Aesthetic Dermatology

Hypersensitivity to implantable devices, albeit rare, is a growing problem. Cutaneous and noncutaneous reactions can occur secondary to metals and metal alloys, according to a report on biological responses to metal implants released by the Food and Drug Administration in September 2019. Large controlled studies are lacking, and the FDA has initiated extensive postmarketing reviews of certain metal implants in response to safety concerns. Further research is needed on the composition of these implants, the diverse spectrum of metals used, the physical environment in which they are implanted, and the immune response associated with implants.

Local and systemic type IV hypersensitivity reactions can result from exposure to metal ions, which are thought to act as haptens and bind to proteins. The hapten-protein complex acts as the antigen for the T cell. Additionally, both acute and chronic inflammatory responses secondary to wound healing and foreign body reactions can occur. Neutrophils and macrophages elicit a tissue response, which can cause aseptic infection, loosening of joints, and tissue damage. Furthermore, corrosion of metal implants can lead to release of metal ions, which can have genotoxic and carcinogenic effects.

Clinical and subclinical effects of implantable devices depend on the device itself, the composition of the device, the tissue type, and an individual’s immune characteristics. Metal debris released from implants can activate innate and adaptive immune responses through a variety of different mechanisms, depending on the implant type and in what tissues the implant is placed. In the case of orthopedic implants, the most common implants, osteoclasts can sense metal and induce proinflammatory cytokines, which can result in corrosion and uptake of metal particles. Metal devices used in the central nervous system, such as intracerebral electrodes, can cause inflammatory responses leading to tissue encapsulation of electrodes. Corrosion of electrodes and release of metal ions can also impede ion channels in the CNS, blocking critical neuron-signaling pathways. Inflammatory reactions surrounding cardiac and vascular implants containing metal activate coagulation cascades, resulting in endothelial injury and activation of thrombi.

Despite the commonly used term “metal allergy” that delineates a type IV hypersensitivity reaction, reports in the literature supports the existence of both innate and adaptive immune responses to metal implanted in tissues. The recommended terminology is “adverse reactions to metal debris.” The clinical presentation may not be straightforward or easily attributed to the implant. Diagnostic tools are limited and may not detect a causal relationship.

Clinical symptoms can range from local rashes and pruritus to cardiac damage, depression, vertigo, and neurologic symptoms; autoimmune/autoinflammatory reactions including chronic fatigue and autoimmune-like systemic symptoms, such as joint pain, headaches, and hair loss, have also been reported in association with implants containing metal. In addition to pruritus, dermatologic manifestations can include erythema, edema, papules, vesicles, as well as systemic hypersensitivity reactions. Typically, cutaneous reactions usually present within 2 days to 24 months of implantation and may be considered surgical-site infections. Although these reactions can be treated with topical or oral corticosteroids, removal of the device is frequently needed for complete clearance.

In clinical practice, it has been frustrating that potential adverse reactions to metal implants are often overlooked because they are thought to be so rare. There are case series documenting metal implant hypersensitivity, but the actual prevalence of hypersensitivity or autoinflammatory reactions is not known. Testing methods are often inaccurate; therefore, identification of at-risk individuals and management of symptomatic patients with implants is important.

The 2016 American Contact Dermatitis Society guidelines do not recommend preimplantation patch testing unless there is a suspected metal allergy. However, patch testing cannot identify the extent of corrosion, autoinflammatory reactions, and foreign body reactions that can occur.

We must keep an open mind in patients who have implanted devices and have unusual or otherwise undefined symptoms. Often, the symptoms do not directly correspond to the site of implantation and the only way to discern whether the implant is the cause and to treat symptoms is removal of the implanted device.

Dr. Wesley and Dr. Talakoub are cocontributors to this column. Dr. Wesley practices dermatology in Beverly Hills, Calif. Dr. Talakoub is in private practice in McLean, Va. This month’s column is by Dr. Talakoub. Write to them at [email protected]. They had no relevant disclosures.

 

References

Food and Drug Administration. Biological Responses to Metal Implants. 2019 Sep. https://www.fda.gov/media/131150/download.

Atwater AR, Reeder M. Cutis. 2020 Feb;105(2):68-70.

Schalock PC et al. Dermatitis. Sep-Oct 2016;27(5):241-7.

Hypersensitivity to implantable devices, albeit rare, is a growing problem. Cutaneous and noncutaneous reactions can occur secondary to metals and metal alloys, according to a report on biological responses to metal implants released by the Food and Drug Administration in September 2019. Large controlled studies are lacking, and the FDA has initiated extensive postmarketing reviews of certain metal implants in response to safety concerns. Further research is needed on the composition of these implants, the diverse spectrum of metals used, the physical environment in which they are implanted, and the immune response associated with implants.

Local and systemic type IV hypersensitivity reactions can result from exposure to metal ions, which are thought to act as haptens and bind to proteins. The hapten-protein complex acts as the antigen for the T cell. Additionally, both acute and chronic inflammatory responses secondary to wound healing and foreign body reactions can occur. Neutrophils and macrophages elicit a tissue response, which can cause aseptic infection, loosening of joints, and tissue damage. Furthermore, corrosion of metal implants can lead to release of metal ions, which can have genotoxic and carcinogenic effects.

Clinical and subclinical effects of implantable devices depend on the device itself, the composition of the device, the tissue type, and an individual’s immune characteristics. Metal debris released from implants can activate innate and adaptive immune responses through a variety of different mechanisms, depending on the implant type and in what tissues the implant is placed. In the case of orthopedic implants, the most common implants, osteoclasts can sense metal and induce proinflammatory cytokines, which can result in corrosion and uptake of metal particles. Metal devices used in the central nervous system, such as intracerebral electrodes, can cause inflammatory responses leading to tissue encapsulation of electrodes. Corrosion of electrodes and release of metal ions can also impede ion channels in the CNS, blocking critical neuron-signaling pathways. Inflammatory reactions surrounding cardiac and vascular implants containing metal activate coagulation cascades, resulting in endothelial injury and activation of thrombi.

Despite the commonly used term “metal allergy” that delineates a type IV hypersensitivity reaction, reports in the literature supports the existence of both innate and adaptive immune responses to metal implanted in tissues. The recommended terminology is “adverse reactions to metal debris.” The clinical presentation may not be straightforward or easily attributed to the implant. Diagnostic tools are limited and may not detect a causal relationship.

Clinical symptoms can range from local rashes and pruritus to cardiac damage, depression, vertigo, and neurologic symptoms; autoimmune/autoinflammatory reactions including chronic fatigue and autoimmune-like systemic symptoms, such as joint pain, headaches, and hair loss, have also been reported in association with implants containing metal. In addition to pruritus, dermatologic manifestations can include erythema, edema, papules, vesicles, as well as systemic hypersensitivity reactions. Typically, cutaneous reactions usually present within 2 days to 24 months of implantation and may be considered surgical-site infections. Although these reactions can be treated with topical or oral corticosteroids, removal of the device is frequently needed for complete clearance.

In clinical practice, it has been frustrating that potential adverse reactions to metal implants are often overlooked because they are thought to be so rare. There are case series documenting metal implant hypersensitivity, but the actual prevalence of hypersensitivity or autoinflammatory reactions is not known. Testing methods are often inaccurate; therefore, identification of at-risk individuals and management of symptomatic patients with implants is important.

The 2016 American Contact Dermatitis Society guidelines do not recommend preimplantation patch testing unless there is a suspected metal allergy. However, patch testing cannot identify the extent of corrosion, autoinflammatory reactions, and foreign body reactions that can occur.

We must keep an open mind in patients who have implanted devices and have unusual or otherwise undefined symptoms. Often, the symptoms do not directly correspond to the site of implantation and the only way to discern whether the implant is the cause and to treat symptoms is removal of the implanted device.

Dr. Wesley and Dr. Talakoub are cocontributors to this column. Dr. Wesley practices dermatology in Beverly Hills, Calif. Dr. Talakoub is in private practice in McLean, Va. This month’s column is by Dr. Talakoub. Write to them at [email protected]. They had no relevant disclosures.

 

References

Food and Drug Administration. Biological Responses to Metal Implants. 2019 Sep. https://www.fda.gov/media/131150/download.

Atwater AR, Reeder M. Cutis. 2020 Feb;105(2):68-70.

Schalock PC et al. Dermatitis. Sep-Oct 2016;27(5):241-7.

Hypersensitivity to implantable devices, albeit rare, is a growing problem. Cutaneous and noncutaneous reactions can occur secondary to metals and metal alloys, according to a report on biological responses to metal implants released by the Food and Drug Administration in September 2019. Large controlled studies are lacking, and the FDA has initiated extensive postmarketing reviews of certain metal implants in response to safety concerns. Further research is needed on the composition of these implants, the diverse spectrum of metals used, the physical environment in which they are implanted, and the immune response associated with implants.

Local and systemic type IV hypersensitivity reactions can result from exposure to metal ions, which are thought to act as haptens and bind to proteins. The hapten-protein complex acts as the antigen for the T cell. Additionally, both acute and chronic inflammatory responses secondary to wound healing and foreign body reactions can occur. Neutrophils and macrophages elicit a tissue response, which can cause aseptic infection, loosening of joints, and tissue damage. Furthermore, corrosion of metal implants can lead to release of metal ions, which can have genotoxic and carcinogenic effects.

Clinical and subclinical effects of implantable devices depend on the device itself, the composition of the device, the tissue type, and an individual’s immune characteristics. Metal debris released from implants can activate innate and adaptive immune responses through a variety of different mechanisms, depending on the implant type and in what tissues the implant is placed. In the case of orthopedic implants, the most common implants, osteoclasts can sense metal and induce proinflammatory cytokines, which can result in corrosion and uptake of metal particles. Metal devices used in the central nervous system, such as intracerebral electrodes, can cause inflammatory responses leading to tissue encapsulation of electrodes. Corrosion of electrodes and release of metal ions can also impede ion channels in the CNS, blocking critical neuron-signaling pathways. Inflammatory reactions surrounding cardiac and vascular implants containing metal activate coagulation cascades, resulting in endothelial injury and activation of thrombi.

Despite the commonly used term “metal allergy” that delineates a type IV hypersensitivity reaction, reports in the literature supports the existence of both innate and adaptive immune responses to metal implanted in tissues. The recommended terminology is “adverse reactions to metal debris.” The clinical presentation may not be straightforward or easily attributed to the implant. Diagnostic tools are limited and may not detect a causal relationship.

Clinical symptoms can range from local rashes and pruritus to cardiac damage, depression, vertigo, and neurologic symptoms; autoimmune/autoinflammatory reactions including chronic fatigue and autoimmune-like systemic symptoms, such as joint pain, headaches, and hair loss, have also been reported in association with implants containing metal. In addition to pruritus, dermatologic manifestations can include erythema, edema, papules, vesicles, as well as systemic hypersensitivity reactions. Typically, cutaneous reactions usually present within 2 days to 24 months of implantation and may be considered surgical-site infections. Although these reactions can be treated with topical or oral corticosteroids, removal of the device is frequently needed for complete clearance.

In clinical practice, it has been frustrating that potential adverse reactions to metal implants are often overlooked because they are thought to be so rare. There are case series documenting metal implant hypersensitivity, but the actual prevalence of hypersensitivity or autoinflammatory reactions is not known. Testing methods are often inaccurate; therefore, identification of at-risk individuals and management of symptomatic patients with implants is important.

The 2016 American Contact Dermatitis Society guidelines do not recommend preimplantation patch testing unless there is a suspected metal allergy. However, patch testing cannot identify the extent of corrosion, autoinflammatory reactions, and foreign body reactions that can occur.

We must keep an open mind in patients who have implanted devices and have unusual or otherwise undefined symptoms. Often, the symptoms do not directly correspond to the site of implantation and the only way to discern whether the implant is the cause and to treat symptoms is removal of the implanted device.

Dr. Wesley and Dr. Talakoub are cocontributors to this column. Dr. Wesley practices dermatology in Beverly Hills, Calif. Dr. Talakoub is in private practice in McLean, Va. This month’s column is by Dr. Talakoub. Write to them at [email protected]. They had no relevant disclosures.

 

References

Food and Drug Administration. Biological Responses to Metal Implants. 2019 Sep. https://www.fda.gov/media/131150/download.

Atwater AR, Reeder M. Cutis. 2020 Feb;105(2):68-70.

Schalock PC et al. Dermatitis. Sep-Oct 2016;27(5):241-7.

A novel formulation of botulinum toxin type A substantially improved the appearance of dynamic forehead lines while garnering favorable patient satisfaction scores in an interim analysis of a phase 2 clinical trial, Jeremy B. Green, MD, said at the virtual annual meeting of the American Academy of Dermatology.

When the study is completed, conclusions can be reached about the investigational product’s durability of benefit for treatment of dynamic forehead lines, which are notoriously challenging to treat. However, much is already known about the product’s durability for treatment of glabellar lines, as demonstrated in SAKURA 1 and SAKURA 2, two pivotal, phase 3, multicenter, randomized, double-blind, placebo-controlled trials totaling 609 patients.

In SAKURA 1 and 2, glabellar line severity didn’t return to baseline until a median of 28 and 26 weeks after injection. In contrast, as the study authors noted, the majority of patients whose glabellar lines are treated with the currently available botulinum toxin type A products are no longer responders by 3-4 months after treatment. Since surveys indicate most patients receive repeated injections every 5-6 months, that means they’re walking around with suboptimal results for the last 2-3 months before their next treatment session (Plast Reconstr Surg. 2020 Jan;145[1]:45-58).

This investigational neuromodulator, known as DaxibotulinumtoxinA for Injection, or DAXI, is composed of a highly purified 150-KDa botulinum toxin type A coupled with a proprietary stabilizing peptide. The product is formulated without human serum albumin and, once reconstituted, is stable at room temperature.

Dr. Green, a dermatologist in private practice in Coral Gables, Fla., reported on 61 participants in the phase 2 study, all with moderate or severe forehead lines and glabellar lines as assessed by both investigators and patients on structured scales. The patients’ glabellar lines were treated with 40 U of DAXI at baseline. Then 2 weeks later, their dynamic forehead lines were treated with either 12 U, 18 U, 24 U, or 30 U of DAXI. This sequential treatment recapitulates the approach widely used in clinical practice, he noted.

At baseline, two-thirds of patients had severe forehead lines at maximum eyebrow elevation as determined by Investigator Global Assessment – Forehead Wrinkle Severity and Patient Forehead Wrinkle Severity. The other third of participants had moderate forehead lines.

The primary endpoint was the presence of no or mild forehead lines by investigator assessment 4 weeks after treatment. This was achieved in 86% of patients who received 12 U of DAXI, 87% who recieved 18 U, 94% who received 24 U, and 100% of those who received 30 U.

“There appears to be a dose-dependent response, but this hasn’t yet been statistically analyzed,” Dr. Green said.

By patient assessment, there were no or only mild forehead lines at 4 weeks in 57% of those who received the lowest dose of DAXI, with rates of 80%, 100%, and 93% in those who received 18 U, 24 U, and 30 U.

At week 4, 57% of patients who got 12 U of DAXI pronounced themselves “satisfied” or “very satisfied” with DAXI therapy, as did 73%, 100%, and 93% of those who got the higher doses.

The treatment-related adverse events consisted of a smattering of cases of edema, erythema, or headache, similar to what’s described in the product labeling of all the neuromodulators.

Revance Therapeutics has applied to the Food and Drug Administration for marketing approval of DAXI for the treatment of glabellar lines. A regulatory decision is expected in late November. The company is also developing DAXI for the treatment of variety of neurologic and musculoskeletal conditions, including poststroke upper limb spasticity.

In an interview, Dr. Green said he was favorably impressed with DAXI’s durability for amelioration of forehead lines in the patients he personally treated in the ongoing phase 2 study, although there was no head-to-head comparison with other neuromodulators in the trial. He’s not aware of any planned phase 3 trial aimed at obtaining a forehead line indication.

“Of course, all four of the neuromodulators currently approved in the U.S. have glabellar line indications, but all are also used off-label in other locations, so I would imagine that DAXI will be used similarly if and when it is FDA-approved,” the dermatologist added.

He reported serving as a paid investigator for Revance.

[email protected]

A novel formulation of botulinum toxin type A substantially improved the appearance of dynamic forehead lines while garnering favorable patient satisfaction scores in an interim analysis of a phase 2 clinical trial, Jeremy B. Green, MD, said at the virtual annual meeting of the American Academy of Dermatology.

When the study is completed, conclusions can be reached about the investigational product’s durability of benefit for treatment of dynamic forehead lines, which are notoriously challenging to treat. However, much is already known about the product’s durability for treatment of glabellar lines, as demonstrated in SAKURA 1 and SAKURA 2, two pivotal, phase 3, multicenter, randomized, double-blind, placebo-controlled trials totaling 609 patients.

In SAKURA 1 and 2, glabellar line severity didn’t return to baseline until a median of 28 and 26 weeks after injection. In contrast, as the study authors noted, the majority of patients whose glabellar lines are treated with the currently available botulinum toxin type A products are no longer responders by 3-4 months after treatment. Since surveys indicate most patients receive repeated injections every 5-6 months, that means they’re walking around with suboptimal results for the last 2-3 months before their next treatment session (Plast Reconstr Surg. 2020 Jan;145[1]:45-58).

This investigational neuromodulator, known as DaxibotulinumtoxinA for Injection, or DAXI, is composed of a highly purified 150-KDa botulinum toxin type A coupled with a proprietary stabilizing peptide. The product is formulated without human serum albumin and, once reconstituted, is stable at room temperature.

Dr. Green, a dermatologist in private practice in Coral Gables, Fla., reported on 61 participants in the phase 2 study, all with moderate or severe forehead lines and glabellar lines as assessed by both investigators and patients on structured scales. The patients’ glabellar lines were treated with 40 U of DAXI at baseline. Then 2 weeks later, their dynamic forehead lines were treated with either 12 U, 18 U, 24 U, or 30 U of DAXI. This sequential treatment recapitulates the approach widely used in clinical practice, he noted.

At baseline, two-thirds of patients had severe forehead lines at maximum eyebrow elevation as determined by Investigator Global Assessment – Forehead Wrinkle Severity and Patient Forehead Wrinkle Severity. The other third of participants had moderate forehead lines.

The primary endpoint was the presence of no or mild forehead lines by investigator assessment 4 weeks after treatment. This was achieved in 86% of patients who received 12 U of DAXI, 87% who recieved 18 U, 94% who received 24 U, and 100% of those who received 30 U.

“There appears to be a dose-dependent response, but this hasn’t yet been statistically analyzed,” Dr. Green said.

By patient assessment, there were no or only mild forehead lines at 4 weeks in 57% of those who received the lowest dose of DAXI, with rates of 80%, 100%, and 93% in those who received 18 U, 24 U, and 30 U.

At week 4, 57% of patients who got 12 U of DAXI pronounced themselves “satisfied” or “very satisfied” with DAXI therapy, as did 73%, 100%, and 93% of those who got the higher doses.

The treatment-related adverse events consisted of a smattering of cases of edema, erythema, or headache, similar to what’s described in the product labeling of all the neuromodulators.

Revance Therapeutics has applied to the Food and Drug Administration for marketing approval of DAXI for the treatment of glabellar lines. A regulatory decision is expected in late November. The company is also developing DAXI for the treatment of variety of neurologic and musculoskeletal conditions, including poststroke upper limb spasticity.

In an interview, Dr. Green said he was favorably impressed with DAXI’s durability for amelioration of forehead lines in the patients he personally treated in the ongoing phase 2 study, although there was no head-to-head comparison with other neuromodulators in the trial. He’s not aware of any planned phase 3 trial aimed at obtaining a forehead line indication.

“Of course, all four of the neuromodulators currently approved in the U.S. have glabellar line indications, but all are also used off-label in other locations, so I would imagine that DAXI will be used similarly if and when it is FDA-approved,” the dermatologist added.

He reported serving as a paid investigator for Revance.

[email protected]

A novel formulation of botulinum toxin type A substantially improved the appearance of dynamic forehead lines while garnering favorable patient satisfaction scores in an interim analysis of a phase 2 clinical trial, Jeremy B. Green, MD, said at the virtual annual meeting of the American Academy of Dermatology.

When the study is completed, conclusions can be reached about the investigational product’s durability of benefit for treatment of dynamic forehead lines, which are notoriously challenging to treat. However, much is already known about the product’s durability for treatment of glabellar lines, as demonstrated in SAKURA 1 and SAKURA 2, two pivotal, phase 3, multicenter, randomized, double-blind, placebo-controlled trials totaling 609 patients.

In SAKURA 1 and 2, glabellar line severity didn’t return to baseline until a median of 28 and 26 weeks after injection. In contrast, as the study authors noted, the majority of patients whose glabellar lines are treated with the currently available botulinum toxin type A products are no longer responders by 3-4 months after treatment. Since surveys indicate most patients receive repeated injections every 5-6 months, that means they’re walking around with suboptimal results for the last 2-3 months before their next treatment session (Plast Reconstr Surg. 2020 Jan;145[1]:45-58).

This investigational neuromodulator, known as DaxibotulinumtoxinA for Injection, or DAXI, is composed of a highly purified 150-KDa botulinum toxin type A coupled with a proprietary stabilizing peptide. The product is formulated without human serum albumin and, once reconstituted, is stable at room temperature.

Dr. Green, a dermatologist in private practice in Coral Gables, Fla., reported on 61 participants in the phase 2 study, all with moderate or severe forehead lines and glabellar lines as assessed by both investigators and patients on structured scales. The patients’ glabellar lines were treated with 40 U of DAXI at baseline. Then 2 weeks later, their dynamic forehead lines were treated with either 12 U, 18 U, 24 U, or 30 U of DAXI. This sequential treatment recapitulates the approach widely used in clinical practice, he noted.

At baseline, two-thirds of patients had severe forehead lines at maximum eyebrow elevation as determined by Investigator Global Assessment – Forehead Wrinkle Severity and Patient Forehead Wrinkle Severity. The other third of participants had moderate forehead lines.

The primary endpoint was the presence of no or mild forehead lines by investigator assessment 4 weeks after treatment. This was achieved in 86% of patients who received 12 U of DAXI, 87% who recieved 18 U, 94% who received 24 U, and 100% of those who received 30 U.

“There appears to be a dose-dependent response, but this hasn’t yet been statistically analyzed,” Dr. Green said.

By patient assessment, there were no or only mild forehead lines at 4 weeks in 57% of those who received the lowest dose of DAXI, with rates of 80%, 100%, and 93% in those who received 18 U, 24 U, and 30 U.

At week 4, 57% of patients who got 12 U of DAXI pronounced themselves “satisfied” or “very satisfied” with DAXI therapy, as did 73%, 100%, and 93% of those who got the higher doses.

The treatment-related adverse events consisted of a smattering of cases of edema, erythema, or headache, similar to what’s described in the product labeling of all the neuromodulators.

Revance Therapeutics has applied to the Food and Drug Administration for marketing approval of DAXI for the treatment of glabellar lines. A regulatory decision is expected in late November. The company is also developing DAXI for the treatment of variety of neurologic and musculoskeletal conditions, including poststroke upper limb spasticity.

In an interview, Dr. Green said he was favorably impressed with DAXI’s durability for amelioration of forehead lines in the patients he personally treated in the ongoing phase 2 study, although there was no head-to-head comparison with other neuromodulators in the trial. He’s not aware of any planned phase 3 trial aimed at obtaining a forehead line indication.

“Of course, all four of the neuromodulators currently approved in the U.S. have glabellar line indications, but all are also used off-label in other locations, so I would imagine that DAXI will be used similarly if and when it is FDA-approved,” the dermatologist added.

He reported serving as a paid investigator for Revance.

[email protected]

The popularity of injectable fillers for aesthetic use continues to rise, and cosmetic injectors must select from an increasing range of options to achieve optimal outcomes. In addition to formulating a treatment plan and having an intimate knowledge of the facial anatomy, filler selection is critical along with an appreciation of both approved and off-label indications for these products. Appropriate patient selection and treatment technique can minimize adverse events (AEs) and allow for the best outcomes.

The US Food and Drug Administration (FDA) approved the first injectable hyaluronic acid (HA) filler in 2003, the first addition since the approval of bovine collagen in 1981. To date, there are now 4 groups of approved fillers: (1) HA (Belotero Balance [Merz North America, Inc], Juvèderm products [Allergan], Restylane products [Galderma Laboratories, LP], Resilient HA products [Revance Therapeutics Inc and Teoxane SA]), (2) calcium hydroxylapatite (Radiesse [Merz North America, Inc]), (3) poly-L-lactic acid (Sculptra Aesthetic [Galderma Laboratories, LP]), and (4) polymethylmethacrylate (Bellafill [Suneva Medical, Inc]).^1-3 Given the versatility of this wide portfolio of products, which often are used in combination with one another, we have advanced from the early goals of filling isolated lines or wrinkles on the face to the 3-dimensional restructuring of an entire treatment area. The increasing diversity of products, particularly the range of rheologic properties of HA fillers, allows the injector to strategically select the type of filler and depth of injection to achieve the desired treatment outcome. The duration of the treatment effects also is related to the properties of the filler.^4,5

Advancements in injectable fillers also have led to new applications both on and off the face. Many pivotal clinical trials of fillers were performed in isolated anatomic areas, most commonly the nasolabial folds, leading to FDA approval of this indication. Other FDA-approved indications for fillers include lip augmentation (Juvèderm Ultra, Juvèderm Volbella, Restylane, Restylane Silk, Restylane Kysse), human immunodeficiency virus–associated lipoatrophy (Sculptra Aesthetic, Radiesse), volumization of the dorsal hands (Radiesse, Restylane Lyft), acne scarring (Bellafill), and age-related volume loss of the midface (Juvèderm Voluma, Restylane Lyft). Although it is considered off label, treatment of the temples, brows, tear troughs, jawline, horizontal neck lines, and etched-in radial cheek lines has been reported.^6-9 It is legal to use fillers to treat these areas, but data have not yet been evaluated by the FDA to officially grant their approval, which likely will change with the conclusion of many ongoing industry-sponsored trials.

Adverse events from filler injections range from the anticipated transient tenderness, swelling, and bruising, which are likely to resolve in a matter of days, to the most severe complications—intravascular occlusion with permanent sequelae, namely tissue necrosis, blindness or visual compromise, and stroke. It is critical to obtain written informed consent prior to proceeding with dermal filler injections. Masterful knowledge of the facial anatomy, in particular the location and depth of key vascular structures, is critical in minimizing these severe AEs. Injection technique, including use of a microcannula, can reduce the risk, in addition to administration of small volumes of filler at a time, aspiration prior to injection, and use of a retrograde injection technique. There also are variations in the predicted courses of vascular structures, as demonstrated in a cadaveric study showing 4 variants of the course of the angular artery.¹⁰

Hyaluronic acid fillers are the most commonly used of the available products, and hyaluronidase, which can dissolve the filler, can be utilized to manage emergent and nonemergent AEs.¹¹ Physical examination findings related to impending necrosis include blanching of the skin in the distribution of a key vessel with a mottled or reticulated purple discoloration. Hyaluronidase, on the order of hundreds of units, may be injected into the area of vascular compromise until reperfusion is achieved, in addition to administering aspirin and applying warm compresses to the area.^11,12 The most severe AEs are blindness and/or stroke, associated with findings such as immediate vision loss, pain, nausea, vomiting, and neurologic compromise. Although the glabella, nose, nasolabial folds, and forehead are the most common anatomic areas associated with these AEs (in order of frequency), injections in all areas of the face have been associated with blindness.^13,14 Retrobulbar and/or peribulbar injection of hyaluronidase for management of vision changes has been reported, but in most cases vision loss associated with dermal filler injections is not reversible.^14,15

Nonemergent uses of enzyme reversal of filler placement include correcting undesirable aesthetic outcomes, such as asymmetry, misplaced filler, or even delayed granulomatous reactions. Hyaluronidase dosage should be determined by the amount and type of filler that was delivered to the patient. All HA fillers are not created equally, and evidence from dosing studies indicates that higher cross-linked and more cohesive fillers require higher doses of hyaluronidase.¹¹ For example, Juvèderm Voluma, created as a mixture of low- and high-molecular-weight HA, has a higher cross-linking ratio. Approximately 30 U of hyaluronidase are suggested to dissolve 0.1 cc of Juvèderm Voluma as compared to 10 U of hyaluronidase for 0.1 cc of Juvèderm Ultra and 5 U for 0.1 cc of Restylane.¹¹

Treatment with dermal fillers generally is safe and effective, and as new fillers come to the market, we must identify how they will help further our goal of improving patient outcomes. The effects of coronavirus disease 19 on aesthetic medicine are still unclear, yet this uncertainty should not deflect treating clinicians from overlooking the fundamentals of dermal fillers. In addition to considering the appropriate use of each filler based on its unique characteristics and indications, we must be sure that we are prepared with the tools to manage any and all possible complications.

The popularity of injectable fillers for aesthetic use continues to rise, and cosmetic injectors must select from an increasing range of options to achieve optimal outcomes. In addition to formulating a treatment plan and having an intimate knowledge of the facial anatomy, filler selection is critical along with an appreciation of both approved and off-label indications for these products. Appropriate patient selection and treatment technique can minimize adverse events (AEs) and allow for the best outcomes.

The US Food and Drug Administration (FDA) approved the first injectable hyaluronic acid (HA) filler in 2003, the first addition since the approval of bovine collagen in 1981. To date, there are now 4 groups of approved fillers: (1) HA (Belotero Balance [Merz North America, Inc], Juvèderm products [Allergan], Restylane products [Galderma Laboratories, LP], Resilient HA products [Revance Therapeutics Inc and Teoxane SA]), (2) calcium hydroxylapatite (Radiesse [Merz North America, Inc]), (3) poly-L-lactic acid (Sculptra Aesthetic [Galderma Laboratories, LP]), and (4) polymethylmethacrylate (Bellafill [Suneva Medical, Inc]).^1-3 Given the versatility of this wide portfolio of products, which often are used in combination with one another, we have advanced from the early goals of filling isolated lines or wrinkles on the face to the 3-dimensional restructuring of an entire treatment area. The increasing diversity of products, particularly the range of rheologic properties of HA fillers, allows the injector to strategically select the type of filler and depth of injection to achieve the desired treatment outcome. The duration of the treatment effects also is related to the properties of the filler.^4,5

Advancements in injectable fillers also have led to new applications both on and off the face. Many pivotal clinical trials of fillers were performed in isolated anatomic areas, most commonly the nasolabial folds, leading to FDA approval of this indication. Other FDA-approved indications for fillers include lip augmentation (Juvèderm Ultra, Juvèderm Volbella, Restylane, Restylane Silk, Restylane Kysse), human immunodeficiency virus–associated lipoatrophy (Sculptra Aesthetic, Radiesse), volumization of the dorsal hands (Radiesse, Restylane Lyft), acne scarring (Bellafill), and age-related volume loss of the midface (Juvèderm Voluma, Restylane Lyft). Although it is considered off label, treatment of the temples, brows, tear troughs, jawline, horizontal neck lines, and etched-in radial cheek lines has been reported.^6-9 It is legal to use fillers to treat these areas, but data have not yet been evaluated by the FDA to officially grant their approval, which likely will change with the conclusion of many ongoing industry-sponsored trials.

Adverse events from filler injections range from the anticipated transient tenderness, swelling, and bruising, which are likely to resolve in a matter of days, to the most severe complications—intravascular occlusion with permanent sequelae, namely tissue necrosis, blindness or visual compromise, and stroke. It is critical to obtain written informed consent prior to proceeding with dermal filler injections. Masterful knowledge of the facial anatomy, in particular the location and depth of key vascular structures, is critical in minimizing these severe AEs. Injection technique, including use of a microcannula, can reduce the risk, in addition to administration of small volumes of filler at a time, aspiration prior to injection, and use of a retrograde injection technique. There also are variations in the predicted courses of vascular structures, as demonstrated in a cadaveric study showing 4 variants of the course of the angular artery.¹⁰

Hyaluronic acid fillers are the most commonly used of the available products, and hyaluronidase, which can dissolve the filler, can be utilized to manage emergent and nonemergent AEs.¹¹ Physical examination findings related to impending necrosis include blanching of the skin in the distribution of a key vessel with a mottled or reticulated purple discoloration. Hyaluronidase, on the order of hundreds of units, may be injected into the area of vascular compromise until reperfusion is achieved, in addition to administering aspirin and applying warm compresses to the area.^11,12 The most severe AEs are blindness and/or stroke, associated with findings such as immediate vision loss, pain, nausea, vomiting, and neurologic compromise. Although the glabella, nose, nasolabial folds, and forehead are the most common anatomic areas associated with these AEs (in order of frequency), injections in all areas of the face have been associated with blindness.^13,14 Retrobulbar and/or peribulbar injection of hyaluronidase for management of vision changes has been reported, but in most cases vision loss associated with dermal filler injections is not reversible.^14,15

Nonemergent uses of enzyme reversal of filler placement include correcting undesirable aesthetic outcomes, such as asymmetry, misplaced filler, or even delayed granulomatous reactions. Hyaluronidase dosage should be determined by the amount and type of filler that was delivered to the patient. All HA fillers are not created equally, and evidence from dosing studies indicates that higher cross-linked and more cohesive fillers require higher doses of hyaluronidase.¹¹ For example, Juvèderm Voluma, created as a mixture of low- and high-molecular-weight HA, has a higher cross-linking ratio. Approximately 30 U of hyaluronidase are suggested to dissolve 0.1 cc of Juvèderm Voluma as compared to 10 U of hyaluronidase for 0.1 cc of Juvèderm Ultra and 5 U for 0.1 cc of Restylane.¹¹

Treatment with dermal fillers generally is safe and effective, and as new fillers come to the market, we must identify how they will help further our goal of improving patient outcomes. The effects of coronavirus disease 19 on aesthetic medicine are still unclear, yet this uncertainty should not deflect treating clinicians from overlooking the fundamentals of dermal fillers. In addition to considering the appropriate use of each filler based on its unique characteristics and indications, we must be sure that we are prepared with the tools to manage any and all possible complications.

The popularity of injectable fillers for aesthetic use continues to rise, and cosmetic injectors must select from an increasing range of options to achieve optimal outcomes. In addition to formulating a treatment plan and having an intimate knowledge of the facial anatomy, filler selection is critical along with an appreciation of both approved and off-label indications for these products. Appropriate patient selection and treatment technique can minimize adverse events (AEs) and allow for the best outcomes.

The US Food and Drug Administration (FDA) approved the first injectable hyaluronic acid (HA) filler in 2003, the first addition since the approval of bovine collagen in 1981. To date, there are now 4 groups of approved fillers: (1) HA (Belotero Balance [Merz North America, Inc], Juvèderm products [Allergan], Restylane products [Galderma Laboratories, LP], Resilient HA products [Revance Therapeutics Inc and Teoxane SA]), (2) calcium hydroxylapatite (Radiesse [Merz North America, Inc]), (3) poly-L-lactic acid (Sculptra Aesthetic [Galderma Laboratories, LP]), and (4) polymethylmethacrylate (Bellafill [Suneva Medical, Inc]).^1-3 Given the versatility of this wide portfolio of products, which often are used in combination with one another, we have advanced from the early goals of filling isolated lines or wrinkles on the face to the 3-dimensional restructuring of an entire treatment area. The increasing diversity of products, particularly the range of rheologic properties of HA fillers, allows the injector to strategically select the type of filler and depth of injection to achieve the desired treatment outcome. The duration of the treatment effects also is related to the properties of the filler.^4,5

Advancements in injectable fillers also have led to new applications both on and off the face. Many pivotal clinical trials of fillers were performed in isolated anatomic areas, most commonly the nasolabial folds, leading to FDA approval of this indication. Other FDA-approved indications for fillers include lip augmentation (Juvèderm Ultra, Juvèderm Volbella, Restylane, Restylane Silk, Restylane Kysse), human immunodeficiency virus–associated lipoatrophy (Sculptra Aesthetic, Radiesse), volumization of the dorsal hands (Radiesse, Restylane Lyft), acne scarring (Bellafill), and age-related volume loss of the midface (Juvèderm Voluma, Restylane Lyft). Although it is considered off label, treatment of the temples, brows, tear troughs, jawline, horizontal neck lines, and etched-in radial cheek lines has been reported.^6-9 It is legal to use fillers to treat these areas, but data have not yet been evaluated by the FDA to officially grant their approval, which likely will change with the conclusion of many ongoing industry-sponsored trials.

Adverse events from filler injections range from the anticipated transient tenderness, swelling, and bruising, which are likely to resolve in a matter of days, to the most severe complications—intravascular occlusion with permanent sequelae, namely tissue necrosis, blindness or visual compromise, and stroke. It is critical to obtain written informed consent prior to proceeding with dermal filler injections. Masterful knowledge of the facial anatomy, in particular the location and depth of key vascular structures, is critical in minimizing these severe AEs. Injection technique, including use of a microcannula, can reduce the risk, in addition to administration of small volumes of filler at a time, aspiration prior to injection, and use of a retrograde injection technique. There also are variations in the predicted courses of vascular structures, as demonstrated in a cadaveric study showing 4 variants of the course of the angular artery.¹⁰

Hyaluronic acid fillers are the most commonly used of the available products, and hyaluronidase, which can dissolve the filler, can be utilized to manage emergent and nonemergent AEs.¹¹ Physical examination findings related to impending necrosis include blanching of the skin in the distribution of a key vessel with a mottled or reticulated purple discoloration. Hyaluronidase, on the order of hundreds of units, may be injected into the area of vascular compromise until reperfusion is achieved, in addition to administering aspirin and applying warm compresses to the area.^11,12 The most severe AEs are blindness and/or stroke, associated with findings such as immediate vision loss, pain, nausea, vomiting, and neurologic compromise. Although the glabella, nose, nasolabial folds, and forehead are the most common anatomic areas associated with these AEs (in order of frequency), injections in all areas of the face have been associated with blindness.^13,14 Retrobulbar and/or peribulbar injection of hyaluronidase for management of vision changes has been reported, but in most cases vision loss associated with dermal filler injections is not reversible.^14,15

Nonemergent uses of enzyme reversal of filler placement include correcting undesirable aesthetic outcomes, such as asymmetry, misplaced filler, or even delayed granulomatous reactions. Hyaluronidase dosage should be determined by the amount and type of filler that was delivered to the patient. All HA fillers are not created equally, and evidence from dosing studies indicates that higher cross-linked and more cohesive fillers require higher doses of hyaluronidase.¹¹ For example, Juvèderm Voluma, created as a mixture of low- and high-molecular-weight HA, has a higher cross-linking ratio. Approximately 30 U of hyaluronidase are suggested to dissolve 0.1 cc of Juvèderm Voluma as compared to 10 U of hyaluronidase for 0.1 cc of Juvèderm Ultra and 5 U for 0.1 cc of Restylane.¹¹

Treatment with dermal fillers generally is safe and effective, and as new fillers come to the market, we must identify how they will help further our goal of improving patient outcomes. The effects of coronavirus disease 19 on aesthetic medicine are still unclear, yet this uncertainty should not deflect treating clinicians from overlooking the fundamentals of dermal fillers. In addition to considering the appropriate use of each filler based on its unique characteristics and indications, we must be sure that we are prepared with the tools to manage any and all possible complications.

A study using safety surveillance data of botulinum toxin found significant associations between its use and antidepressant effects, across several indications and different injection sites, according to the study’s authors.

Their results show that the antidepressant effect of botulinum toxin “administered for various indications goes beyond the control of the intended disease states and does not depend on the location of the injection,” according to Tigran Makunts, PharmD, of the Skaggs School of Pharmacy and Pharmaceutical Sciences at the University of California, San Diego, and coauthors.

Previous high-quality studies have found botulinum toxin treatment has been associated with antidepressant effects when administered to the glabellar region of the face, they noted. The study was published in Scientific Reports.

The researchers evaluated adverse events reported to the Food and Drug Administration’s current adverse event reporting system (FAERS) between September 2012 and December 2019, and the FDA’s previous adverse event reporting system between January 2004 and August 2012. Overall, they analyzed 174,243 reports, which were divided into eight treatment-related groups based on the indication for botulinum toxin: Cosmetic use (20,684 patients), migraine (4,180 patients), spasms and spasticity not involving facial muscles (2,335 patients), neurological and urinary bladder disorders (915 patients), torticollis (1,360 patients), hyperhidrosis (601 patients), blepharospasm (487 patients), and sialorrhea (157 patients). Each group was matched to controls from the FAERS database, who had different treatments for the same indications. (Reports in which patients were on an antidepressant or where depression was listed as an indication were not included).

In nearly all treatment groups, reports of depression and depression-related adverse events were significantly lower among those who received botulinum toxin, compared with controls: For those who received botulinum toxin injections in facial muscles for cosmetic uses, the reporting odds ratio was 0.46 (95% confidence interval, 0.27-0.78). Significant effects were also see in the following groups: those who received injections into facial and head muscles for migraine (ROR, 0.60; 95% CI, 0.48-0.74), injections into the upper and lower limbs for spasms and spasticity (ROR, 0.28; 95% CI, 0.18-0.42), injections into neck muscles for torticollis and neck pain (ROR, 0.30; 95% CI, 0.20-0.44), injections into eyelid muscles for blepharospasm (ROR, 0.13; 95% CI, 0.05-0.39), and injections into the axilla and palm for hyperhidrosis (ROR, 0.12; 95% CI, 0.04-0.33).

There were no cases of depression or depression-related adverse event reports among those treated with botulinum toxin for sialorrhea with injections into the parotid and submandibular glands, and there were decreased reports of depression among those who received detrusor muscle injections for neurological and urinary bladder disorders, but the results in both groups were not statistically significant, according to the researchers.

In an interview, Ruben Abagyan, PhD, study coauthor and professor at Skaggs School of Pharmacy and Pharmaceutical Sciences, said the study’s finding go “beyond breaking a positive feedback loop between depression and the ‘frown’ wrinkles in the glabellar region of the forehead.” The data showing efficacy with botulinum toxin injected in other areas of the body can help clinicians “expand their search for the most effective injection location and dose beyond the facial injections to improve the depression-related therapeutic outcomes.”

Another takeaway from the study, he noted, is that botulinum toxin can have effects beyond the local effect seen near an injection site. Administering botulinum toxin for spasms and spasticity, excessive sweating, migraine, urinary bladder disorders, blepharospasm, or excessive salivation/drooling could result in reduced depression and improved systemic neurological effects.

“Severe depression remains a very difficult condition to treat. The existing drugs have dangerous side effects, the onset of the therapeutic action is delayed by at least a month, and the adherence to the medication is suboptimal. Therefore, finding new ways to treat depression is critical,” Dr. Abagyan said. “Botulinum toxin opens up a new physiological mechanism to be tried to reduce depression.”

Michelle Magid, MD, MBA, of the department of psychiatry at the University of Texas at Austin, said in an interview that, although the study was retrospective, “physicians can feel confident that botulinum toxin treatment will not cause depression; it may very well lead to improved mood in some of their patients.” Dr. Magid was not an author of this study, but has studied botulinum toxin as a possible treatment of depression.

“Previous studies have shown that botulinum toxin injected into the forehead region can improve symptoms of depression. The studies were small and confined to treating the glabellar region only,” she added. “This is a large retrospective study showing that botulinum toxin injected into other regions, such as the neck, underarms, bladder, hands, arms, and legs, can also have an antidepressant effect.”

Dr. Magid agreed that the use of botulinum toxin as an antidepressant should be investigated further, and could be a tool for patients who do not respond well to traditional antidepressant medications.

In their paper, the authors offered several plausible mechanisms for the antidepressant effects of botulinum toxin, including transneuronal transport to the parts of the central nervous system that regulate mood and emotion, systemic distribution, distributed muscle stress memory, and efficacy in the primary indication treatment. Although the mechanism of action is not well understood, Dr. Magid noted it could be the removal of somatic symptoms that contribute to an improvement in mood.

“It is possible that alleviating the psychological distress associated with neck spasms, excessive sweating [and so on] can be causing the antidepressive effects,” she said. “However, it is also possible that depression is actualized by a series of somatic symptoms – body aches, insomnia, sweating, for example. By removing somatic symptoms, one may also remove the correlating mood dysregulation.”

The study “certainly raises a lot of questions,” particularly about the “apparent multiple mechanisms of action of BoNT that we don’t understand yet,” Mark Rubin, MD, a cosmetic dermatologist who practices in Beverly Hills, Calif., said in an interview. “I believe it lends great deal of credence to the use of [botulinum toxin] for depression and certainly validates the need for more robust clinical trials for that indication,” he added.

“I think what we all as clinicians need to take away from this paper is that there is a great deal we don’t understand about the global pharmacologic effects of [botulinum toxin] and equally important, that there are apparently other pharmacologic pathways we need to explore in the treatment of depression, said Dr. Rubin, of the department of dermatology at the University of California, San Diego, who was not an investigator in the study.

One author reported being a consultant for Allergan. Dr. Makunts and the other author report no relevant conflicts of interest; Dr. Magid reported being a consultant for Allergan and a speaker for Ipsen. Dr. Rubin had no related disclosures.

SOURCE: Makunts T et al. Sci Rep. 2020 Jul 30;10(1):12851. doi: 10.1038/s41598-020-69773-7.

A study using safety surveillance data of botulinum toxin found significant associations between its use and antidepressant effects, across several indications and different injection sites, according to the study’s authors.

Their results show that the antidepressant effect of botulinum toxin “administered for various indications goes beyond the control of the intended disease states and does not depend on the location of the injection,” according to Tigran Makunts, PharmD, of the Skaggs School of Pharmacy and Pharmaceutical Sciences at the University of California, San Diego, and coauthors.

Previous high-quality studies have found botulinum toxin treatment has been associated with antidepressant effects when administered to the glabellar region of the face, they noted. The study was published in Scientific Reports.

The researchers evaluated adverse events reported to the Food and Drug Administration’s current adverse event reporting system (FAERS) between September 2012 and December 2019, and the FDA’s previous adverse event reporting system between January 2004 and August 2012. Overall, they analyzed 174,243 reports, which were divided into eight treatment-related groups based on the indication for botulinum toxin: Cosmetic use (20,684 patients), migraine (4,180 patients), spasms and spasticity not involving facial muscles (2,335 patients), neurological and urinary bladder disorders (915 patients), torticollis (1,360 patients), hyperhidrosis (601 patients), blepharospasm (487 patients), and sialorrhea (157 patients). Each group was matched to controls from the FAERS database, who had different treatments for the same indications. (Reports in which patients were on an antidepressant or where depression was listed as an indication were not included).

In nearly all treatment groups, reports of depression and depression-related adverse events were significantly lower among those who received botulinum toxin, compared with controls: For those who received botulinum toxin injections in facial muscles for cosmetic uses, the reporting odds ratio was 0.46 (95% confidence interval, 0.27-0.78). Significant effects were also see in the following groups: those who received injections into facial and head muscles for migraine (ROR, 0.60; 95% CI, 0.48-0.74), injections into the upper and lower limbs for spasms and spasticity (ROR, 0.28; 95% CI, 0.18-0.42), injections into neck muscles for torticollis and neck pain (ROR, 0.30; 95% CI, 0.20-0.44), injections into eyelid muscles for blepharospasm (ROR, 0.13; 95% CI, 0.05-0.39), and injections into the axilla and palm for hyperhidrosis (ROR, 0.12; 95% CI, 0.04-0.33).

There were no cases of depression or depression-related adverse event reports among those treated with botulinum toxin for sialorrhea with injections into the parotid and submandibular glands, and there were decreased reports of depression among those who received detrusor muscle injections for neurological and urinary bladder disorders, but the results in both groups were not statistically significant, according to the researchers.

In an interview, Ruben Abagyan, PhD, study coauthor and professor at Skaggs School of Pharmacy and Pharmaceutical Sciences, said the study’s finding go “beyond breaking a positive feedback loop between depression and the ‘frown’ wrinkles in the glabellar region of the forehead.” The data showing efficacy with botulinum toxin injected in other areas of the body can help clinicians “expand their search for the most effective injection location and dose beyond the facial injections to improve the depression-related therapeutic outcomes.”

Another takeaway from the study, he noted, is that botulinum toxin can have effects beyond the local effect seen near an injection site. Administering botulinum toxin for spasms and spasticity, excessive sweating, migraine, urinary bladder disorders, blepharospasm, or excessive salivation/drooling could result in reduced depression and improved systemic neurological effects.

“Severe depression remains a very difficult condition to treat. The existing drugs have dangerous side effects, the onset of the therapeutic action is delayed by at least a month, and the adherence to the medication is suboptimal. Therefore, finding new ways to treat depression is critical,” Dr. Abagyan said. “Botulinum toxin opens up a new physiological mechanism to be tried to reduce depression.”

Michelle Magid, MD, MBA, of the department of psychiatry at the University of Texas at Austin, said in an interview that, although the study was retrospective, “physicians can feel confident that botulinum toxin treatment will not cause depression; it may very well lead to improved mood in some of their patients.” Dr. Magid was not an author of this study, but has studied botulinum toxin as a possible treatment of depression.

“Previous studies have shown that botulinum toxin injected into the forehead region can improve symptoms of depression. The studies were small and confined to treating the glabellar region only,” she added. “This is a large retrospective study showing that botulinum toxin injected into other regions, such as the neck, underarms, bladder, hands, arms, and legs, can also have an antidepressant effect.”

Dr. Magid agreed that the use of botulinum toxin as an antidepressant should be investigated further, and could be a tool for patients who do not respond well to traditional antidepressant medications.

In their paper, the authors offered several plausible mechanisms for the antidepressant effects of botulinum toxin, including transneuronal transport to the parts of the central nervous system that regulate mood and emotion, systemic distribution, distributed muscle stress memory, and efficacy in the primary indication treatment. Although the mechanism of action is not well understood, Dr. Magid noted it could be the removal of somatic symptoms that contribute to an improvement in mood.

“It is possible that alleviating the psychological distress associated with neck spasms, excessive sweating [and so on] can be causing the antidepressive effects,” she said. “However, it is also possible that depression is actualized by a series of somatic symptoms – body aches, insomnia, sweating, for example. By removing somatic symptoms, one may also remove the correlating mood dysregulation.”

The study “certainly raises a lot of questions,” particularly about the “apparent multiple mechanisms of action of BoNT that we don’t understand yet,” Mark Rubin, MD, a cosmetic dermatologist who practices in Beverly Hills, Calif., said in an interview. “I believe it lends great deal of credence to the use of [botulinum toxin] for depression and certainly validates the need for more robust clinical trials for that indication,” he added.

“I think what we all as clinicians need to take away from this paper is that there is a great deal we don’t understand about the global pharmacologic effects of [botulinum toxin] and equally important, that there are apparently other pharmacologic pathways we need to explore in the treatment of depression, said Dr. Rubin, of the department of dermatology at the University of California, San Diego, who was not an investigator in the study.

One author reported being a consultant for Allergan. Dr. Makunts and the other author report no relevant conflicts of interest; Dr. Magid reported being a consultant for Allergan and a speaker for Ipsen. Dr. Rubin had no related disclosures.

SOURCE: Makunts T et al. Sci Rep. 2020 Jul 30;10(1):12851. doi: 10.1038/s41598-020-69773-7.

A study using safety surveillance data of botulinum toxin found significant associations between its use and antidepressant effects, across several indications and different injection sites, according to the study’s authors.

Their results show that the antidepressant effect of botulinum toxin “administered for various indications goes beyond the control of the intended disease states and does not depend on the location of the injection,” according to Tigran Makunts, PharmD, of the Skaggs School of Pharmacy and Pharmaceutical Sciences at the University of California, San Diego, and coauthors.

Previous high-quality studies have found botulinum toxin treatment has been associated with antidepressant effects when administered to the glabellar region of the face, they noted. The study was published in Scientific Reports.

The researchers evaluated adverse events reported to the Food and Drug Administration’s current adverse event reporting system (FAERS) between September 2012 and December 2019, and the FDA’s previous adverse event reporting system between January 2004 and August 2012. Overall, they analyzed 174,243 reports, which were divided into eight treatment-related groups based on the indication for botulinum toxin: Cosmetic use (20,684 patients), migraine (4,180 patients), spasms and spasticity not involving facial muscles (2,335 patients), neurological and urinary bladder disorders (915 patients), torticollis (1,360 patients), hyperhidrosis (601 patients), blepharospasm (487 patients), and sialorrhea (157 patients). Each group was matched to controls from the FAERS database, who had different treatments for the same indications. (Reports in which patients were on an antidepressant or where depression was listed as an indication were not included).

In nearly all treatment groups, reports of depression and depression-related adverse events were significantly lower among those who received botulinum toxin, compared with controls: For those who received botulinum toxin injections in facial muscles for cosmetic uses, the reporting odds ratio was 0.46 (95% confidence interval, 0.27-0.78). Significant effects were also see in the following groups: those who received injections into facial and head muscles for migraine (ROR, 0.60; 95% CI, 0.48-0.74), injections into the upper and lower limbs for spasms and spasticity (ROR, 0.28; 95% CI, 0.18-0.42), injections into neck muscles for torticollis and neck pain (ROR, 0.30; 95% CI, 0.20-0.44), injections into eyelid muscles for blepharospasm (ROR, 0.13; 95% CI, 0.05-0.39), and injections into the axilla and palm for hyperhidrosis (ROR, 0.12; 95% CI, 0.04-0.33).

There were no cases of depression or depression-related adverse event reports among those treated with botulinum toxin for sialorrhea with injections into the parotid and submandibular glands, and there were decreased reports of depression among those who received detrusor muscle injections for neurological and urinary bladder disorders, but the results in both groups were not statistically significant, according to the researchers.

In an interview, Ruben Abagyan, PhD, study coauthor and professor at Skaggs School of Pharmacy and Pharmaceutical Sciences, said the study’s finding go “beyond breaking a positive feedback loop between depression and the ‘frown’ wrinkles in the glabellar region of the forehead.” The data showing efficacy with botulinum toxin injected in other areas of the body can help clinicians “expand their search for the most effective injection location and dose beyond the facial injections to improve the depression-related therapeutic outcomes.”

Another takeaway from the study, he noted, is that botulinum toxin can have effects beyond the local effect seen near an injection site. Administering botulinum toxin for spasms and spasticity, excessive sweating, migraine, urinary bladder disorders, blepharospasm, or excessive salivation/drooling could result in reduced depression and improved systemic neurological effects.

“Severe depression remains a very difficult condition to treat. The existing drugs have dangerous side effects, the onset of the therapeutic action is delayed by at least a month, and the adherence to the medication is suboptimal. Therefore, finding new ways to treat depression is critical,” Dr. Abagyan said. “Botulinum toxin opens up a new physiological mechanism to be tried to reduce depression.”

Michelle Magid, MD, MBA, of the department of psychiatry at the University of Texas at Austin, said in an interview that, although the study was retrospective, “physicians can feel confident that botulinum toxin treatment will not cause depression; it may very well lead to improved mood in some of their patients.” Dr. Magid was not an author of this study, but has studied botulinum toxin as a possible treatment of depression.

“Previous studies have shown that botulinum toxin injected into the forehead region can improve symptoms of depression. The studies were small and confined to treating the glabellar region only,” she added. “This is a large retrospective study showing that botulinum toxin injected into other regions, such as the neck, underarms, bladder, hands, arms, and legs, can also have an antidepressant effect.”

Dr. Magid agreed that the use of botulinum toxin as an antidepressant should be investigated further, and could be a tool for patients who do not respond well to traditional antidepressant medications.

In their paper, the authors offered several plausible mechanisms for the antidepressant effects of botulinum toxin, including transneuronal transport to the parts of the central nervous system that regulate mood and emotion, systemic distribution, distributed muscle stress memory, and efficacy in the primary indication treatment. Although the mechanism of action is not well understood, Dr. Magid noted it could be the removal of somatic symptoms that contribute to an improvement in mood.

“It is possible that alleviating the psychological distress associated with neck spasms, excessive sweating [and so on] can be causing the antidepressive effects,” she said. “However, it is also possible that depression is actualized by a series of somatic symptoms – body aches, insomnia, sweating, for example. By removing somatic symptoms, one may also remove the correlating mood dysregulation.”

The study “certainly raises a lot of questions,” particularly about the “apparent multiple mechanisms of action of BoNT that we don’t understand yet,” Mark Rubin, MD, a cosmetic dermatologist who practices in Beverly Hills, Calif., said in an interview. “I believe it lends great deal of credence to the use of [botulinum toxin] for depression and certainly validates the need for more robust clinical trials for that indication,” he added.

“I think what we all as clinicians need to take away from this paper is that there is a great deal we don’t understand about the global pharmacologic effects of [botulinum toxin] and equally important, that there are apparently other pharmacologic pathways we need to explore in the treatment of depression, said Dr. Rubin, of the department of dermatology at the University of California, San Diego, who was not an investigator in the study.

One author reported being a consultant for Allergan. Dr. Makunts and the other author report no relevant conflicts of interest; Dr. Magid reported being a consultant for Allergan and a speaker for Ipsen. Dr. Rubin had no related disclosures.

SOURCE: Makunts T et al. Sci Rep. 2020 Jul 30;10(1):12851. doi: 10.1038/s41598-020-69773-7.

With the world currently really listening and engaged (hopefully) on making positive changes with regards to racism and systemic racial injustices, skin color has come to the forefront. Racism because of skin color has been an unfortunate part of our history and foundation of the United States with a capitalist society built and thriving on the profits of slavery, and a democracy founded on equality – unless you had black skin. These issues are at the forefront in the United States, but have also significantly impacted other parts of the world, including the Caribbean and South America having a significant African slave trade history and impacts, with Brazil currently facing the same systemic racial injustices and police brutality among black men, and King Leopold II of Belgium slaughtering an estimated 10-15 million Congolese people in the name of colonialism, slavery, and robbing resources (natural resources as well as servitude) in the Congo as late as the early 1900s.

These are just a few of the many historical examples of racial injustice, which remains ingrained in many parts of our society today. With this worldwide history, it has been advantageous for people to have lighter skin with regards to money, politics, jobs, education, the justice system, modeling/acting opportunities and contracts, home ownership, and opportunities for generational wealth for years to come. It has ingrained some unfortunate beliefs among some that having lighter skin is better, advantageous, and will make them more desirable or more beautiful.

Colorism, its social impact, and consequences on the beauty industry with skin-whitening products is evident all over the world, particularly parts of Asia (especially South Korea and China), India, and across the African continent. It is estimated that 77% of women in Nigeria and 55% of women in China use bleaching creams to achieve overall skin lightening. Unilever’s Fair & Lovely skin-whitening cream has long been a popular over-the-counter product in India, with an estimated market worth of 270 billion rupees ($4 billion USD). On June 25, 2020, Unilever vowed to rename and rebrand Fair & Lovely. With such an offensive name for a product that further promotes colorism, this is an effort in the right direction and has been a long time coming since its debut in 1975. Unilever’s Fair and Lovely Foundation for women’s causes still exists, and has not been renamed at the time of this writing.

Controversy remains on whether this product and other products such as these should exist for the purposes they are used for. Johnson & Johnson has decided that it will no longer produce and sell the Neutrogena Fine Fairness line, sold only in Asia and the Middle East, and the Clean & Clear Fairness line, sold in India. There are arguments to the contrary that halting production of skin-lightening products altogether may result in an influx of unsafe alternatives.

As dermatologists, we use skin-lightening products appropriately for the purposes of treating skin conditions such as postinflammatory hyperpigmentation, melasma, and photoaging. This is where the use of such products should largely end. While it is up to individuals about what they do with their skin and their bodies, we, as health care skin professionals, should be furthering the notion that all skin colors and types are beautiful. Moreover, we should not be encouraging the use of these products for overall skin whitening. Part of the issue is that these products are available often at high concentrations over the counter or in the illegal market, especially in parts of Asia and Africa where colorism is more common and skin whitening is more commonly practiced. The dangers are not only the risk of ochronosis with high concentrations or long term use of hydroquinone, but also what the Centre for Science and Environment found in a 2014 study, that 44% of the skin “fairness” creams in India contained mercury, which is illegal and a health concern.

In my practice, I have also had patients (several originally from Nigeria) who have admitted to long term use of skin-bleaching products for the purposes of all over face- and body-skin lightening who now suffer from very sensitive skin and experience bouts of eczematous dermatitis from time to time, despite having stopped using lightening cream. While there are adverse physical effects resulting from the use of these topicals for this purpose, the effects on the psyche are what concern me the most.

The beauty industry has also been an unfortunate part of furthering thoughts and attitudes concerning colorism over the years with lighter skin and Caucasian ideals being set as standards of beauty. One of many examples is a deodorant ad in the Middle East with the tagline “White is Purity” on a woman, which was pulled by Nivea in 2017 after it was slammed as racist. Another is the 2017 Dove ad for body wash that showed a smiling black woman peel off her brown shirt to reveal a white woman in a lighter-color shirt.

A shift has occurred in recent years with more ethnic images of beauty appearing in magazines and film. However, such opportunities are still less plentiful, pay discrepancies still occur, and sexual objectification of women of color as opposed to beautification is still rampant. As such, it is also up to us to do our part in studying and utilizing ethnic and racial differences in skin and beauty to maximize our efforts in promoting what is inherently beautiful as opposed to one standard of beauty. The education begins with the images we see, what we teach our children, loving ourselves, and as doctors, being knowledgeable about the right aesthetic choices for patients with different skin colors and types.

Dr. Wesley and Dr. Talakoub are cocontributors to this column. Dr. Wesley practices dermatology in Beverly Hills, Calif. Dr. Talakoub is in private practice in McLean, Va. This month’s column is by Dr. Wesley. Write to them at [email protected]. They had no relevant disclosures.

With the world currently really listening and engaged (hopefully) on making positive changes with regards to racism and systemic racial injustices, skin color has come to the forefront. Racism because of skin color has been an unfortunate part of our history and foundation of the United States with a capitalist society built and thriving on the profits of slavery, and a democracy founded on equality – unless you had black skin. These issues are at the forefront in the United States, but have also significantly impacted other parts of the world, including the Caribbean and South America having a significant African slave trade history and impacts, with Brazil currently facing the same systemic racial injustices and police brutality among black men, and King Leopold II of Belgium slaughtering an estimated 10-15 million Congolese people in the name of colonialism, slavery, and robbing resources (natural resources as well as servitude) in the Congo as late as the early 1900s.

These are just a few of the many historical examples of racial injustice, which remains ingrained in many parts of our society today. With this worldwide history, it has been advantageous for people to have lighter skin with regards to money, politics, jobs, education, the justice system, modeling/acting opportunities and contracts, home ownership, and opportunities for generational wealth for years to come. It has ingrained some unfortunate beliefs among some that having lighter skin is better, advantageous, and will make them more desirable or more beautiful.

Colorism, its social impact, and consequences on the beauty industry with skin-whitening products is evident all over the world, particularly parts of Asia (especially South Korea and China), India, and across the African continent. It is estimated that 77% of women in Nigeria and 55% of women in China use bleaching creams to achieve overall skin lightening. Unilever’s Fair & Lovely skin-whitening cream has long been a popular over-the-counter product in India, with an estimated market worth of 270 billion rupees ($4 billion USD). On June 25, 2020, Unilever vowed to rename and rebrand Fair & Lovely. With such an offensive name for a product that further promotes colorism, this is an effort in the right direction and has been a long time coming since its debut in 1975. Unilever’s Fair and Lovely Foundation for women’s causes still exists, and has not been renamed at the time of this writing.

Controversy remains on whether this product and other products such as these should exist for the purposes they are used for. Johnson & Johnson has decided that it will no longer produce and sell the Neutrogena Fine Fairness line, sold only in Asia and the Middle East, and the Clean & Clear Fairness line, sold in India. There are arguments to the contrary that halting production of skin-lightening products altogether may result in an influx of unsafe alternatives.

As dermatologists, we use skin-lightening products appropriately for the purposes of treating skin conditions such as postinflammatory hyperpigmentation, melasma, and photoaging. This is where the use of such products should largely end. While it is up to individuals about what they do with their skin and their bodies, we, as health care skin professionals, should be furthering the notion that all skin colors and types are beautiful. Moreover, we should not be encouraging the use of these products for overall skin whitening. Part of the issue is that these products are available often at high concentrations over the counter or in the illegal market, especially in parts of Asia and Africa where colorism is more common and skin whitening is more commonly practiced. The dangers are not only the risk of ochronosis with high concentrations or long term use of hydroquinone, but also what the Centre for Science and Environment found in a 2014 study, that 44% of the skin “fairness” creams in India contained mercury, which is illegal and a health concern.

In my practice, I have also had patients (several originally from Nigeria) who have admitted to long term use of skin-bleaching products for the purposes of all over face- and body-skin lightening who now suffer from very sensitive skin and experience bouts of eczematous dermatitis from time to time, despite having stopped using lightening cream. While there are adverse physical effects resulting from the use of these topicals for this purpose, the effects on the psyche are what concern me the most.

The beauty industry has also been an unfortunate part of furthering thoughts and attitudes concerning colorism over the years with lighter skin and Caucasian ideals being set as standards of beauty. One of many examples is a deodorant ad in the Middle East with the tagline “White is Purity” on a woman, which was pulled by Nivea in 2017 after it was slammed as racist. Another is the 2017 Dove ad for body wash that showed a smiling black woman peel off her brown shirt to reveal a white woman in a lighter-color shirt.

A shift has occurred in recent years with more ethnic images of beauty appearing in magazines and film. However, such opportunities are still less plentiful, pay discrepancies still occur, and sexual objectification of women of color as opposed to beautification is still rampant. As such, it is also up to us to do our part in studying and utilizing ethnic and racial differences in skin and beauty to maximize our efforts in promoting what is inherently beautiful as opposed to one standard of beauty. The education begins with the images we see, what we teach our children, loving ourselves, and as doctors, being knowledgeable about the right aesthetic choices for patients with different skin colors and types.

Dr. Wesley and Dr. Talakoub are cocontributors to this column. Dr. Wesley practices dermatology in Beverly Hills, Calif. Dr. Talakoub is in private practice in McLean, Va. This month’s column is by Dr. Wesley. Write to them at [email protected]. They had no relevant disclosures.

With the world currently really listening and engaged (hopefully) on making positive changes with regards to racism and systemic racial injustices, skin color has come to the forefront. Racism because of skin color has been an unfortunate part of our history and foundation of the United States with a capitalist society built and thriving on the profits of slavery, and a democracy founded on equality – unless you had black skin. These issues are at the forefront in the United States, but have also significantly impacted other parts of the world, including the Caribbean and South America having a significant African slave trade history and impacts, with Brazil currently facing the same systemic racial injustices and police brutality among black men, and King Leopold II of Belgium slaughtering an estimated 10-15 million Congolese people in the name of colonialism, slavery, and robbing resources (natural resources as well as servitude) in the Congo as late as the early 1900s.

These are just a few of the many historical examples of racial injustice, which remains ingrained in many parts of our society today. With this worldwide history, it has been advantageous for people to have lighter skin with regards to money, politics, jobs, education, the justice system, modeling/acting opportunities and contracts, home ownership, and opportunities for generational wealth for years to come. It has ingrained some unfortunate beliefs among some that having lighter skin is better, advantageous, and will make them more desirable or more beautiful.

Colorism, its social impact, and consequences on the beauty industry with skin-whitening products is evident all over the world, particularly parts of Asia (especially South Korea and China), India, and across the African continent. It is estimated that 77% of women in Nigeria and 55% of women in China use bleaching creams to achieve overall skin lightening. Unilever’s Fair & Lovely skin-whitening cream has long been a popular over-the-counter product in India, with an estimated market worth of 270 billion rupees ($4 billion USD). On June 25, 2020, Unilever vowed to rename and rebrand Fair & Lovely. With such an offensive name for a product that further promotes colorism, this is an effort in the right direction and has been a long time coming since its debut in 1975. Unilever’s Fair and Lovely Foundation for women’s causes still exists, and has not been renamed at the time of this writing.

Controversy remains on whether this product and other products such as these should exist for the purposes they are used for. Johnson & Johnson has decided that it will no longer produce and sell the Neutrogena Fine Fairness line, sold only in Asia and the Middle East, and the Clean & Clear Fairness line, sold in India. There are arguments to the contrary that halting production of skin-lightening products altogether may result in an influx of unsafe alternatives.

As dermatologists, we use skin-lightening products appropriately for the purposes of treating skin conditions such as postinflammatory hyperpigmentation, melasma, and photoaging. This is where the use of such products should largely end. While it is up to individuals about what they do with their skin and their bodies, we, as health care skin professionals, should be furthering the notion that all skin colors and types are beautiful. Moreover, we should not be encouraging the use of these products for overall skin whitening. Part of the issue is that these products are available often at high concentrations over the counter or in the illegal market, especially in parts of Asia and Africa where colorism is more common and skin whitening is more commonly practiced. The dangers are not only the risk of ochronosis with high concentrations or long term use of hydroquinone, but also what the Centre for Science and Environment found in a 2014 study, that 44% of the skin “fairness” creams in India contained mercury, which is illegal and a health concern.

In my practice, I have also had patients (several originally from Nigeria) who have admitted to long term use of skin-bleaching products for the purposes of all over face- and body-skin lightening who now suffer from very sensitive skin and experience bouts of eczematous dermatitis from time to time, despite having stopped using lightening cream. While there are adverse physical effects resulting from the use of these topicals for this purpose, the effects on the psyche are what concern me the most.

The beauty industry has also been an unfortunate part of furthering thoughts and attitudes concerning colorism over the years with lighter skin and Caucasian ideals being set as standards of beauty. One of many examples is a deodorant ad in the Middle East with the tagline “White is Purity” on a woman, which was pulled by Nivea in 2017 after it was slammed as racist. Another is the 2017 Dove ad for body wash that showed a smiling black woman peel off her brown shirt to reveal a white woman in a lighter-color shirt.

A shift has occurred in recent years with more ethnic images of beauty appearing in magazines and film. However, such opportunities are still less plentiful, pay discrepancies still occur, and sexual objectification of women of color as opposed to beautification is still rampant. As such, it is also up to us to do our part in studying and utilizing ethnic and racial differences in skin and beauty to maximize our efforts in promoting what is inherently beautiful as opposed to one standard of beauty. The education begins with the images we see, what we teach our children, loving ourselves, and as doctors, being knowledgeable about the right aesthetic choices for patients with different skin colors and types.

Dr. Wesley and Dr. Talakoub are cocontributors to this column. Dr. Wesley practices dermatology in Beverly Hills, Calif. Dr. Talakoub is in private practice in McLean, Va. This month’s column is by Dr. Wesley. Write to them at [email protected]. They had no relevant disclosures.

Bufexamac, a nonsteroidal anti-inflammatory drug agent used cutaneously and rectally, is well known globally as an initiator of allergic contact dermatitis. In fact, it has been removed from the European market (except Switzerland) for inducing allergic reactions, and is also banned in Japan, New Zealand, and the United States (where it was never approved).¹ This column will primarily discuss recent findings in human trials and weigh in on the issue.

Antioxidant activity

In addition to its known anti-inflammatory activity, bufexamac has been found to exert antioxidant effects. In 2003, Trommer and Neubert demonstrated that bufexamac displayed antioxidant activity in lipid models and HaCaT keratinocytes, as measured through mass spectrometry.² In a 2005 in vitro study of the impact of 47 drugs, plant extracts and ingredients, and polysaccharides on lipid peroxidation engendered by UV irradiation, Trommer and Neubert found that bufexamac was among the drugs shown to exhibit antioxidant activity.³

Minor allergen? Worth using?

In a 2009 study on the prevalence and risk factors for allergic contact dermatitis to topical atopic dermatitis (AD) treatments, Mailhol et al. patch tested 641 children with AD using seven then-common ingredients (chlorhexidine, hexamidine, budesonide, tixocortol pivalate, bufexamac, sodium fusidate and with the current emollient used by the child). Bufexamac was identified as an allergen in only 2.5% of the 41 positive patch tests.⁴

To ban or not to ban

In 2012, the European Medicines Agency’s Committee for Medicinal Products for Human Use recommended that the marketing of formulations containing bufexamac be disallowed throughout the European Union because of a tendency toward inducing severe allergic contact dermatitis.⁵

Given its continuing use in Australia for the local treatment of several dermatoses, Pan and Nixon, in 2012, retrospectively reviewed patch-test data at the Skin and Cancer Foundation Inc. and found 19 cases of positive reactions to bufexamac (5% petrolatum) from 451 people patch tested. In 13 of 19 patients (68%), the reaction to bufexamac was considered to be associated with the identified dermatitis. The authors concluded that allergic contact dermatitis from bufexamac exposure is underreported in the English-language literature and cautioned that physicians should consider bufexamac allergy in patients who have a history of exposure.⁵

Bufexamac remained available over the counter in topical formulations in Australia as of early 2019. In response, Harris et al. presented several cases of patients who experienced severe skin eruptions after using such preparations in support of their advocacy to the Therapeutic Goods Administration in Australia to ban its use.⁶

In the middle of that year, Wong et al. reported on the hospitalization of a 41-year-old administrative worker who applied a first aid cream containing bufexamac (5%), lignocaine (1%), and chlorhexidine (0.1%) to a superficial right foot abrasion and who developed facial edema and widespread polymorphic eruptions 2 hours later. The authors suggested that this case reinforced the need to remove bufexamac from the markets where it remains because of the tendency to provoke severe allergic contact dermatoses and lack of efficacy.¹

Conclusion

Bufexamac offers the somewhat rare opportunity for advocacy. That is to say, I think there is sufficient evidence to justify the removal of this potent allergen from the market in Australia, Switzerland, and other countries where it may be available.

Dr. Baumann is a private practice dermatologist, researcher, author, and entrepreneur who practices in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann has written two textbooks and a New York Times Best Sellers book for consumers. Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Evolus, Galderma, and Revance. She is the founder and CEO of Skin Type Solutions Franchise Systems LLC. She had no relevant disclosures. Write to her at [email protected].

References

1. Wong GN et al. Contact Dermatitis. 2019 Jun;80(6):395-7.

2. Trommer H et al. J Pharm Pharmacol. 2003 Oct;55(10):1379-88.

3. Trommer H, Neubert RH. J Pharm Pharm Sci. 2005 Sep 15;8(3):494-506.

4. Mailhol C et al. Allergy. 2009 May;64(5):801-6.

5. Pan Y, Nixon R. Australas J Dermatol. 2012 Aug;53(3):207-10.

6. Harris AG et al. Australas J Dermatol. 2019 Feb;60(1):53-6.

Bufexamac, a nonsteroidal anti-inflammatory drug agent used cutaneously and rectally, is well known globally as an initiator of allergic contact dermatitis. In fact, it has been removed from the European market (except Switzerland) for inducing allergic reactions, and is also banned in Japan, New Zealand, and the United States (where it was never approved).¹ This column will primarily discuss recent findings in human trials and weigh in on the issue.

Antioxidant activity

In addition to its known anti-inflammatory activity, bufexamac has been found to exert antioxidant effects. In 2003, Trommer and Neubert demonstrated that bufexamac displayed antioxidant activity in lipid models and HaCaT keratinocytes, as measured through mass spectrometry.² In a 2005 in vitro study of the impact of 47 drugs, plant extracts and ingredients, and polysaccharides on lipid peroxidation engendered by UV irradiation, Trommer and Neubert found that bufexamac was among the drugs shown to exhibit antioxidant activity.³

Minor allergen? Worth using?

In a 2009 study on the prevalence and risk factors for allergic contact dermatitis to topical atopic dermatitis (AD) treatments, Mailhol et al. patch tested 641 children with AD using seven then-common ingredients (chlorhexidine, hexamidine, budesonide, tixocortol pivalate, bufexamac, sodium fusidate and with the current emollient used by the child). Bufexamac was identified as an allergen in only 2.5% of the 41 positive patch tests.⁴

To ban or not to ban

In 2012, the European Medicines Agency’s Committee for Medicinal Products for Human Use recommended that the marketing of formulations containing bufexamac be disallowed throughout the European Union because of a tendency toward inducing severe allergic contact dermatitis.⁵

Given its continuing use in Australia for the local treatment of several dermatoses, Pan and Nixon, in 2012, retrospectively reviewed patch-test data at the Skin and Cancer Foundation Inc. and found 19 cases of positive reactions to bufexamac (5% petrolatum) from 451 people patch tested. In 13 of 19 patients (68%), the reaction to bufexamac was considered to be associated with the identified dermatitis. The authors concluded that allergic contact dermatitis from bufexamac exposure is underreported in the English-language literature and cautioned that physicians should consider bufexamac allergy in patients who have a history of exposure.⁵

Bufexamac remained available over the counter in topical formulations in Australia as of early 2019. In response, Harris et al. presented several cases of patients who experienced severe skin eruptions after using such preparations in support of their advocacy to the Therapeutic Goods Administration in Australia to ban its use.⁶

In the middle of that year, Wong et al. reported on the hospitalization of a 41-year-old administrative worker who applied a first aid cream containing bufexamac (5%), lignocaine (1%), and chlorhexidine (0.1%) to a superficial right foot abrasion and who developed facial edema and widespread polymorphic eruptions 2 hours later. The authors suggested that this case reinforced the need to remove bufexamac from the markets where it remains because of the tendency to provoke severe allergic contact dermatoses and lack of efficacy.¹

Conclusion

Bufexamac offers the somewhat rare opportunity for advocacy. That is to say, I think there is sufficient evidence to justify the removal of this potent allergen from the market in Australia, Switzerland, and other countries where it may be available.

Dr. Baumann is a private practice dermatologist, researcher, author, and entrepreneur who practices in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann has written two textbooks and a New York Times Best Sellers book for consumers. Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Evolus, Galderma, and Revance. She is the founder and CEO of Skin Type Solutions Franchise Systems LLC. She had no relevant disclosures. Write to her at [email protected].

References

1. Wong GN et al. Contact Dermatitis. 2019 Jun;80(6):395-7.

2. Trommer H et al. J Pharm Pharmacol. 2003 Oct;55(10):1379-88.

3. Trommer H, Neubert RH. J Pharm Pharm Sci. 2005 Sep 15;8(3):494-506.

4. Mailhol C et al. Allergy. 2009 May;64(5):801-6.

5. Pan Y, Nixon R. Australas J Dermatol. 2012 Aug;53(3):207-10.

6. Harris AG et al. Australas J Dermatol. 2019 Feb;60(1):53-6.

Bufexamac, a nonsteroidal anti-inflammatory drug agent used cutaneously and rectally, is well known globally as an initiator of allergic contact dermatitis. In fact, it has been removed from the European market (except Switzerland) for inducing allergic reactions, and is also banned in Japan, New Zealand, and the United States (where it was never approved).¹ This column will primarily discuss recent findings in human trials and weigh in on the issue.

Antioxidant activity

In addition to its known anti-inflammatory activity, bufexamac has been found to exert antioxidant effects. In 2003, Trommer and Neubert demonstrated that bufexamac displayed antioxidant activity in lipid models and HaCaT keratinocytes, as measured through mass spectrometry.² In a 2005 in vitro study of the impact of 47 drugs, plant extracts and ingredients, and polysaccharides on lipid peroxidation engendered by UV irradiation, Trommer and Neubert found that bufexamac was among the drugs shown to exhibit antioxidant activity.³

Minor allergen? Worth using?

In a 2009 study on the prevalence and risk factors for allergic contact dermatitis to topical atopic dermatitis (AD) treatments, Mailhol et al. patch tested 641 children with AD using seven then-common ingredients (chlorhexidine, hexamidine, budesonide, tixocortol pivalate, bufexamac, sodium fusidate and with the current emollient used by the child). Bufexamac was identified as an allergen in only 2.5% of the 41 positive patch tests.⁴

To ban or not to ban

In 2012, the European Medicines Agency’s Committee for Medicinal Products for Human Use recommended that the marketing of formulations containing bufexamac be disallowed throughout the European Union because of a tendency toward inducing severe allergic contact dermatitis.⁵

Given its continuing use in Australia for the local treatment of several dermatoses, Pan and Nixon, in 2012, retrospectively reviewed patch-test data at the Skin and Cancer Foundation Inc. and found 19 cases of positive reactions to bufexamac (5% petrolatum) from 451 people patch tested. In 13 of 19 patients (68%), the reaction to bufexamac was considered to be associated with the identified dermatitis. The authors concluded that allergic contact dermatitis from bufexamac exposure is underreported in the English-language literature and cautioned that physicians should consider bufexamac allergy in patients who have a history of exposure.⁵

Bufexamac remained available over the counter in topical formulations in Australia as of early 2019. In response, Harris et al. presented several cases of patients who experienced severe skin eruptions after using such preparations in support of their advocacy to the Therapeutic Goods Administration in Australia to ban its use.⁶

In the middle of that year, Wong et al. reported on the hospitalization of a 41-year-old administrative worker who applied a first aid cream containing bufexamac (5%), lignocaine (1%), and chlorhexidine (0.1%) to a superficial right foot abrasion and who developed facial edema and widespread polymorphic eruptions 2 hours later. The authors suggested that this case reinforced the need to remove bufexamac from the markets where it remains because of the tendency to provoke severe allergic contact dermatoses and lack of efficacy.¹

Conclusion

Bufexamac offers the somewhat rare opportunity for advocacy. That is to say, I think there is sufficient evidence to justify the removal of this potent allergen from the market in Australia, Switzerland, and other countries where it may be available.

Dr. Baumann is a private practice dermatologist, researcher, author, and entrepreneur who practices in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann has written two textbooks and a New York Times Best Sellers book for consumers. Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Evolus, Galderma, and Revance. She is the founder and CEO of Skin Type Solutions Franchise Systems LLC. She had no relevant disclosures. Write to her at [email protected].

References

1. Wong GN et al. Contact Dermatitis. 2019 Jun;80(6):395-7.

2. Trommer H et al. J Pharm Pharmacol. 2003 Oct;55(10):1379-88.

3. Trommer H, Neubert RH. J Pharm Pharm Sci. 2005 Sep 15;8(3):494-506.

4. Mailhol C et al. Allergy. 2009 May;64(5):801-6.

5. Pan Y, Nixon R. Australas J Dermatol. 2012 Aug;53(3):207-10.

6. Harris AG et al. Australas J Dermatol. 2019 Feb;60(1):53-6.

The Food and Drug Administration has approved collagenase clostridium histolyticum–aaes (Qwo, Endo International) for the treatment of moderate to severe cellulite in the buttocks of adult women. The drug is the first injectable treatment for cellulite to receive regulatory approval.

Wikimedia Commons/FitzColinGerald/ Creative Commons License

In cellulite, fibrous septae are a primary contributing factor. The septae make up the fibrous connective tissue that connects the skin perpendicularly to the fascia below and tether the skin, drawing it downward and leading to a mattress-like appearance, commonly referred to as “dimpling.” When injected into the treatment area, Qwo is thought to release the fibrous septae enzymatically by specifically targeting types 1 and 3 collagen, which may result in smoothing of the skin and an improved appearance of cellulite.

The most common side effects of Qwo include injection site bruising, pain, areas of hardness, itching, redness, discoloration, swelling, and warmth in the treatment area.

Qwo is expected to be available throughout the United States at aesthetic health care practitioner’s offices starting in Spring 2021.

“Qwo could be a game-changer for many women with cellulite,” Anne Chapas, MD, a board-certified dermatologist at Union Square Laser Dermatology in New York, said in a press release. “I am thrilled there will now be an FDA-approved injectable treatment option proven to address a root cause of cellulite. What is exciting about Qwo is that it is a cutting-edge cellulite treatment, without the cutting,” Dr. Chapas, said.

[email protected]

The Food and Drug Administration has approved collagenase clostridium histolyticum–aaes (Qwo, Endo International) for the treatment of moderate to severe cellulite in the buttocks of adult women. The drug is the first injectable treatment for cellulite to receive regulatory approval.

Wikimedia Commons/FitzColinGerald/ Creative Commons License

In cellulite, fibrous septae are a primary contributing factor. The septae make up the fibrous connective tissue that connects the skin perpendicularly to the fascia below and tether the skin, drawing it downward and leading to a mattress-like appearance, commonly referred to as “dimpling.” When injected into the treatment area, Qwo is thought to release the fibrous septae enzymatically by specifically targeting types 1 and 3 collagen, which may result in smoothing of the skin and an improved appearance of cellulite.

The most common side effects of Qwo include injection site bruising, pain, areas of hardness, itching, redness, discoloration, swelling, and warmth in the treatment area.

Qwo is expected to be available throughout the United States at aesthetic health care practitioner’s offices starting in Spring 2021.

“Qwo could be a game-changer for many women with cellulite,” Anne Chapas, MD, a board-certified dermatologist at Union Square Laser Dermatology in New York, said in a press release. “I am thrilled there will now be an FDA-approved injectable treatment option proven to address a root cause of cellulite. What is exciting about Qwo is that it is a cutting-edge cellulite treatment, without the cutting,” Dr. Chapas, said.

[email protected]

The Food and Drug Administration has approved collagenase clostridium histolyticum–aaes (Qwo, Endo International) for the treatment of moderate to severe cellulite in the buttocks of adult women. The drug is the first injectable treatment for cellulite to receive regulatory approval.

Wikimedia Commons/FitzColinGerald/ Creative Commons License

In cellulite, fibrous septae are a primary contributing factor. The septae make up the fibrous connective tissue that connects the skin perpendicularly to the fascia below and tether the skin, drawing it downward and leading to a mattress-like appearance, commonly referred to as “dimpling.” When injected into the treatment area, Qwo is thought to release the fibrous septae enzymatically by specifically targeting types 1 and 3 collagen, which may result in smoothing of the skin and an improved appearance of cellulite.

The most common side effects of Qwo include injection site bruising, pain, areas of hardness, itching, redness, discoloration, swelling, and warmth in the treatment area.

Qwo is expected to be available throughout the United States at aesthetic health care practitioner’s offices starting in Spring 2021.

“Qwo could be a game-changer for many women with cellulite,” Anne Chapas, MD, a board-certified dermatologist at Union Square Laser Dermatology in New York, said in a press release. “I am thrilled there will now be an FDA-approved injectable treatment option proven to address a root cause of cellulite. What is exciting about Qwo is that it is a cutting-edge cellulite treatment, without the cutting,” Dr. Chapas, said.

[email protected]

Acoustic subscision represents a novel, noninvasive treatment to improve the appearance of cellulite, results from a pivotal multicenter study demonstrated.

After a single treatment, it provided a roughly 1.16 point reduction in the five-point Cellulite Severity Scale at 12 weeks, which corresponds to a roughly 32.5% reduction in cellulite.

“In cellulite, we know that the septa within the fat – those fibrous bands that pull down the skin and tether – lead to the traditional look of cellulite dimples and ridges,” lead study author Elizabeth Tanzi, MD, said during a late-breaking abstract session at the virtual annual meeting of the American Academy of Dermatology. A rapid acoustic pulse (RAP) device being developed by Soliton emits rapid acoustic pulses and shock waves at 50 Hz that are transmitted through the skin. The pulses “rupture and shear the fibrotic septa, which causes release of the septa and smoothing of the skin dimples,” explained Dr. Tanzi, director of Capital Laser & Skin Care in Chevy Chase, Md.

She added that the repetition rate of the RAP device makes it stand out from other technologies currently on the market for cellulite treatment. “The repetition rate and very short rise times provide microscopic mechanical destruction to the targeted cellular level structures and the vacuoles,” Dr. Tanzi said. “The high peak pressure and fast repetition rate exploit the viscoelastic nature of the tissue. It’s the rapid rate at which the energy is being delivered, as well as the very short times that energy is being delivered, that makes the technology an entirely different device-tissue interaction.”

The physical effects observed occur in the extracellular matrix and in the destruction of fibrous septa. “That’s the acoustic subcision,” she continued. “But also, there’s no cavitation and there are nonthermal physical effects. There is some investigational research going into what biologic effects those shock waves have on the rest of the tissue, looking into neocollagenesis, potential angiogenesis, potential lymphangiogenesis, as well as inflammation inhibition.”

In a prospective pivotal clinical trial conducted at four sites, Dr. Tanzi and her colleagues evaluated the safety and effectiveness of the RAP device in 62 female patients who were treated with a single, rapid acoustic pulse treatment comprised of 1-2 minutes on each identified dimple or large ridge of cellulite. This amounted to a 19- to 33-minute treatment session for each patient. No anesthesia was required, and photographs were taken on all sites with QuantifiCare medical imaging software.

“It’s completely noninvasive and it’s truly an incisionless treatment,” Dr. Tanzi said of the procedure. “The skin’s never punctured. There’s physician oversight, but it is highly delegatable, and there is no recovery time for the patient.”

Following treatment, adverse effects and tolerability were reported, and safety and efficacy were assessed at 12 weeks. Efficacy was determined by photographic assessment by three blinded independent physicians who used a validated, simplified version of the Cellulite Severity Scale (CSS), a 0-5 scale based on the number of cellulite depressions, as well as the average depth of those depressions.

The mean age of patients was 43 years, 92% were white, and their mean body mass index was 24.5 kg/m². The average time of treatment was 28 minutes. Based on the CSS scores, the researchers found that 87% of the study subjects had some improvement of their cellulite after a single RAP treatment. “If you break the data down further, half of patients had at least a 30% reduction of their CSS, and almost one-quarter had a 50% improvement of their CSS,” Dr. Tanzi said. “Overall, we saw a reduction of a 1.16 level on that six-point scale, which translates roughly into 32.5% reduction of the look of their cellulite from the baseline score.”

In addition, 84% of the time, the blinded assessors were able to correctly identify pre- and posttreatment unlabeled photos that they were presented at the 3-month mark. Those same blinded assessors graded about 86% of the treated cellulite areas as appearing either improved, much improved, or very much improved on the Global Aesthetic Improvement Scale (GAIS).

“We found a very favorable side-effect profile, although 95% of patients had some redness to their skin,” Dr. Tanzi added. “They had some erythema and folliculitis, but it was transient and very mild. In addition, 98% of patients said that the procedure was tolerable.”

As for pain, on a 0-10 scale, with 10 being the worst, subjects rated their pain level at 2.4 during the treatment and 0.3 immediately afterward. On subject satisfaction surveys, 92% of the patient said that they “agree” or “strongly agree” that their cellulite appeared improved.

“Patients with moderate cellulite seem to respond [to this treatment], too,” Dr. Tanzi said. “I don’t think there’s a ceiling or a floor to which we have to pigeonhole patients into potentially treating with this device. I think the key is [targeting] cellulite and not necessarily skin laxity.”

She emphasized that much remains to be known about the RAP device for treating cellulite. “What happens if we do multiple treatments to the tissue?” she asked. “Also, we need to further investigate what’s happening in the tissue, because not only does it seem like we’re getting a cleaving of the fibrous septa, but what is happening to the fibroblasts? What’s really happening in the tissue on a molecular level when those rapid acoustic pulses are going through the skin? There’s a lot of unanswered questions, but this is exciting technology.”

According to a news release from Soliton, the company is further reviewing and analyzing these results for inclusion in a marketing application to the Food and Drug Administration.

Soliton sponsored the trial. Dr. Tanzi disclosed that she is either a consultant for or is a member of the scientific advisory board for Allergan/Coolsculpting, Beiersdorf, Cutera, Merz/Ulthera, Pulse Biosciences, Sciton, Soliton, Solta, and Syneron/Candela.

[email protected]

Acoustic subscision represents a novel, noninvasive treatment to improve the appearance of cellulite, results from a pivotal multicenter study demonstrated.

After a single treatment, it provided a roughly 1.16 point reduction in the five-point Cellulite Severity Scale at 12 weeks, which corresponds to a roughly 32.5% reduction in cellulite.

“In cellulite, we know that the septa within the fat – those fibrous bands that pull down the skin and tether – lead to the traditional look of cellulite dimples and ridges,” lead study author Elizabeth Tanzi, MD, said during a late-breaking abstract session at the virtual annual meeting of the American Academy of Dermatology. A rapid acoustic pulse (RAP) device being developed by Soliton emits rapid acoustic pulses and shock waves at 50 Hz that are transmitted through the skin. The pulses “rupture and shear the fibrotic septa, which causes release of the septa and smoothing of the skin dimples,” explained Dr. Tanzi, director of Capital Laser & Skin Care in Chevy Chase, Md.

She added that the repetition rate of the RAP device makes it stand out from other technologies currently on the market for cellulite treatment. “The repetition rate and very short rise times provide microscopic mechanical destruction to the targeted cellular level structures and the vacuoles,” Dr. Tanzi said. “The high peak pressure and fast repetition rate exploit the viscoelastic nature of the tissue. It’s the rapid rate at which the energy is being delivered, as well as the very short times that energy is being delivered, that makes the technology an entirely different device-tissue interaction.”

The physical effects observed occur in the extracellular matrix and in the destruction of fibrous septa. “That’s the acoustic subcision,” she continued. “But also, there’s no cavitation and there are nonthermal physical effects. There is some investigational research going into what biologic effects those shock waves have on the rest of the tissue, looking into neocollagenesis, potential angiogenesis, potential lymphangiogenesis, as well as inflammation inhibition.”

In a prospective pivotal clinical trial conducted at four sites, Dr. Tanzi and her colleagues evaluated the safety and effectiveness of the RAP device in 62 female patients who were treated with a single, rapid acoustic pulse treatment comprised of 1-2 minutes on each identified dimple or large ridge of cellulite. This amounted to a 19- to 33-minute treatment session for each patient. No anesthesia was required, and photographs were taken on all sites with QuantifiCare medical imaging software.

“It’s completely noninvasive and it’s truly an incisionless treatment,” Dr. Tanzi said of the procedure. “The skin’s never punctured. There’s physician oversight, but it is highly delegatable, and there is no recovery time for the patient.”

Following treatment, adverse effects and tolerability were reported, and safety and efficacy were assessed at 12 weeks. Efficacy was determined by photographic assessment by three blinded independent physicians who used a validated, simplified version of the Cellulite Severity Scale (CSS), a 0-5 scale based on the number of cellulite depressions, as well as the average depth of those depressions.

The mean age of patients was 43 years, 92% were white, and their mean body mass index was 24.5 kg/m². The average time of treatment was 28 minutes. Based on the CSS scores, the researchers found that 87% of the study subjects had some improvement of their cellulite after a single RAP treatment. “If you break the data down further, half of patients had at least a 30% reduction of their CSS, and almost one-quarter had a 50% improvement of their CSS,” Dr. Tanzi said. “Overall, we saw a reduction of a 1.16 level on that six-point scale, which translates roughly into 32.5% reduction of the look of their cellulite from the baseline score.”

In addition, 84% of the time, the blinded assessors were able to correctly identify pre- and posttreatment unlabeled photos that they were presented at the 3-month mark. Those same blinded assessors graded about 86% of the treated cellulite areas as appearing either improved, much improved, or very much improved on the Global Aesthetic Improvement Scale (GAIS).

“We found a very favorable side-effect profile, although 95% of patients had some redness to their skin,” Dr. Tanzi added. “They had some erythema and folliculitis, but it was transient and very mild. In addition, 98% of patients said that the procedure was tolerable.”

As for pain, on a 0-10 scale, with 10 being the worst, subjects rated their pain level at 2.4 during the treatment and 0.3 immediately afterward. On subject satisfaction surveys, 92% of the patient said that they “agree” or “strongly agree” that their cellulite appeared improved.

“Patients with moderate cellulite seem to respond [to this treatment], too,” Dr. Tanzi said. “I don’t think there’s a ceiling or a floor to which we have to pigeonhole patients into potentially treating with this device. I think the key is [targeting] cellulite and not necessarily skin laxity.”

She emphasized that much remains to be known about the RAP device for treating cellulite. “What happens if we do multiple treatments to the tissue?” she asked. “Also, we need to further investigate what’s happening in the tissue, because not only does it seem like we’re getting a cleaving of the fibrous septa, but what is happening to the fibroblasts? What’s really happening in the tissue on a molecular level when those rapid acoustic pulses are going through the skin? There’s a lot of unanswered questions, but this is exciting technology.”

According to a news release from Soliton, the company is further reviewing and analyzing these results for inclusion in a marketing application to the Food and Drug Administration.

Soliton sponsored the trial. Dr. Tanzi disclosed that she is either a consultant for or is a member of the scientific advisory board for Allergan/Coolsculpting, Beiersdorf, Cutera, Merz/Ulthera, Pulse Biosciences, Sciton, Soliton, Solta, and Syneron/Candela.

[email protected]

Acoustic subscision represents a novel, noninvasive treatment to improve the appearance of cellulite, results from a pivotal multicenter study demonstrated.

After a single treatment, it provided a roughly 1.16 point reduction in the five-point Cellulite Severity Scale at 12 weeks, which corresponds to a roughly 32.5% reduction in cellulite.

“In cellulite, we know that the septa within the fat – those fibrous bands that pull down the skin and tether – lead to the traditional look of cellulite dimples and ridges,” lead study author Elizabeth Tanzi, MD, said during a late-breaking abstract session at the virtual annual meeting of the American Academy of Dermatology. A rapid acoustic pulse (RAP) device being developed by Soliton emits rapid acoustic pulses and shock waves at 50 Hz that are transmitted through the skin. The pulses “rupture and shear the fibrotic septa, which causes release of the septa and smoothing of the skin dimples,” explained Dr. Tanzi, director of Capital Laser & Skin Care in Chevy Chase, Md.

She added that the repetition rate of the RAP device makes it stand out from other technologies currently on the market for cellulite treatment. “The repetition rate and very short rise times provide microscopic mechanical destruction to the targeted cellular level structures and the vacuoles,” Dr. Tanzi said. “The high peak pressure and fast repetition rate exploit the viscoelastic nature of the tissue. It’s the rapid rate at which the energy is being delivered, as well as the very short times that energy is being delivered, that makes the technology an entirely different device-tissue interaction.”

The physical effects observed occur in the extracellular matrix and in the destruction of fibrous septa. “That’s the acoustic subcision,” she continued. “But also, there’s no cavitation and there are nonthermal physical effects. There is some investigational research going into what biologic effects those shock waves have on the rest of the tissue, looking into neocollagenesis, potential angiogenesis, potential lymphangiogenesis, as well as inflammation inhibition.”

In a prospective pivotal clinical trial conducted at four sites, Dr. Tanzi and her colleagues evaluated the safety and effectiveness of the RAP device in 62 female patients who were treated with a single, rapid acoustic pulse treatment comprised of 1-2 minutes on each identified dimple or large ridge of cellulite. This amounted to a 19- to 33-minute treatment session for each patient. No anesthesia was required, and photographs were taken on all sites with QuantifiCare medical imaging software.

“It’s completely noninvasive and it’s truly an incisionless treatment,” Dr. Tanzi said of the procedure. “The skin’s never punctured. There’s physician oversight, but it is highly delegatable, and there is no recovery time for the patient.”

Following treatment, adverse effects and tolerability were reported, and safety and efficacy were assessed at 12 weeks. Efficacy was determined by photographic assessment by three blinded independent physicians who used a validated, simplified version of the Cellulite Severity Scale (CSS), a 0-5 scale based on the number of cellulite depressions, as well as the average depth of those depressions.

The mean age of patients was 43 years, 92% were white, and their mean body mass index was 24.5 kg/m². The average time of treatment was 28 minutes. Based on the CSS scores, the researchers found that 87% of the study subjects had some improvement of their cellulite after a single RAP treatment. “If you break the data down further, half of patients had at least a 30% reduction of their CSS, and almost one-quarter had a 50% improvement of their CSS,” Dr. Tanzi said. “Overall, we saw a reduction of a 1.16 level on that six-point scale, which translates roughly into 32.5% reduction of the look of their cellulite from the baseline score.”

In addition, 84% of the time, the blinded assessors were able to correctly identify pre- and posttreatment unlabeled photos that they were presented at the 3-month mark. Those same blinded assessors graded about 86% of the treated cellulite areas as appearing either improved, much improved, or very much improved on the Global Aesthetic Improvement Scale (GAIS).

“We found a very favorable side-effect profile, although 95% of patients had some redness to their skin,” Dr. Tanzi added. “They had some erythema and folliculitis, but it was transient and very mild. In addition, 98% of patients said that the procedure was tolerable.”

As for pain, on a 0-10 scale, with 10 being the worst, subjects rated their pain level at 2.4 during the treatment and 0.3 immediately afterward. On subject satisfaction surveys, 92% of the patient said that they “agree” or “strongly agree” that their cellulite appeared improved.

“Patients with moderate cellulite seem to respond [to this treatment], too,” Dr. Tanzi said. “I don’t think there’s a ceiling or a floor to which we have to pigeonhole patients into potentially treating with this device. I think the key is [targeting] cellulite and not necessarily skin laxity.”

She emphasized that much remains to be known about the RAP device for treating cellulite. “What happens if we do multiple treatments to the tissue?” she asked. “Also, we need to further investigate what’s happening in the tissue, because not only does it seem like we’re getting a cleaving of the fibrous septa, but what is happening to the fibroblasts? What’s really happening in the tissue on a molecular level when those rapid acoustic pulses are going through the skin? There’s a lot of unanswered questions, but this is exciting technology.”

According to a news release from Soliton, the company is further reviewing and analyzing these results for inclusion in a marketing application to the Food and Drug Administration.

Soliton sponsored the trial. Dr. Tanzi disclosed that she is either a consultant for or is a member of the scientific advisory board for Allergan/Coolsculpting, Beiersdorf, Cutera, Merz/Ulthera, Pulse Biosciences, Sciton, Soliton, Solta, and Syneron/Candela.

[email protected]

In a study of patients with mild to moderate infraorbital dark circles, treatment with carbon dioxide laser resurfacing did not produce a significant improvement in infraorbital hyperpigmentation. However, the combination of microneedling and 10% trichloroacetic acid peels did.

The finding comes from what is believed to be the first head-to-head comparison of the two procedures for infraorbital dark circles, which are a common cosmetic concern with increased age.

During a late-breaking abstract session at the virtual annual meeting of the American Academy of Dermatology, lead study author Banu Farabi, MD, said that dark circles seen in the periorbital area are defined as bilateral, round homogeneous pigmented macules whose etiology is thought to be multifactorial. Available treatments include bleaching creams, topical retinoids, chemical peels, lasers, autologous fat transplantation, injectable fillers, and blepharoplasty.

“Microneedling has been recently suggested as an effective and efficient method for reducing infraorbital dark circles,” Dr. Farabi said. “This technique is based on creating microchannels that can stimulate the production of subcutaneous collagen and elastin. It also enhances the revascularization and fibroblast activity, which increases the skin thickness and gives a shiny appearance to the skin. The fractional CO₂ has also been introduced as an effective procedure to remove infraorbital dark circles. However, there are some potential complications with that therapy.”

For the current study, Dr. Farabi, of the department of dermatology at Ankara (Turkey) University, and Mohamad Goldust, MD, of University Hospital Basel (Switzerland), randomly assigned the 62 patients with mild to moderate infraorbital dark circles to receive microneedling and 10% trichloroacetic acid peels or carbon dioxide laser resurfacing monthly for three consecutive sessions. They used the handheld Automatic Microneedle Therapy System-Handhold from MCure. After creating microchannels, the investigators topically applied 10% trichloroacetic acid peels to each infraorbital area and waited for 5 minutes.

In the carbon dioxide laser group, a Lutronic CO₂ laser was used with a pulse energy of 10 J/cm², a 100-microsecond pulse rate, 30 W of power, and a pulse width of 4 mm. The treatment outcome was assessed with the patient’s satisfaction and the physician’s judgment, which were no response, partial response, and complete response. Patients in both study groups were followed up for blinded-investigator assessment of infraorbital hyperpigmentation, adverse events, and improvement, compared with baseline.

The mean age of patients was 40 years, with a range between 27 and 58 years. About one-third of patients in each group had Fitzpatrick skin types II, III, and IV, respectively. In the blinded investigator assessment, the laser-resurfacing procedure did not demonstrate a significant improvement in infraorbital hyperpigmentation at day 90 (P = .24). However, the combination of microneedling and 10% trichloroacetic acid peels significantly improved infraorbital hyperpigmentation by day 90, with improvement maintained through day 180 (P = .012 and .002, respectively).

Adverse events were mild and temporary in both groups. In the laser-resurfacing group, 7 of the patients (22.5%) developed transient infraorbital hyperpigmentation postoperatively that lasted 4 weeks. In the combination treatment group, 18 patients (58%) developed transient erythema that lasted for up to 1 week.

“We suggest using microneedling plus 10% [trichloroacetic acid] as a cost-effective and efficient method for reducing infraorbital dark circles,” Dr. Farabi concluded.

The researchers reported having no financial disclosures.

[email protected]

In a study of patients with mild to moderate infraorbital dark circles, treatment with carbon dioxide laser resurfacing did not produce a significant improvement in infraorbital hyperpigmentation. However, the combination of microneedling and 10% trichloroacetic acid peels did.

The finding comes from what is believed to be the first head-to-head comparison of the two procedures for infraorbital dark circles, which are a common cosmetic concern with increased age.

During a late-breaking abstract session at the virtual annual meeting of the American Academy of Dermatology, lead study author Banu Farabi, MD, said that dark circles seen in the periorbital area are defined as bilateral, round homogeneous pigmented macules whose etiology is thought to be multifactorial. Available treatments include bleaching creams, topical retinoids, chemical peels, lasers, autologous fat transplantation, injectable fillers, and blepharoplasty.

“Microneedling has been recently suggested as an effective and efficient method for reducing infraorbital dark circles,” Dr. Farabi said. “This technique is based on creating microchannels that can stimulate the production of subcutaneous collagen and elastin. It also enhances the revascularization and fibroblast activity, which increases the skin thickness and gives a shiny appearance to the skin. The fractional CO₂ has also been introduced as an effective procedure to remove infraorbital dark circles. However, there are some potential complications with that therapy.”

For the current study, Dr. Farabi, of the department of dermatology at Ankara (Turkey) University, and Mohamad Goldust, MD, of University Hospital Basel (Switzerland), randomly assigned the 62 patients with mild to moderate infraorbital dark circles to receive microneedling and 10% trichloroacetic acid peels or carbon dioxide laser resurfacing monthly for three consecutive sessions. They used the handheld Automatic Microneedle Therapy System-Handhold from MCure. After creating microchannels, the investigators topically applied 10% trichloroacetic acid peels to each infraorbital area and waited for 5 minutes.

In the carbon dioxide laser group, a Lutronic CO₂ laser was used with a pulse energy of 10 J/cm², a 100-microsecond pulse rate, 30 W of power, and a pulse width of 4 mm. The treatment outcome was assessed with the patient’s satisfaction and the physician’s judgment, which were no response, partial response, and complete response. Patients in both study groups were followed up for blinded-investigator assessment of infraorbital hyperpigmentation, adverse events, and improvement, compared with baseline.

The mean age of patients was 40 years, with a range between 27 and 58 years. About one-third of patients in each group had Fitzpatrick skin types II, III, and IV, respectively. In the blinded investigator assessment, the laser-resurfacing procedure did not demonstrate a significant improvement in infraorbital hyperpigmentation at day 90 (P = .24). However, the combination of microneedling and 10% trichloroacetic acid peels significantly improved infraorbital hyperpigmentation by day 90, with improvement maintained through day 180 (P = .012 and .002, respectively).

Adverse events were mild and temporary in both groups. In the laser-resurfacing group, 7 of the patients (22.5%) developed transient infraorbital hyperpigmentation postoperatively that lasted 4 weeks. In the combination treatment group, 18 patients (58%) developed transient erythema that lasted for up to 1 week.

“We suggest using microneedling plus 10% [trichloroacetic acid] as a cost-effective and efficient method for reducing infraorbital dark circles,” Dr. Farabi concluded.

The researchers reported having no financial disclosures.

[email protected]

In a study of patients with mild to moderate infraorbital dark circles, treatment with carbon dioxide laser resurfacing did not produce a significant improvement in infraorbital hyperpigmentation. However, the combination of microneedling and 10% trichloroacetic acid peels did.

The finding comes from what is believed to be the first head-to-head comparison of the two procedures for infraorbital dark circles, which are a common cosmetic concern with increased age.

During a late-breaking abstract session at the virtual annual meeting of the American Academy of Dermatology, lead study author Banu Farabi, MD, said that dark circles seen in the periorbital area are defined as bilateral, round homogeneous pigmented macules whose etiology is thought to be multifactorial. Available treatments include bleaching creams, topical retinoids, chemical peels, lasers, autologous fat transplantation, injectable fillers, and blepharoplasty.

“Microneedling has been recently suggested as an effective and efficient method for reducing infraorbital dark circles,” Dr. Farabi said. “This technique is based on creating microchannels that can stimulate the production of subcutaneous collagen and elastin. It also enhances the revascularization and fibroblast activity, which increases the skin thickness and gives a shiny appearance to the skin. The fractional CO₂ has also been introduced as an effective procedure to remove infraorbital dark circles. However, there are some potential complications with that therapy.”

For the current study, Dr. Farabi, of the department of dermatology at Ankara (Turkey) University, and Mohamad Goldust, MD, of University Hospital Basel (Switzerland), randomly assigned the 62 patients with mild to moderate infraorbital dark circles to receive microneedling and 10% trichloroacetic acid peels or carbon dioxide laser resurfacing monthly for three consecutive sessions. They used the handheld Automatic Microneedle Therapy System-Handhold from MCure. After creating microchannels, the investigators topically applied 10% trichloroacetic acid peels to each infraorbital area and waited for 5 minutes.

In the carbon dioxide laser group, a Lutronic CO₂ laser was used with a pulse energy of 10 J/cm², a 100-microsecond pulse rate, 30 W of power, and a pulse width of 4 mm. The treatment outcome was assessed with the patient’s satisfaction and the physician’s judgment, which were no response, partial response, and complete response. Patients in both study groups were followed up for blinded-investigator assessment of infraorbital hyperpigmentation, adverse events, and improvement, compared with baseline.

The mean age of patients was 40 years, with a range between 27 and 58 years. About one-third of patients in each group had Fitzpatrick skin types II, III, and IV, respectively. In the blinded investigator assessment, the laser-resurfacing procedure did not demonstrate a significant improvement in infraorbital hyperpigmentation at day 90 (P = .24). However, the combination of microneedling and 10% trichloroacetic acid peels significantly improved infraorbital hyperpigmentation by day 90, with improvement maintained through day 180 (P = .012 and .002, respectively).

Adverse events were mild and temporary in both groups. In the laser-resurfacing group, 7 of the patients (22.5%) developed transient infraorbital hyperpigmentation postoperatively that lasted 4 weeks. In the combination treatment group, 18 patients (58%) developed transient erythema that lasted for up to 1 week.

“We suggest using microneedling plus 10% [trichloroacetic acid] as a cost-effective and efficient method for reducing infraorbital dark circles,” Dr. Farabi concluded.

The researchers reported having no financial disclosures.

[email protected]

Recent studies have shown a correlation between many dietary elements and skin diseases including acne, rosacea, and perioral dermatitis. In my practice, nutritional counseling is as important as skincare counseling. I have found that inflammatory skin conditions can be improved to some extent with dietary modifications, and there is now evidence that the aging process can also be slowed with a healthy diet. Previous studies have shown that intake of vegetables, fish, and foods high in vitamin C, carotenoids, olive oil, and linoleic acid are associated with decreased wrinkles.

Lisovskaya/iStock/Getty Images

In a Dutch population-based cohort study published in the Journal of the American Academy of Dermatology in 2019, Mekić et al. investigated the association between diet and facial wrinkles in an elderly population. Facial photographs were used to evaluate wrinkle severity and diet of the participants was assessed with the Food Frequency Questionnaire and adherence to the Dutch Healthy Diet Index (DHDI).

The DHDI is a measure of the ability to adhere to the Dutch Guidelines for a Healthy Diet. The guidelines recommend a daily intake in the diet of at least 200 g of vegetables daily; at least 200 g of fruit; 90 g of brown bread, wholemeal bread, or other whole-grain products; and at least 15 g of unsalted nuts. One serving of fish (preferably oily fish) per week and little to no dairy, alcohol, red meat, cooking fats, and sugar is also recommended.

The study revealed that better adherence to the DHDI was significantly associated with fewer wrinkles among women but not men. Women who ate more animal meat and fats and carbohydrates had more wrinkles than did those with a fruit-dominant diet.

Although other healthy behaviors such as exercise and alcohol are likely to play a role in confounding these data, UV exposure as a cause of wrinkling was accounted for, and in the study, increased outdoor exercise was associated with more wrinkles. Unhealthy food can induce oxidative stress, increased skin and gut inflammation, and glycation, which are some of the physiologic mechanisms suggested to increase wrinkle formation. In contrast, nutrients in fruits and vegetables stimulate collagen production and DNA repair and reduce oxidative stress on the skin.

Nutritional advice is largely rare in internal medicine, cardiology, and even endocrinology. We are developing better ways to assess and understand the way foods interact and cause inflammation of the gut and the body and skin. I highly recommend nutritional education be a part of our residency training programs and to make better guidelines on the prevention of skin disease and aging available for both practitioners and patients.


Dr. Wesley and Dr. Talakoub are cocontributors to this column. Dr. Wesley practices dermatology in Beverly Hills, Calif. Dr. Talakoub is in private practice in McLean, Va. This month’s column is by Dr. Talakoub. Write to them at [email protected]. They had no relevant disclosures.


References

Mekić S et al. J Am Acad Dermatol. 2019 May;80(5):1358-1363.e2.

Purba MB et al. J Am Coll Nutr. 2001;20(1):71‐80.

van Lee L et al. Nutr J. 2012 Jul 20;11:49.

Kromhout D et al. Eur J Clin Nutr. 2016 Aug;70(8):869‐78.


 

Recent studies have shown a correlation between many dietary elements and skin diseases including acne, rosacea, and perioral dermatitis. In my practice, nutritional counseling is as important as skincare counseling. I have found that inflammatory skin conditions can be improved to some extent with dietary modifications, and there is now evidence that the aging process can also be slowed with a healthy diet. Previous studies have shown that intake of vegetables, fish, and foods high in vitamin C, carotenoids, olive oil, and linoleic acid are associated with decreased wrinkles.

Lisovskaya/iStock/Getty Images

In a Dutch population-based cohort study published in the Journal of the American Academy of Dermatology in 2019, Mekić et al. investigated the association between diet and facial wrinkles in an elderly population. Facial photographs were used to evaluate wrinkle severity and diet of the participants was assessed with the Food Frequency Questionnaire and adherence to the Dutch Healthy Diet Index (DHDI).

The DHDI is a measure of the ability to adhere to the Dutch Guidelines for a Healthy Diet. The guidelines recommend a daily intake in the diet of at least 200 g of vegetables daily; at least 200 g of fruit; 90 g of brown bread, wholemeal bread, or other whole-grain products; and at least 15 g of unsalted nuts. One serving of fish (preferably oily fish) per week and little to no dairy, alcohol, red meat, cooking fats, and sugar is also recommended.

The study revealed that better adherence to the DHDI was significantly associated with fewer wrinkles among women but not men. Women who ate more animal meat and fats and carbohydrates had more wrinkles than did those with a fruit-dominant diet.

Although other healthy behaviors such as exercise and alcohol are likely to play a role in confounding these data, UV exposure as a cause of wrinkling was accounted for, and in the study, increased outdoor exercise was associated with more wrinkles. Unhealthy food can induce oxidative stress, increased skin and gut inflammation, and glycation, which are some of the physiologic mechanisms suggested to increase wrinkle formation. In contrast, nutrients in fruits and vegetables stimulate collagen production and DNA repair and reduce oxidative stress on the skin.

Nutritional advice is largely rare in internal medicine, cardiology, and even endocrinology. We are developing better ways to assess and understand the way foods interact and cause inflammation of the gut and the body and skin. I highly recommend nutritional education be a part of our residency training programs and to make better guidelines on the prevention of skin disease and aging available for both practitioners and patients.


Dr. Wesley and Dr. Talakoub are cocontributors to this column. Dr. Wesley practices dermatology in Beverly Hills, Calif. Dr. Talakoub is in private practice in McLean, Va. This month’s column is by Dr. Talakoub. Write to them at [email protected]. They had no relevant disclosures.


References

Mekić S et al. J Am Acad Dermatol. 2019 May;80(5):1358-1363.e2.

Purba MB et al. J Am Coll Nutr. 2001;20(1):71‐80.

van Lee L et al. Nutr J. 2012 Jul 20;11:49.

Kromhout D et al. Eur J Clin Nutr. 2016 Aug;70(8):869‐78.


 

Recent studies have shown a correlation between many dietary elements and skin diseases including acne, rosacea, and perioral dermatitis. In my practice, nutritional counseling is as important as skincare counseling. I have found that inflammatory skin conditions can be improved to some extent with dietary modifications, and there is now evidence that the aging process can also be slowed with a healthy diet. Previous studies have shown that intake of vegetables, fish, and foods high in vitamin C, carotenoids, olive oil, and linoleic acid are associated with decreased wrinkles.

Lisovskaya/iStock/Getty Images

In a Dutch population-based cohort study published in the Journal of the American Academy of Dermatology in 2019, Mekić et al. investigated the association between diet and facial wrinkles in an elderly population. Facial photographs were used to evaluate wrinkle severity and diet of the participants was assessed with the Food Frequency Questionnaire and adherence to the Dutch Healthy Diet Index (DHDI).

The DHDI is a measure of the ability to adhere to the Dutch Guidelines for a Healthy Diet. The guidelines recommend a daily intake in the diet of at least 200 g of vegetables daily; at least 200 g of fruit; 90 g of brown bread, wholemeal bread, or other whole-grain products; and at least 15 g of unsalted nuts. One serving of fish (preferably oily fish) per week and little to no dairy, alcohol, red meat, cooking fats, and sugar is also recommended.

The study revealed that better adherence to the DHDI was significantly associated with fewer wrinkles among women but not men. Women who ate more animal meat and fats and carbohydrates had more wrinkles than did those with a fruit-dominant diet.

Although other healthy behaviors such as exercise and alcohol are likely to play a role in confounding these data, UV exposure as a cause of wrinkling was accounted for, and in the study, increased outdoor exercise was associated with more wrinkles. Unhealthy food can induce oxidative stress, increased skin and gut inflammation, and glycation, which are some of the physiologic mechanisms suggested to increase wrinkle formation. In contrast, nutrients in fruits and vegetables stimulate collagen production and DNA repair and reduce oxidative stress on the skin.

Nutritional advice is largely rare in internal medicine, cardiology, and even endocrinology. We are developing better ways to assess and understand the way foods interact and cause inflammation of the gut and the body and skin. I highly recommend nutritional education be a part of our residency training programs and to make better guidelines on the prevention of skin disease and aging available for both practitioners and patients.


Dr. Wesley and Dr. Talakoub are cocontributors to this column. Dr. Wesley practices dermatology in Beverly Hills, Calif. Dr. Talakoub is in private practice in McLean, Va. This month’s column is by Dr. Talakoub. Write to them at [email protected]. They had no relevant disclosures.


References

Mekić S et al. J Am Acad Dermatol. 2019 May;80(5):1358-1363.e2.

Purba MB et al. J Am Coll Nutr. 2001;20(1):71‐80.

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