a gel consistency that delivered sustained release of the oil for 24 hours. Preclinical and clinical results in patients were encouraging for the topical photodynamic treatment of vitiligo, with the nanostructured lipid carriers improving the photostability and photodynamic activity of bergamot oil.⁶

Photoaging, photoprotection, and safety concerns

Three decades ago, an international cooperative study of the photophysical, photomutagenic, and photocarcinogenic characteristics of bergamot oil and the effect of UVA and UVB sunscreens found that UVB and UVA sunscreens at low concentration (0.5%-1%) in perfumes could not inhibit the phototoxicity of bergamot oil on human skin.¹¹

In a 2015 study assessing the impact of 38% bergamot polyphenolic fraction (a highly concentrated Citrus bergamia fruit extract) on UVB-generated photoaging, Nisticò et al. found that the bergamot compound dose-dependently protected HaCaT cells against UVB-caused oxidative stress and photoaging markers. Suggesting that the high-antioxidant bergamot polyphenolic fraction has potential for use in skin care formulations, the researchers added that the extract seems to induce antiproliferative, immune-modulating, and antiaging activity.¹²In 2022, Alexa et al. performed in vitro tests and found that natural preparations containing bergamot, orange, and clove essential oils do not significantly alter physiological skin parameters and were deemed safe for topical use. An emulsion with bergamot essential oil was also found to reduce the viability of oral squamous cell carcinoma cells.¹³

Conclusion

As a photosensitizing agent, bergamot has an established role in skin care. Beyond its niche role in treatments for vitiligo and psoriasis, this botanical product appears to show potential as an anti-inflammatory agent as well as an ingredient to combat photoaging and skin cancer. Much more research is needed to elucidate the possible wider benefits of this Mediterranean staple.

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

References

1. Juber M. Health benefits of bergamot. WebMD. November 29, 2022. Accessed March 21, 2023.

2. Sun P et al. Mediators Inflamm. 2020 Oct 6;2020:8868107.

3. Cristiano MC et al. Biomedicines. 2022 Apr 30;10(5):1039.

4. Liang Y et al. Phytother Res. 2021 Nov;35(11):6131-47.

5. Quetglas-Llabrés MM et al. Oxid Med Cell Longev. 2022 Apr 25;2022:8615242.

6. Shaaban M et al. Expert Opin Drug Deliv. 2021 Jan;18(1):139-50.

7. McNeely W, Goa KL. Drugs. 1998 Oct;56(4):667-90.

8. Han X, Beaumont C, Stevens N. Biochim Open. 2017 Apr 26;5:1-7.

9. Perna S et al. Food Sci Nutr. 2019 Jan 25;7(2):369-84.

10. Shaaban M et al. Drug Deliv Transl Res. 2019 Dec;9(6):1106-16.

11. Dubertret L et al. J Photochem Photobiol B. 1990 Nov;7(2-4):251-9.

12. Nisticò S et al. J Biol Regul Homeost Agents. 2015 Jul-Sep;29(3):723-8.

13. Alexa VT et al. Molecules. 2022 Feb 1;27(3):990.

During 2 days of hearings on potential modifications to the isotretinoin iPLEDGE Risk Evaluation and Mitigation Strategy (REMS), there was much agreement among dermatologists, industry representatives, and Food and Drug Administration representatives that provider and patient burdens persist after the chaotic rollout of the new REMS platform at the end of 2021.

On March 29, at the end of the FDA’s joint meeting of two advisory committees that addressed ways to improve the iPLEDGE program, most panelists voted to change the 19-day lockout period for patients who can become pregnant, and the requirement that every month, providers must document counseling of those who cannot get pregnant and are taking the drug for acne.

However, there was no consensus on whether there should be a lockout at all or for how long, and what an appropriate interval for counseling those who cannot get pregnant would be, if not monthly. Those voting on the questions repeatedly cited a lack of data to make well-informed decisions.

The meeting of the two panels, the FDA’s Drug Safety and Risk Management Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee, was held March 28-29, to discuss proposed changes to iPLEDGE requirements, to minimize the program’s burden on patients, prescribers, and pharmacies – while maintaining safe use of the highly teratogenic drug.

Lockout based on outdated reasoning

John S. Barbieri, MD, a dermatologist and epidemiologist, and director of the Advanced Acne Therapeutics Clinic at Brigham and Women’s Hospital in Boston, speaking as deputy chair of the American Academy of Dermatology Association (AADA) iPLEDGE work group, described the burden of getting the drug to patients. He was not on the panel, but spoke during the open public hearing.

“Compared to other acne medications, the time it takes to successfully go from prescribed (isotretinoin) to when the patient actually has it in their hands is 5- to 10-fold higher,” he said.

Many don’t have a monthly cycle

But Dr. Barbieri said that reasoning is outdated.

“The current program’s focus on the menstrual cycle is really an antiquated approach,” he said. “Many patients do not have a monthly cycle due to medical conditions like polycystic ovarian syndrome, or due to [certain kinds of] contraception.”

He added, “By removing this 19-day lockout and, really, the archaic timing around the menstrual cycle in general in this program, we can simplify the program, improve it, and better align it with the real-world biology of our patients.” He added that patients are often missing the 7-day window for picking up their prescriptions through no fault of their own. Speakers at the hearing also mentioned insurance hassles and ordering delays.


 

Communication with IPMG

Ilona Frieden, MD, professor of dermatology and pediatrics at the University of California, San Francisco, and outgoing chair of the AADA iPLEDGE work group, cited difficulty in working with IPMG on modifications as another barrier. She also spoke during the open public hearing.

UCSF

“Despite many, many attempts to work with the IPMG, we are not aware of any organizational structure or key leaders to communicate with. Instead we have been given repeatedly a generic email address for trying to establish a working relationship and we believe this may explain the inaction of the IPMG since our proposals 4 years ago in 2019.”

Among those proposals, she said, were allowing telemedicine visits as part of the iPLEDGE REMS program and reducing counseling attestation to every 6 months instead of monthly for those who cannot become pregnant.

She pointed to the chaotic rollout of modifications to the iPLEDGE program on a new website at the end of 2021.

In 2021, she said, “despite 6 months of notification, no prescriber input was solicited before revamping the website. This lack of transparency and accountability has been a major hurdle in improving iPLEDGE.”

Dr. Barbieri called the rollout “a debacle” that could have been mitigated with communication with IPMG. “We warned about every issue that happened and talked about ways to mitigate it and were largely ignored,” he said.

“By including dermatologists and key stakeholders in these discussions, as we move forward with changes to improve this program, we can make sure that it’s patient-centered.”

IPMG did not address the specific complaints about the working relationship with the AADA workgroup at the meeting.
 

Monthly attestation for counseling patients who cannot get pregnant

Dr. Barbieri said the monthly requirement to counsel patients who cannot get pregnant and document that counseling unfairly burdens clinicians and patients. “We’re essentially asking patients to come in monthly just to tell them not to share their drugs [or] donate blood,” he said.

Ken Katz, MD, MSc, a dermatologist at Kaiser Permanente in San Francisco, was among the panel members voting not to continue the 19-day lockout.

“I think this places an unduly high burden physically and psychologically on our patients. It seems arbitrary,” he said. “Likely we will miss some pregnancies; we are missing some already. But the burden is not matched by the benefit.”

IPMG representative Dr. Wedin, said, “while we cannot support eliminating or extending the confirmation interval to a year, the [iPLEDGE] sponsors are agreeable [to] a 120-day confirmation interval.”

He said that while an extension to 120 days would reduce burden on prescribers, it comes with the risk in reducing oversight by a certified iPLEDGE prescriber and potentially increasing the risk for drug sharing.

“A patient may be more likely to share their drug with another person the further along with therapy they get as their condition improves,” Dr. Wedin said.
 

Home pregnancy testing

The advisory groups were also tasked with discussing whether home pregnancy tests, allowed during the COVID-19 public health emergency, should continue to be allowed. Most committee members and those in the public hearing who spoke on the issue agreed that home tests should continue in an effort to increase access and decrease burden.

During the pandemic, iPLEDGE rules have been relaxed from having a pregnancy test done only at a Clinical Laboratory Improvement Amendments–certified laboratory.

Lindsey Crist, PharmD, a risk management analyst at the FDA, who presented the FDA review committee’s analysis, said that the FDA’s review committee recommends ending the allowance of home tests, citing insufficient data on use and the discovery of instances of falsification of pregnancy tests.

“One study at an academic medical center reviewed the medical records of 89 patients who used home pregnancy tests while taking isotretinoin during the public health emergency. It found that 15.7% submitted falsified pregnancy test results,” Dr. Crist said.

Dr. Crist added, however, that the review committee recommends allowing the tests to be done in a provider’s office as an alternative.
 

Workaround to avoid falsification

Advisory committee member Brian P. Green, DO, associate professor of dermatology at Penn State University, Hershey, Pa., spoke in support of home pregnancy tests.

“What we have people do for telemedicine is take the stick, write their name, write the date on it, and send a picture of that the same day as their visit,” he said. “That way we have the pregnancy test the same day. Allowing this to continue to happen at home is important. Bringing people in is burdensome and costly.”

Emmy Graber, MD, a dermatologist who practices in Boston, and a director of the American Acne and Rosacea Society (AARS), relayed an example of the burden for a patient using isotretinoin who lives 1.5 hours away from the dermatology office. She is able to meet the requirements of iPLEDGE only through telehealth.

Suggestions for improvement

At the end of the hearing, advisory committee members were asked to propose improvements to the iPLEDGE REMS program.

Dr. Green advocated for the addition of an iPLEDGE mobile app.

“Most people go to their phones rather than their computers, particularly teenagers and younger people,” he noted.

Advisory committee member Megha M. Tollefson, MD, professor of dermatology and pediatric and adolescent medicine at Mayo Clinic in Rochester, Minn., echoed the need for an iPLEDGE app.

The young patients getting isotretinoin “don’t respond to email, they don’t necessarily go onto web pages. If we’re going to be as effective as possible, it’s going to have to be through an app-based system.”

Dr. Tollefson said she would like to see patient counseling standardized through the app. “I think there’s a lot of variability in what counseling is given when it’s left to the individual prescriber or practice,” she said.
 

Exceptions for long-acting contraceptives?

Advisory committee member Abbey B. Berenson, MD, PhD, professor of obstetrics and gynecology at University of Texas Medical Branch in Galveston, said that patients taking long-acting reversible contraceptives (LARCs) may need to be considered differently when deciding the intervals for attestation or whether to have a lockout period.

“LARC methods’ rate of failure is extremely low,” she said. “While it is true, as it has been pointed out, that all methods can fail, when they’re over 99% effective, I think that we can treat those methods differently than we treat methods such as birth control pills or abstinence that fail far more often. That is one way we could minimize burden on the providers and the patients.”

She also suggested using members of the health care team other than physicians to complete counseling, such as a nurse or pharmacist.
 

Prescriptions for emergency contraception

Advisory committee member Sascha Dublin, MD, PhD, senior scientific investigator for Kaiser Permanente Washington Health Research Institute in Seattle, said most patients taking the drug who can get pregnant should get a prescription for emergency contraception at the time of the first isotretinoin prescription.

“They don’t have to buy it, but to make it available at the very beginning sets the expectation that it would be good to have in your medicine cabinet, particularly if the [contraception] choice is abstinence or birth control pills.”

Dr. Dublin also called for better transparency surrounding the role of IPMG.

She said IPMG should be expected to collect data in a way that allows examination of health disparities, including by race and ethnicity and insurance status. Dr. Dublin added that she was concerned about the poor communication between dermatological societies and IPMG.

“The FDA should really require that IPMG hold periodic, regularly scheduled stakeholder forums,” she said. “There has to be a mechanism in place for IPMG to listen to those concerns in real time and respond.”

The advisory committees’ recommendations to the FDA are nonbinding, but the FDA generally follows the recommendations of advisory panels.

During 2 days of hearings on potential modifications to the isotretinoin iPLEDGE Risk Evaluation and Mitigation Strategy (REMS), there was much agreement among dermatologists, industry representatives, and Food and Drug Administration representatives that provider and patient burdens persist after the chaotic rollout of the new REMS platform at the end of 2021.

On March 29, at the end of the FDA’s joint meeting of two advisory committees that addressed ways to improve the iPLEDGE program, most panelists voted to change the 19-day lockout period for patients who can become pregnant, and the requirement that every month, providers must document counseling of those who cannot get pregnant and are taking the drug for acne.

However, there was no consensus on whether there should be a lockout at all or for how long, and what an appropriate interval for counseling those who cannot get pregnant would be, if not monthly. Those voting on the questions repeatedly cited a lack of data to make well-informed decisions.

The meeting of the two panels, the FDA’s Drug Safety and Risk Management Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee, was held March 28-29, to discuss proposed changes to iPLEDGE requirements, to minimize the program’s burden on patients, prescribers, and pharmacies – while maintaining safe use of the highly teratogenic drug.

Lockout based on outdated reasoning

John S. Barbieri, MD, a dermatologist and epidemiologist, and director of the Advanced Acne Therapeutics Clinic at Brigham and Women’s Hospital in Boston, speaking as deputy chair of the American Academy of Dermatology Association (AADA) iPLEDGE work group, described the burden of getting the drug to patients. He was not on the panel, but spoke during the open public hearing.

“Compared to other acne medications, the time it takes to successfully go from prescribed (isotretinoin) to when the patient actually has it in their hands is 5- to 10-fold higher,” he said.

Many don’t have a monthly cycle

But Dr. Barbieri said that reasoning is outdated.

“The current program’s focus on the menstrual cycle is really an antiquated approach,” he said. “Many patients do not have a monthly cycle due to medical conditions like polycystic ovarian syndrome, or due to [certain kinds of] contraception.”

He added, “By removing this 19-day lockout and, really, the archaic timing around the menstrual cycle in general in this program, we can simplify the program, improve it, and better align it with the real-world biology of our patients.” He added that patients are often missing the 7-day window for picking up their prescriptions through no fault of their own. Speakers at the hearing also mentioned insurance hassles and ordering delays.


 

Communication with IPMG

Ilona Frieden, MD, professor of dermatology and pediatrics at the University of California, San Francisco, and outgoing chair of the AADA iPLEDGE work group, cited difficulty in working with IPMG on modifications as another barrier. She also spoke during the open public hearing.

UCSF

“Despite many, many attempts to work with the IPMG, we are not aware of any organizational structure or key leaders to communicate with. Instead we have been given repeatedly a generic email address for trying to establish a working relationship and we believe this may explain the inaction of the IPMG since our proposals 4 years ago in 2019.”

Among those proposals, she said, were allowing telemedicine visits as part of the iPLEDGE REMS program and reducing counseling attestation to every 6 months instead of monthly for those who cannot become pregnant.

She pointed to the chaotic rollout of modifications to the iPLEDGE program on a new website at the end of 2021.

In 2021, she said, “despite 6 months of notification, no prescriber input was solicited before revamping the website. This lack of transparency and accountability has been a major hurdle in improving iPLEDGE.”

Dr. Barbieri called the rollout “a debacle” that could have been mitigated with communication with IPMG. “We warned about every issue that happened and talked about ways to mitigate it and were largely ignored,” he said.

“By including dermatologists and key stakeholders in these discussions, as we move forward with changes to improve this program, we can make sure that it’s patient-centered.”

IPMG did not address the specific complaints about the working relationship with the AADA workgroup at the meeting.
 

Monthly attestation for counseling patients who cannot get pregnant

Dr. Barbieri said the monthly requirement to counsel patients who cannot get pregnant and document that counseling unfairly burdens clinicians and patients. “We’re essentially asking patients to come in monthly just to tell them not to share their drugs [or] donate blood,” he said.

Ken Katz, MD, MSc, a dermatologist at Kaiser Permanente in San Francisco, was among the panel members voting not to continue the 19-day lockout.

“I think this places an unduly high burden physically and psychologically on our patients. It seems arbitrary,” he said. “Likely we will miss some pregnancies; we are missing some already. But the burden is not matched by the benefit.”

IPMG representative Dr. Wedin, said, “while we cannot support eliminating or extending the confirmation interval to a year, the [iPLEDGE] sponsors are agreeable [to] a 120-day confirmation interval.”

He said that while an extension to 120 days would reduce burden on prescribers, it comes with the risk in reducing oversight by a certified iPLEDGE prescriber and potentially increasing the risk for drug sharing.

“A patient may be more likely to share their drug with another person the further along with therapy they get as their condition improves,” Dr. Wedin said.
 

Home pregnancy testing

The advisory groups were also tasked with discussing whether home pregnancy tests, allowed during the COVID-19 public health emergency, should continue to be allowed. Most committee members and those in the public hearing who spoke on the issue agreed that home tests should continue in an effort to increase access and decrease burden.

During the pandemic, iPLEDGE rules have been relaxed from having a pregnancy test done only at a Clinical Laboratory Improvement Amendments–certified laboratory.

Lindsey Crist, PharmD, a risk management analyst at the FDA, who presented the FDA review committee’s analysis, said that the FDA’s review committee recommends ending the allowance of home tests, citing insufficient data on use and the discovery of instances of falsification of pregnancy tests.

“One study at an academic medical center reviewed the medical records of 89 patients who used home pregnancy tests while taking isotretinoin during the public health emergency. It found that 15.7% submitted falsified pregnancy test results,” Dr. Crist said.

Dr. Crist added, however, that the review committee recommends allowing the tests to be done in a provider’s office as an alternative.
 

Workaround to avoid falsification

Advisory committee member Brian P. Green, DO, associate professor of dermatology at Penn State University, Hershey, Pa., spoke in support of home pregnancy tests.

“What we have people do for telemedicine is take the stick, write their name, write the date on it, and send a picture of that the same day as their visit,” he said. “That way we have the pregnancy test the same day. Allowing this to continue to happen at home is important. Bringing people in is burdensome and costly.”

Emmy Graber, MD, a dermatologist who practices in Boston, and a director of the American Acne and Rosacea Society (AARS), relayed an example of the burden for a patient using isotretinoin who lives 1.5 hours away from the dermatology office. She is able to meet the requirements of iPLEDGE only through telehealth.

Suggestions for improvement

At the end of the hearing, advisory committee members were asked to propose improvements to the iPLEDGE REMS program.

Dr. Green advocated for the addition of an iPLEDGE mobile app.

“Most people go to their phones rather than their computers, particularly teenagers and younger people,” he noted.

Advisory committee member Megha M. Tollefson, MD, professor of dermatology and pediatric and adolescent medicine at Mayo Clinic in Rochester, Minn., echoed the need for an iPLEDGE app.

The young patients getting isotretinoin “don’t respond to email, they don’t necessarily go onto web pages. If we’re going to be as effective as possible, it’s going to have to be through an app-based system.”

Dr. Tollefson said she would like to see patient counseling standardized through the app. “I think there’s a lot of variability in what counseling is given when it’s left to the individual prescriber or practice,” she said.
 

Exceptions for long-acting contraceptives?

Advisory committee member Abbey B. Berenson, MD, PhD, professor of obstetrics and gynecology at University of Texas Medical Branch in Galveston, said that patients taking long-acting reversible contraceptives (LARCs) may need to be considered differently when deciding the intervals for attestation or whether to have a lockout period.

“LARC methods’ rate of failure is extremely low,” she said. “While it is true, as it has been pointed out, that all methods can fail, when they’re over 99% effective, I think that we can treat those methods differently than we treat methods such as birth control pills or abstinence that fail far more often. That is one way we could minimize burden on the providers and the patients.”

She also suggested using members of the health care team other than physicians to complete counseling, such as a nurse or pharmacist.
 

Prescriptions for emergency contraception

Advisory committee member Sascha Dublin, MD, PhD, senior scientific investigator for Kaiser Permanente Washington Health Research Institute in Seattle, said most patients taking the drug who can get pregnant should get a prescription for emergency contraception at the time of the first isotretinoin prescription.

“They don’t have to buy it, but to make it available at the very beginning sets the expectation that it would be good to have in your medicine cabinet, particularly if the [contraception] choice is abstinence or birth control pills.”

Dr. Dublin also called for better transparency surrounding the role of IPMG.

She said IPMG should be expected to collect data in a way that allows examination of health disparities, including by race and ethnicity and insurance status. Dr. Dublin added that she was concerned about the poor communication between dermatological societies and IPMG.

“The FDA should really require that IPMG hold periodic, regularly scheduled stakeholder forums,” she said. “There has to be a mechanism in place for IPMG to listen to those concerns in real time and respond.”

The advisory committees’ recommendations to the FDA are nonbinding, but the FDA generally follows the recommendations of advisory panels.

During 2 days of hearings on potential modifications to the isotretinoin iPLEDGE Risk Evaluation and Mitigation Strategy (REMS), there was much agreement among dermatologists, industry representatives, and Food and Drug Administration representatives that provider and patient burdens persist after the chaotic rollout of the new REMS platform at the end of 2021.

On March 29, at the end of the FDA’s joint meeting of two advisory committees that addressed ways to improve the iPLEDGE program, most panelists voted to change the 19-day lockout period for patients who can become pregnant, and the requirement that every month, providers must document counseling of those who cannot get pregnant and are taking the drug for acne.

However, there was no consensus on whether there should be a lockout at all or for how long, and what an appropriate interval for counseling those who cannot get pregnant would be, if not monthly. Those voting on the questions repeatedly cited a lack of data to make well-informed decisions.

The meeting of the two panels, the FDA’s Drug Safety and Risk Management Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee, was held March 28-29, to discuss proposed changes to iPLEDGE requirements, to minimize the program’s burden on patients, prescribers, and pharmacies – while maintaining safe use of the highly teratogenic drug.

Lockout based on outdated reasoning

John S. Barbieri, MD, a dermatologist and epidemiologist, and director of the Advanced Acne Therapeutics Clinic at Brigham and Women’s Hospital in Boston, speaking as deputy chair of the American Academy of Dermatology Association (AADA) iPLEDGE work group, described the burden of getting the drug to patients. He was not on the panel, but spoke during the open public hearing.

“Compared to other acne medications, the time it takes to successfully go from prescribed (isotretinoin) to when the patient actually has it in their hands is 5- to 10-fold higher,” he said.

Many don’t have a monthly cycle

But Dr. Barbieri said that reasoning is outdated.

“The current program’s focus on the menstrual cycle is really an antiquated approach,” he said. “Many patients do not have a monthly cycle due to medical conditions like polycystic ovarian syndrome, or due to [certain kinds of] contraception.”

He added, “By removing this 19-day lockout and, really, the archaic timing around the menstrual cycle in general in this program, we can simplify the program, improve it, and better align it with the real-world biology of our patients.” He added that patients are often missing the 7-day window for picking up their prescriptions through no fault of their own. Speakers at the hearing also mentioned insurance hassles and ordering delays.


 

Communication with IPMG

Ilona Frieden, MD, professor of dermatology and pediatrics at the University of California, San Francisco, and outgoing chair of the AADA iPLEDGE work group, cited difficulty in working with IPMG on modifications as another barrier. She also spoke during the open public hearing.

UCSF

“Despite many, many attempts to work with the IPMG, we are not aware of any organizational structure or key leaders to communicate with. Instead we have been given repeatedly a generic email address for trying to establish a working relationship and we believe this may explain the inaction of the IPMG since our proposals 4 years ago in 2019.”

Among those proposals, she said, were allowing telemedicine visits as part of the iPLEDGE REMS program and reducing counseling attestation to every 6 months instead of monthly for those who cannot become pregnant.

She pointed to the chaotic rollout of modifications to the iPLEDGE program on a new website at the end of 2021.

In 2021, she said, “despite 6 months of notification, no prescriber input was solicited before revamping the website. This lack of transparency and accountability has been a major hurdle in improving iPLEDGE.”

Dr. Barbieri called the rollout “a debacle” that could have been mitigated with communication with IPMG. “We warned about every issue that happened and talked about ways to mitigate it and were largely ignored,” he said.

“By including dermatologists and key stakeholders in these discussions, as we move forward with changes to improve this program, we can make sure that it’s patient-centered.”

IPMG did not address the specific complaints about the working relationship with the AADA workgroup at the meeting.
 

Monthly attestation for counseling patients who cannot get pregnant

Dr. Barbieri said the monthly requirement to counsel patients who cannot get pregnant and document that counseling unfairly burdens clinicians and patients. “We’re essentially asking patients to come in monthly just to tell them not to share their drugs [or] donate blood,” he said.

Ken Katz, MD, MSc, a dermatologist at Kaiser Permanente in San Francisco, was among the panel members voting not to continue the 19-day lockout.

“I think this places an unduly high burden physically and psychologically on our patients. It seems arbitrary,” he said. “Likely we will miss some pregnancies; we are missing some already. But the burden is not matched by the benefit.”

IPMG representative Dr. Wedin, said, “while we cannot support eliminating or extending the confirmation interval to a year, the [iPLEDGE] sponsors are agreeable [to] a 120-day confirmation interval.”

He said that while an extension to 120 days would reduce burden on prescribers, it comes with the risk in reducing oversight by a certified iPLEDGE prescriber and potentially increasing the risk for drug sharing.

“A patient may be more likely to share their drug with another person the further along with therapy they get as their condition improves,” Dr. Wedin said.
 

Home pregnancy testing

The advisory groups were also tasked with discussing whether home pregnancy tests, allowed during the COVID-19 public health emergency, should continue to be allowed. Most committee members and those in the public hearing who spoke on the issue agreed that home tests should continue in an effort to increase access and decrease burden.

During the pandemic, iPLEDGE rules have been relaxed from having a pregnancy test done only at a Clinical Laboratory Improvement Amendments–certified laboratory.

Lindsey Crist, PharmD, a risk management analyst at the FDA, who presented the FDA review committee’s analysis, said that the FDA’s review committee recommends ending the allowance of home tests, citing insufficient data on use and the discovery of instances of falsification of pregnancy tests.

“One study at an academic medical center reviewed the medical records of 89 patients who used home pregnancy tests while taking isotretinoin during the public health emergency. It found that 15.7% submitted falsified pregnancy test results,” Dr. Crist said.

Dr. Crist added, however, that the review committee recommends allowing the tests to be done in a provider’s office as an alternative.
 

Workaround to avoid falsification

Advisory committee member Brian P. Green, DO, associate professor of dermatology at Penn State University, Hershey, Pa., spoke in support of home pregnancy tests.

“What we have people do for telemedicine is take the stick, write their name, write the date on it, and send a picture of that the same day as their visit,” he said. “That way we have the pregnancy test the same day. Allowing this to continue to happen at home is important. Bringing people in is burdensome and costly.”

Emmy Graber, MD, a dermatologist who practices in Boston, and a director of the American Acne and Rosacea Society (AARS), relayed an example of the burden for a patient using isotretinoin who lives 1.5 hours away from the dermatology office. She is able to meet the requirements of iPLEDGE only through telehealth.

Suggestions for improvement

At the end of the hearing, advisory committee members were asked to propose improvements to the iPLEDGE REMS program.

Dr. Green advocated for the addition of an iPLEDGE mobile app.

“Most people go to their phones rather than their computers, particularly teenagers and younger people,” he noted.

Advisory committee member Megha M. Tollefson, MD, professor of dermatology and pediatric and adolescent medicine at Mayo Clinic in Rochester, Minn., echoed the need for an iPLEDGE app.

The young patients getting isotretinoin “don’t respond to email, they don’t necessarily go onto web pages. If we’re going to be as effective as possible, it’s going to have to be through an app-based system.”

Dr. Tollefson said she would like to see patient counseling standardized through the app. “I think there’s a lot of variability in what counseling is given when it’s left to the individual prescriber or practice,” she said.
 

Exceptions for long-acting contraceptives?

Advisory committee member Abbey B. Berenson, MD, PhD, professor of obstetrics and gynecology at University of Texas Medical Branch in Galveston, said that patients taking long-acting reversible contraceptives (LARCs) may need to be considered differently when deciding the intervals for attestation or whether to have a lockout period.

“LARC methods’ rate of failure is extremely low,” she said. “While it is true, as it has been pointed out, that all methods can fail, when they’re over 99% effective, I think that we can treat those methods differently than we treat methods such as birth control pills or abstinence that fail far more often. That is one way we could minimize burden on the providers and the patients.”

She also suggested using members of the health care team other than physicians to complete counseling, such as a nurse or pharmacist.
 

Prescriptions for emergency contraception

Advisory committee member Sascha Dublin, MD, PhD, senior scientific investigator for Kaiser Permanente Washington Health Research Institute in Seattle, said most patients taking the drug who can get pregnant should get a prescription for emergency contraception at the time of the first isotretinoin prescription.

“They don’t have to buy it, but to make it available at the very beginning sets the expectation that it would be good to have in your medicine cabinet, particularly if the [contraception] choice is abstinence or birth control pills.”

Dr. Dublin also called for better transparency surrounding the role of IPMG.

She said IPMG should be expected to collect data in a way that allows examination of health disparities, including by race and ethnicity and insurance status. Dr. Dublin added that she was concerned about the poor communication between dermatological societies and IPMG.

“The FDA should really require that IPMG hold periodic, regularly scheduled stakeholder forums,” she said. “There has to be a mechanism in place for IPMG to listen to those concerns in real time and respond.”

The advisory committees’ recommendations to the FDA are nonbinding, but the FDA generally follows the recommendations of advisory panels.

At a joint meeting of two Food and Drug Administration advisory committees on March 29, panelists voted to modify two aspects of the iPLEDGE Risk Evaluation and Mitigation Strategy (REMS) for isotretinoin, a drug for severe, nodular acne that is highly teratogenic.

The first vote was on whether to continue the 19-day lockout period for patients who can become pregnant and do not pick up their first prescription of isotretinoin within the 7-day prescription window. Those patients currently have to wait 19 days to get their second pregnancy test and receive the medication.

Most (17) of the 22 voting members voted not to continue the 19-day period; 4 voted to keep it; and 1 abstained. But there was no consensus on when the second pregnancy test should occur if the 19-day lockout is changed.

Ken Katz, MD, MSc, a dermatologist at Kaiser Permanente in San Francisco, was among those voting not to continue the 19-day lockout.

“I think this places an unduly high burden physically and psychologically on our patients. It seems arbitrary,” he said. “Likely we will miss some pregnancies; we are missing some already. But the burden is not matched by the benefit.”

The second question concerned patients who cannot become pregnant, and it asked when REMS should require that the prescriber document counseling the patient in the iPLEDGE system. The current requirement is monthly.

Listed options and the number of votes for each were:

• Only with the first prescription as part of patient enrollment (10)
• Monthly (1)
• Every 120 days (6)
• Some other frequency (5)

For this question too, while the members largely agreed the current monthly requirement is too burdensome, there was little agreement on what the most appropriate interval should be.

Lack of data

On both questions, several advisory committee members cited a lack of data on which they could base their decision.

On the documentation question, Megha Tollefson, MD, professor of dermatology at the Mayo Clinic, Rochester, Minn., said she voted for the fourth option (some other frequency) with the thought of yearly attestation.

“As a part of this, providers have to provide monthly counseling,” Dr. Tollefson said. “This is just a documentation requirement in the iPLEDGE system. I think most prescribers do document their monthly counseling in their own medical records. I would say it would be okay not to redocument that in iPLEDGE.”

The two votes came at the end of the second day of a joint meeting of the FDA’s Drug Safety and Risk Management Advisory Committee and Dermatologic and Ophthalmic Drugs Advisory Committee in which experts addressed ways to improve the iPLEDGE REMS for isotretinoin. A transition to a new platform for the iPLEDGE program caused chaos after its rollout at the end of 2021, resulting in extensive delays and denial of prescriptions.

The committees sought to balance reducing burden with maintaining safety and preventing fetal exposures to isotretinoin.

They were also tasked with discussing other REMS requirements without taking a vote on each topic.

Among those topics was whether home pregnancy tests, allowed during the COVID-19 public health emergency, should continue to be allowed. Most who spoke to the issue agreed that home tests should continue in an effort to increase access and decrease burden. Members suggested safeguards against falsified results that have been documented, including assigning names and barcodes to the test results and uploading the verification to the iPLEDGE website.

The advisory committees also discussed recommendations to encourage more participation in the iPLEDGE Pregnancy Registry.

The advisory committees’ recommendations to the FDA are nonbinding, but the FDA generally follows the recommendations of advisory panels.

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

At a joint meeting of two Food and Drug Administration advisory committees on March 29, panelists voted to modify two aspects of the iPLEDGE Risk Evaluation and Mitigation Strategy (REMS) for isotretinoin, a drug for severe, nodular acne that is highly teratogenic.

The first vote was on whether to continue the 19-day lockout period for patients who can become pregnant and do not pick up their first prescription of isotretinoin within the 7-day prescription window. Those patients currently have to wait 19 days to get their second pregnancy test and receive the medication.

Most (17) of the 22 voting members voted not to continue the 19-day period; 4 voted to keep it; and 1 abstained. But there was no consensus on when the second pregnancy test should occur if the 19-day lockout is changed.

Ken Katz, MD, MSc, a dermatologist at Kaiser Permanente in San Francisco, was among those voting not to continue the 19-day lockout.

“I think this places an unduly high burden physically and psychologically on our patients. It seems arbitrary,” he said. “Likely we will miss some pregnancies; we are missing some already. But the burden is not matched by the benefit.”

The second question concerned patients who cannot become pregnant, and it asked when REMS should require that the prescriber document counseling the patient in the iPLEDGE system. The current requirement is monthly.

Listed options and the number of votes for each were:

• Only with the first prescription as part of patient enrollment (10)
• Monthly (1)
• Every 120 days (6)
• Some other frequency (5)

For this question too, while the members largely agreed the current monthly requirement is too burdensome, there was little agreement on what the most appropriate interval should be.

Lack of data

On both questions, several advisory committee members cited a lack of data on which they could base their decision.

On the documentation question, Megha Tollefson, MD, professor of dermatology at the Mayo Clinic, Rochester, Minn., said she voted for the fourth option (some other frequency) with the thought of yearly attestation.

“As a part of this, providers have to provide monthly counseling,” Dr. Tollefson said. “This is just a documentation requirement in the iPLEDGE system. I think most prescribers do document their monthly counseling in their own medical records. I would say it would be okay not to redocument that in iPLEDGE.”

The two votes came at the end of the second day of a joint meeting of the FDA’s Drug Safety and Risk Management Advisory Committee and Dermatologic and Ophthalmic Drugs Advisory Committee in which experts addressed ways to improve the iPLEDGE REMS for isotretinoin. A transition to a new platform for the iPLEDGE program caused chaos after its rollout at the end of 2021, resulting in extensive delays and denial of prescriptions.

The committees sought to balance reducing burden with maintaining safety and preventing fetal exposures to isotretinoin.

They were also tasked with discussing other REMS requirements without taking a vote on each topic.

Among those topics was whether home pregnancy tests, allowed during the COVID-19 public health emergency, should continue to be allowed. Most who spoke to the issue agreed that home tests should continue in an effort to increase access and decrease burden. Members suggested safeguards against falsified results that have been documented, including assigning names and barcodes to the test results and uploading the verification to the iPLEDGE website.

The advisory committees also discussed recommendations to encourage more participation in the iPLEDGE Pregnancy Registry.

The advisory committees’ recommendations to the FDA are nonbinding, but the FDA generally follows the recommendations of advisory panels.

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

At a joint meeting of two Food and Drug Administration advisory committees on March 29, panelists voted to modify two aspects of the iPLEDGE Risk Evaluation and Mitigation Strategy (REMS) for isotretinoin, a drug for severe, nodular acne that is highly teratogenic.

The first vote was on whether to continue the 19-day lockout period for patients who can become pregnant and do not pick up their first prescription of isotretinoin within the 7-day prescription window. Those patients currently have to wait 19 days to get their second pregnancy test and receive the medication.

Most (17) of the 22 voting members voted not to continue the 19-day period; 4 voted to keep it; and 1 abstained. But there was no consensus on when the second pregnancy test should occur if the 19-day lockout is changed.

Ken Katz, MD, MSc, a dermatologist at Kaiser Permanente in San Francisco, was among those voting not to continue the 19-day lockout.

“I think this places an unduly high burden physically and psychologically on our patients. It seems arbitrary,” he said. “Likely we will miss some pregnancies; we are missing some already. But the burden is not matched by the benefit.”

The second question concerned patients who cannot become pregnant, and it asked when REMS should require that the prescriber document counseling the patient in the iPLEDGE system. The current requirement is monthly.

Listed options and the number of votes for each were:

• Only with the first prescription as part of patient enrollment (10)
• Monthly (1)
• Every 120 days (6)
• Some other frequency (5)

For this question too, while the members largely agreed the current monthly requirement is too burdensome, there was little agreement on what the most appropriate interval should be.

Lack of data

On both questions, several advisory committee members cited a lack of data on which they could base their decision.

On the documentation question, Megha Tollefson, MD, professor of dermatology at the Mayo Clinic, Rochester, Minn., said she voted for the fourth option (some other frequency) with the thought of yearly attestation.

“As a part of this, providers have to provide monthly counseling,” Dr. Tollefson said. “This is just a documentation requirement in the iPLEDGE system. I think most prescribers do document their monthly counseling in their own medical records. I would say it would be okay not to redocument that in iPLEDGE.”

The two votes came at the end of the second day of a joint meeting of the FDA’s Drug Safety and Risk Management Advisory Committee and Dermatologic and Ophthalmic Drugs Advisory Committee in which experts addressed ways to improve the iPLEDGE REMS for isotretinoin. A transition to a new platform for the iPLEDGE program caused chaos after its rollout at the end of 2021, resulting in extensive delays and denial of prescriptions.

The committees sought to balance reducing burden with maintaining safety and preventing fetal exposures to isotretinoin.

They were also tasked with discussing other REMS requirements without taking a vote on each topic.

Among those topics was whether home pregnancy tests, allowed during the COVID-19 public health emergency, should continue to be allowed. Most who spoke to the issue agreed that home tests should continue in an effort to increase access and decrease burden. Members suggested safeguards against falsified results that have been documented, including assigning names and barcodes to the test results and uploading the verification to the iPLEDGE website.

The advisory committees also discussed recommendations to encourage more participation in the iPLEDGE Pregnancy Registry.

The advisory committees’ recommendations to the FDA are nonbinding, but the FDA generally follows the recommendations of advisory panels.

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

Isotretinoin, for severe, nodular acne, comes with complex safety requirements, and on March 28, two Food and Drug Administration advisory committees began a 2-day meeting examining how to relieve some of those burdens for patients, pharmacies, and prescribers.
 

Isotretinoin, previously called Accutane, is marketed as Absorica, Absorica LD, Claravis, Amnesteem, Myorisan, and Zenatane.

In a joint meeting of the FDA’s Drug Safety and Risk Management Advisory Committee and Dermatologic and Ophthalmic Drugs Advisory Committee, experts addressed ways to improve the modified iPLEDGE Risk Evaluation and Mitigation Strategy (iPLEDGE REMS) for isotretinoin that caused chaos after its rollout at the end of 2021.

In January 2022, problems were multiplying with the program for clinicians, pharmacists, and patients, causing extensive delays and prescription denials. In response, the FDA said it would continue to meet with the Isotretinoin Products Manufacturers Group (IPMG) to resolve problems.

March 28 was the first day of a 2-day meeting addressing what can be done to reduce burden with the iPLEDGE REMS while maintaining safety and preventing fetal exposure to the drug.
 

Key areas of concern

The meeting focused on several key areas.

The 19-day lockout period

The lockout is a current restriction for patients who can become pregnant and do not pick up their first prescription of isotretinoin within the specified 7-day prescription window. Currently, those who miss the window must wait 19 days from the date of the first pregnancy test to take an additional pregnancy test to be eligible to receive the drug.

Lindsey Crist, PharmD, a risk management analyst for the FDA, who presented the FDA review committee’s analysis, acknowledged that the lockout period causes delays in treatment and adds frustration and costs.

She said it’s important to remember that the lockout applies only to the first prescription. “It’s intended as an additional layer of screening to detect pregnancy,” she said.

“At least 12 pregnancies have been identified during the 19-day lockout from March 2017–September of 2022,” she noted.

The FDA is looking to the advisory committee to provide recommendations on whether the lockout period should be changed.
 

Home testing

During the pandemic, iPLEDGE rules have been relaxed from having a pregnancy test done only at a Clinical Laboratory Improvement Amendments–certified laboratory and home pregnancy tests have been allowed. The question now is whether home tests should continue to be allowed.

Ms. Crist said that the FDA’s review committee recommends ending the allowance of home tests, citing insufficient data on use and the discovery of instances of falsification of pregnancy tests.

“One study at an academic medical center reviewed the medical records of 89 patients who used home pregnancy tests while taking isotretinoin during the public health emergency. It found that 15.7% submitted falsified pregnancy test results,” she said.

Ms. Crist added, however, that the review committee recommends allowing the tests to be done in a provider’s office as an alternative.

Documenting counseling patients who cannot get pregnant

Currently, this documentation must be done monthly, primarily to counsel patients against drug sharing or giving blood. Proposed changes include extending the intervals for attestation or eliminating it to reduce burden on clinicians.

IPMG representative Gregory Wedin, PharmD, pharmacovigilance and risk management director for Upsher-Smith Laboratories, said, “while we cannot support eliminating or extending the confirmation interval to a year, the [iPLEDGE] sponsors are agreeable [to] a 120-day confirmation interval.”

He said that while extending to 120 days would reduce burden on prescribers, it comes with risk in reducing oversight by a certified iPLEDGE prescriber and potentially increasing the risk for drug sharing.

“A patient may be more likely to share their drug with another person the further along with therapy they get as their condition improves,” Mr. Wedin said.

On March 29, the panel will hear more recommendations for and against modifications to iPLEDGE REMS and will vote on select modifications at the end of the meeting.

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

Isotretinoin, for severe, nodular acne, comes with complex safety requirements, and on March 28, two Food and Drug Administration advisory committees began a 2-day meeting examining how to relieve some of those burdens for patients, pharmacies, and prescribers.
 

Isotretinoin, previously called Accutane, is marketed as Absorica, Absorica LD, Claravis, Amnesteem, Myorisan, and Zenatane.

In a joint meeting of the FDA’s Drug Safety and Risk Management Advisory Committee and Dermatologic and Ophthalmic Drugs Advisory Committee, experts addressed ways to improve the modified iPLEDGE Risk Evaluation and Mitigation Strategy (iPLEDGE REMS) for isotretinoin that caused chaos after its rollout at the end of 2021.

In January 2022, problems were multiplying with the program for clinicians, pharmacists, and patients, causing extensive delays and prescription denials. In response, the FDA said it would continue to meet with the Isotretinoin Products Manufacturers Group (IPMG) to resolve problems.

March 28 was the first day of a 2-day meeting addressing what can be done to reduce burden with the iPLEDGE REMS while maintaining safety and preventing fetal exposure to the drug.
 

Key areas of concern

The meeting focused on several key areas.

The 19-day lockout period

The lockout is a current restriction for patients who can become pregnant and do not pick up their first prescription of isotretinoin within the specified 7-day prescription window. Currently, those who miss the window must wait 19 days from the date of the first pregnancy test to take an additional pregnancy test to be eligible to receive the drug.

Lindsey Crist, PharmD, a risk management analyst for the FDA, who presented the FDA review committee’s analysis, acknowledged that the lockout period causes delays in treatment and adds frustration and costs.

She said it’s important to remember that the lockout applies only to the first prescription. “It’s intended as an additional layer of screening to detect pregnancy,” she said.

“At least 12 pregnancies have been identified during the 19-day lockout from March 2017–September of 2022,” she noted.

The FDA is looking to the advisory committee to provide recommendations on whether the lockout period should be changed.
 

Home testing

During the pandemic, iPLEDGE rules have been relaxed from having a pregnancy test done only at a Clinical Laboratory Improvement Amendments–certified laboratory and home pregnancy tests have been allowed. The question now is whether home tests should continue to be allowed.

Ms. Crist said that the FDA’s review committee recommends ending the allowance of home tests, citing insufficient data on use and the discovery of instances of falsification of pregnancy tests.

“One study at an academic medical center reviewed the medical records of 89 patients who used home pregnancy tests while taking isotretinoin during the public health emergency. It found that 15.7% submitted falsified pregnancy test results,” she said.

Ms. Crist added, however, that the review committee recommends allowing the tests to be done in a provider’s office as an alternative.

Documenting counseling patients who cannot get pregnant

Currently, this documentation must be done monthly, primarily to counsel patients against drug sharing or giving blood. Proposed changes include extending the intervals for attestation or eliminating it to reduce burden on clinicians.

IPMG representative Gregory Wedin, PharmD, pharmacovigilance and risk management director for Upsher-Smith Laboratories, said, “while we cannot support eliminating or extending the confirmation interval to a year, the [iPLEDGE] sponsors are agreeable [to] a 120-day confirmation interval.”

He said that while extending to 120 days would reduce burden on prescribers, it comes with risk in reducing oversight by a certified iPLEDGE prescriber and potentially increasing the risk for drug sharing.

“A patient may be more likely to share their drug with another person the further along with therapy they get as their condition improves,” Mr. Wedin said.

On March 29, the panel will hear more recommendations for and against modifications to iPLEDGE REMS and will vote on select modifications at the end of the meeting.

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

Isotretinoin, for severe, nodular acne, comes with complex safety requirements, and on March 28, two Food and Drug Administration advisory committees began a 2-day meeting examining how to relieve some of those burdens for patients, pharmacies, and prescribers.
 

Isotretinoin, previously called Accutane, is marketed as Absorica, Absorica LD, Claravis, Amnesteem, Myorisan, and Zenatane.

In a joint meeting of the FDA’s Drug Safety and Risk Management Advisory Committee and Dermatologic and Ophthalmic Drugs Advisory Committee, experts addressed ways to improve the modified iPLEDGE Risk Evaluation and Mitigation Strategy (iPLEDGE REMS) for isotretinoin that caused chaos after its rollout at the end of 2021.

In January 2022, problems were multiplying with the program for clinicians, pharmacists, and patients, causing extensive delays and prescription denials. In response, the FDA said it would continue to meet with the Isotretinoin Products Manufacturers Group (IPMG) to resolve problems.

March 28 was the first day of a 2-day meeting addressing what can be done to reduce burden with the iPLEDGE REMS while maintaining safety and preventing fetal exposure to the drug.
 

Key areas of concern

The meeting focused on several key areas.

The 19-day lockout period

The lockout is a current restriction for patients who can become pregnant and do not pick up their first prescription of isotretinoin within the specified 7-day prescription window. Currently, those who miss the window must wait 19 days from the date of the first pregnancy test to take an additional pregnancy test to be eligible to receive the drug.

Lindsey Crist, PharmD, a risk management analyst for the FDA, who presented the FDA review committee’s analysis, acknowledged that the lockout period causes delays in treatment and adds frustration and costs.

She said it’s important to remember that the lockout applies only to the first prescription. “It’s intended as an additional layer of screening to detect pregnancy,” she said.

“At least 12 pregnancies have been identified during the 19-day lockout from March 2017–September of 2022,” she noted.

The FDA is looking to the advisory committee to provide recommendations on whether the lockout period should be changed.
 

Home testing

During the pandemic, iPLEDGE rules have been relaxed from having a pregnancy test done only at a Clinical Laboratory Improvement Amendments–certified laboratory and home pregnancy tests have been allowed. The question now is whether home tests should continue to be allowed.

Ms. Crist said that the FDA’s review committee recommends ending the allowance of home tests, citing insufficient data on use and the discovery of instances of falsification of pregnancy tests.

“One study at an academic medical center reviewed the medical records of 89 patients who used home pregnancy tests while taking isotretinoin during the public health emergency. It found that 15.7% submitted falsified pregnancy test results,” she said.

Ms. Crist added, however, that the review committee recommends allowing the tests to be done in a provider’s office as an alternative.

Documenting counseling patients who cannot get pregnant

Currently, this documentation must be done monthly, primarily to counsel patients against drug sharing or giving blood. Proposed changes include extending the intervals for attestation or eliminating it to reduce burden on clinicians.

IPMG representative Gregory Wedin, PharmD, pharmacovigilance and risk management director for Upsher-Smith Laboratories, said, “while we cannot support eliminating or extending the confirmation interval to a year, the [iPLEDGE] sponsors are agreeable [to] a 120-day confirmation interval.”

He said that while extending to 120 days would reduce burden on prescribers, it comes with risk in reducing oversight by a certified iPLEDGE prescriber and potentially increasing the risk for drug sharing.

“A patient may be more likely to share their drug with another person the further along with therapy they get as their condition improves,” Mr. Wedin said.

On March 29, the panel will hear more recommendations for and against modifications to iPLEDGE REMS and will vote on select modifications at the end of the meeting.

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

HONOLULU – In the clinical experience of Julie C. Harper, MD, an increasing number of women with acne are turning to off-label, long-term treatment with spironolactone.

“Spironolactone is fairly accessible, inexpensive, and effective for our patients,” Dr. Harper, a dermatologist who practices in Birmingham, Ala., said at the Hawaii Dermatology Seminar provided by MedscapeLIVE!

An aldosterone receptor antagonist commonly used to treat high blood pressure and heart failure, spironolactone also has antiandrogenic properties with a proven track record for treating acne and hirsutism. It reduces androgen production, inhibits 5-alpha reductase, and increases sex hormone binding globulin. The dosing range for treating acne is 25 mg to 200 mg per day, but Dr. Harper prefers a maximum dose of 100 mg per day.

According to a systematic review of its use for acne in adult women, the most common side effect is menstrual irregularity, while other common side effects include breast tenderness/swelling, fatigue, and headaches.

“The higher the dose, the higher the rate of side effects,” she said. Concomitant use of an oral contraceptive lessens menstrual irregularities and prevents pregnancies, to avoid exposure during pregnancy and the hypothetical risk of feminization of the male fetus with exposure late in the first trimester. “Early in my career, I used to say if you’re going to be on spironolactone you’re also going to be on an oral contraceptive. But the longer I’ve practiced, I’ve learned that women who have a contraindication to birth control pills or who don’t want to take it can still benefit from an oral antiandrogen by being on spironolactone.”

A large retrospective analysis of 14-year data concluded that routine potassium monitoring is unnecessary for healthy women taking spironolactone for acne. “If you’re between the ages of 18 and 45, healthy, and not taking other medications where I’m worried about potassium levels, I’m not checking those levels at all,” Dr. Harper said.

Spironolactone labeling includes a boxed warning regarding the potential for tumorigenicity based on rat studies, but the dosages used in those studies were 25-250 times higher than the exposure dose in humans, Dr. Harper said.

Results from a systematic review and meta-analysis of seven studies in the medical literature found no evidence of an increased risk of breast cancer in women with exposure to spironolactone. “However, the certainty of the evidence was low and future studies are needed, including among diverse populations such as younger individuals and those with acne or hirsutism,” the study authors wrote.

In a separate study, researchers drew from patients in the Humana Insurance database from 2005 to 2017 to address whether spironolactone is associated with an increased risk of recurrence of breast cancer. Recurrent breast cancer was examined in 29,146 women with continuous health insurance for 2 years after a diagnosis of breast cancer. Of these, 746 were prescribed spironolactone, and the remainder were not. The researchers found that 123 women (16.5%) who were prescribed spironolactone had a breast cancer recurrence, compared with 3,649 women (12.8%) with a breast cancer recurrence who had not been prescribed spironolactone (P = .004). Adjusted Cox regression analysis following propensity matching showed no association between spironolactone and increased breast cancer recurrence (adjusted hazard ratio, 0.966; P = .953).

According to Dr. Harper, spironolactone may take about 3 months to kick in. “Likely this is a long-term treatment, and most of the time we’re going to be using it in combination with other acne treatments such as topical retinoids or topical benzoyl peroxide, oral antibiotics, or even isotretinoin.”

A study of long-term spironolactone use in 403 women found that the most common dose prescribed was 100 mg/day, and 68% of the women were concurrently prescribed a topical retinoid, 2.2% an oral antibiotic, and 40.7% an oral contraceptive.

The study population included 32 patients with a history of polycystic ovarian syndrome, 1 with a history of breast cancer, and 5 were hypercoagulable. Patients took the drug for a mean of 471 days. “As opposed to our antibiotics, where the course for patients is generally 3-4 months, when you start someone on spironolactone, they may end up staying on it,” Dr. Harper said.

Dr. Harper disclosed that she serves as an advisor or consultant for Almirall, Cassiopeia, Cutera, EPI, Galderma, L’Oreal, Ortho Dermatologics, Sol Gel, and Vyne. She also serves as a speaker or member of a speaker’s bureau for Almirall, Cassiopeia, Cutera, EPI, Galderma, Journey Almirall, L’Oreal, Ortho Dermatologics, Sun Pharmaceutical Industries, and Vyne.

Medscape and this news organization are owned by the same parent company.

HONOLULU – In the clinical experience of Julie C. Harper, MD, an increasing number of women with acne are turning to off-label, long-term treatment with spironolactone.

“Spironolactone is fairly accessible, inexpensive, and effective for our patients,” Dr. Harper, a dermatologist who practices in Birmingham, Ala., said at the Hawaii Dermatology Seminar provided by MedscapeLIVE!

An aldosterone receptor antagonist commonly used to treat high blood pressure and heart failure, spironolactone also has antiandrogenic properties with a proven track record for treating acne and hirsutism. It reduces androgen production, inhibits 5-alpha reductase, and increases sex hormone binding globulin. The dosing range for treating acne is 25 mg to 200 mg per day, but Dr. Harper prefers a maximum dose of 100 mg per day.

According to a systematic review of its use for acne in adult women, the most common side effect is menstrual irregularity, while other common side effects include breast tenderness/swelling, fatigue, and headaches.

“The higher the dose, the higher the rate of side effects,” she said. Concomitant use of an oral contraceptive lessens menstrual irregularities and prevents pregnancies, to avoid exposure during pregnancy and the hypothetical risk of feminization of the male fetus with exposure late in the first trimester. “Early in my career, I used to say if you’re going to be on spironolactone you’re also going to be on an oral contraceptive. But the longer I’ve practiced, I’ve learned that women who have a contraindication to birth control pills or who don’t want to take it can still benefit from an oral antiandrogen by being on spironolactone.”

A large retrospective analysis of 14-year data concluded that routine potassium monitoring is unnecessary for healthy women taking spironolactone for acne. “If you’re between the ages of 18 and 45, healthy, and not taking other medications where I’m worried about potassium levels, I’m not checking those levels at all,” Dr. Harper said.

Spironolactone labeling includes a boxed warning regarding the potential for tumorigenicity based on rat studies, but the dosages used in those studies were 25-250 times higher than the exposure dose in humans, Dr. Harper said.

Results from a systematic review and meta-analysis of seven studies in the medical literature found no evidence of an increased risk of breast cancer in women with exposure to spironolactone. “However, the certainty of the evidence was low and future studies are needed, including among diverse populations such as younger individuals and those with acne or hirsutism,” the study authors wrote.

In a separate study, researchers drew from patients in the Humana Insurance database from 2005 to 2017 to address whether spironolactone is associated with an increased risk of recurrence of breast cancer. Recurrent breast cancer was examined in 29,146 women with continuous health insurance for 2 years after a diagnosis of breast cancer. Of these, 746 were prescribed spironolactone, and the remainder were not. The researchers found that 123 women (16.5%) who were prescribed spironolactone had a breast cancer recurrence, compared with 3,649 women (12.8%) with a breast cancer recurrence who had not been prescribed spironolactone (P = .004). Adjusted Cox regression analysis following propensity matching showed no association between spironolactone and increased breast cancer recurrence (adjusted hazard ratio, 0.966; P = .953).

According to Dr. Harper, spironolactone may take about 3 months to kick in. “Likely this is a long-term treatment, and most of the time we’re going to be using it in combination with other acne treatments such as topical retinoids or topical benzoyl peroxide, oral antibiotics, or even isotretinoin.”

A study of long-term spironolactone use in 403 women found that the most common dose prescribed was 100 mg/day, and 68% of the women were concurrently prescribed a topical retinoid, 2.2% an oral antibiotic, and 40.7% an oral contraceptive.

The study population included 32 patients with a history of polycystic ovarian syndrome, 1 with a history of breast cancer, and 5 were hypercoagulable. Patients took the drug for a mean of 471 days. “As opposed to our antibiotics, where the course for patients is generally 3-4 months, when you start someone on spironolactone, they may end up staying on it,” Dr. Harper said.

Dr. Harper disclosed that she serves as an advisor or consultant for Almirall, Cassiopeia, Cutera, EPI, Galderma, L’Oreal, Ortho Dermatologics, Sol Gel, and Vyne. She also serves as a speaker or member of a speaker’s bureau for Almirall, Cassiopeia, Cutera, EPI, Galderma, Journey Almirall, L’Oreal, Ortho Dermatologics, Sun Pharmaceutical Industries, and Vyne.

Medscape and this news organization are owned by the same parent company.

HONOLULU – In the clinical experience of Julie C. Harper, MD, an increasing number of women with acne are turning to off-label, long-term treatment with spironolactone.

“Spironolactone is fairly accessible, inexpensive, and effective for our patients,” Dr. Harper, a dermatologist who practices in Birmingham, Ala., said at the Hawaii Dermatology Seminar provided by MedscapeLIVE!

An aldosterone receptor antagonist commonly used to treat high blood pressure and heart failure, spironolactone also has antiandrogenic properties with a proven track record for treating acne and hirsutism. It reduces androgen production, inhibits 5-alpha reductase, and increases sex hormone binding globulin. The dosing range for treating acne is 25 mg to 200 mg per day, but Dr. Harper prefers a maximum dose of 100 mg per day.

According to a systematic review of its use for acne in adult women, the most common side effect is menstrual irregularity, while other common side effects include breast tenderness/swelling, fatigue, and headaches.

“The higher the dose, the higher the rate of side effects,” she said. Concomitant use of an oral contraceptive lessens menstrual irregularities and prevents pregnancies, to avoid exposure during pregnancy and the hypothetical risk of feminization of the male fetus with exposure late in the first trimester. “Early in my career, I used to say if you’re going to be on spironolactone you’re also going to be on an oral contraceptive. But the longer I’ve practiced, I’ve learned that women who have a contraindication to birth control pills or who don’t want to take it can still benefit from an oral antiandrogen by being on spironolactone.”

A large retrospective analysis of 14-year data concluded that routine potassium monitoring is unnecessary for healthy women taking spironolactone for acne. “If you’re between the ages of 18 and 45, healthy, and not taking other medications where I’m worried about potassium levels, I’m not checking those levels at all,” Dr. Harper said.

Spironolactone labeling includes a boxed warning regarding the potential for tumorigenicity based on rat studies, but the dosages used in those studies were 25-250 times higher than the exposure dose in humans, Dr. Harper said.

Results from a systematic review and meta-analysis of seven studies in the medical literature found no evidence of an increased risk of breast cancer in women with exposure to spironolactone. “However, the certainty of the evidence was low and future studies are needed, including among diverse populations such as younger individuals and those with acne or hirsutism,” the study authors wrote.

In a separate study, researchers drew from patients in the Humana Insurance database from 2005 to 2017 to address whether spironolactone is associated with an increased risk of recurrence of breast cancer. Recurrent breast cancer was examined in 29,146 women with continuous health insurance for 2 years after a diagnosis of breast cancer. Of these, 746 were prescribed spironolactone, and the remainder were not. The researchers found that 123 women (16.5%) who were prescribed spironolactone had a breast cancer recurrence, compared with 3,649 women (12.8%) with a breast cancer recurrence who had not been prescribed spironolactone (P = .004). Adjusted Cox regression analysis following propensity matching showed no association between spironolactone and increased breast cancer recurrence (adjusted hazard ratio, 0.966; P = .953).

According to Dr. Harper, spironolactone may take about 3 months to kick in. “Likely this is a long-term treatment, and most of the time we’re going to be using it in combination with other acne treatments such as topical retinoids or topical benzoyl peroxide, oral antibiotics, or even isotretinoin.”

A study of long-term spironolactone use in 403 women found that the most common dose prescribed was 100 mg/day, and 68% of the women were concurrently prescribed a topical retinoid, 2.2% an oral antibiotic, and 40.7% an oral contraceptive.

The study population included 32 patients with a history of polycystic ovarian syndrome, 1 with a history of breast cancer, and 5 were hypercoagulable. Patients took the drug for a mean of 471 days. “As opposed to our antibiotics, where the course for patients is generally 3-4 months, when you start someone on spironolactone, they may end up staying on it,” Dr. Harper said.

Dr. Harper disclosed that she serves as an advisor or consultant for Almirall, Cassiopeia, Cutera, EPI, Galderma, L’Oreal, Ortho Dermatologics, Sol Gel, and Vyne. She also serves as a speaker or member of a speaker’s bureau for Almirall, Cassiopeia, Cutera, EPI, Galderma, Journey Almirall, L’Oreal, Ortho Dermatologics, Sun Pharmaceutical Industries, and Vyne.

Medscape and this news organization are owned by the same parent company.