Psoriasis is a systemic immune-mediated disorder characterized by erythematous, scaly, well-demarcated plaques on the skin that affects approximately 3% of the world’s population.¹ Although topical therapies often are the first-line treatment of mild to moderate psoriasis, approximately 1 in 6 individuals has moderate to severe disease that requires systemic treatment such as biologics or phototherapy.² In patients with localized disease that is refractory to treatment or who have moderate to severe psoriasis requiring systemic treatment, phototherapy should be considered as a potential low-risk treatment option.

In July 2019, the American Academy of Dermatology (AAD) and National Psoriasis Foundation (NPF) released an updated set of guidelines for the use of phototherapy in treating adult patients with psoriasis.³ Since the prior guidelines were released in 2010, there have been numerous studies affirming the efficacy of phototherapy, with several large meta-analyses helping to refine clinical recommendations.^4,5 Each treatment was ranked using Strength of Recommendation Taxonomy, with a score of A, B, or C based on the strength of the evidence supporting the given modality. With the ever-increasing number of treatment options for patients with psoriasis, these guidelines inform dermatologists of the recommendations for the initiation, maintenance, and optimization of phototherapy in the treatment of psoriasis.

The AAD-NPF recommendations discuss the mechanism of action, efficacy, safety, and frequency of adverse events of 10 commonly used phototherapy/photochemotherapy modalities. They also address dosing regimens, the potential to combine phototherapy with other therapies, and the efficacy of treatment modalities for different types of psoriasis.³ The purpose of this discussion is to present these guidelines in a condensed form for prescribers of phototherapy and to review the most clinically significant considerations during each step of treatment. Of note, we only highlight the treatment of adult patients and do not discuss information relevant to pediatric patients with psoriasis.

Choosing a Phototherapy Modality

Phototherapy may be considered for patients with psoriasis that affects more than 3% body surface area or for localized disease refractory to conventional treatments. UV light is believed to provide relief from psoriasis via multiple mechanisms, such as through favorable alterations in cytokine profiles, initiation of apoptosis, and local immunosupression.⁶ There is no single first-line phototherapeutic modality recommended for all patients with psoriasis. Rather, the decision to implement a particular modality should be individualized to the patient, considering factors such as percentage of body surface area affected by disease, quality-of-life assessment, comorbidities, lifestyle, and cost of treatment.

Of the 10 phototherapy modalities reviewed in these guidelines, 4 were ranked by the AAD and NPF as having grade A evidence for efficacy in the treatment of moderate to severe plaque psoriasis. Treatments with a grade A level of recommendation included narrowband UVB (NB-UVB), broadband UVB (BB-UVB), targeted phototherapy (excimer laser and excimer lamp), and oral psoralen plus UVA (PUVA) therapy. Photodynamic therapy for psoriasis was given an A-level recommendation against its use, as it was found to be ineffective with an unfavorable side-effect profile. Treatments with a grade B level of recommendation—nonoral routes of PUVA therapy, pulsed dye laser/intense pulsed light for nail psoriasis only, Goeckerman therapy, and climatotherapy—have sufficient evidence available to support their treatment of moderate to severe psoriasis in some cases. Treatments with a grade C level of recommendation—Grenz ray therapy (also called borderline or ultrasoft therapy) and visible light therapy—have insufficient evidence to support their use in patients with moderate to severe psoriasis (Table 1).

Psoralen plus UVA, which may be used topically (ie, bathwater PUVA) or taken orally, refers to treatment with photosensitizing psoralens. Psoralens are agents that intercalate with DNA and enhance the efficacy of phototherapy.¹⁰ Topical PUVA, with a grade B level of recommendation, is an effective treatment option for patients with localized disease and has been shown to be particularly efficacious in the treatment of palmoplantar pustular psoriasis. Oral PUVA is an effective option for psoriasis with a grade A recommendation, while bathwater PUVA has a grade B level of recommendation for moderate to severe plaque psoriasis. Oral PUVA is associated with greater systemic side effects (both acute and subacute) compared with NB-UVB and also is associated with photocarcinogenesis, particularly squamous cell carcinoma in white patients.¹¹ Other side effects from PUVA include pigmented macules in sun-protected areas (known as PUVA lentigines), which may make evaluation of skin lesions challenging. Because of the increased risk for cancer with oral PUVA, NB-UVB is preferable as a first-line treatment vs PUVA, especially in patients with a history of skin cancer.^12,13

Goeckerman therapy, which involves the synergistic combination of UVB and crude coal tar, is an older treatment that has shown efficacy in the treatment of severe or recalcitrant psoriasis (grade B level of recommendation). One prior case-control study comparing the efficacy of Goeckerman therapy with newer treatments, such as biologic therapies, steroids, and oral immunosuppressants, found a similar reduction in symptoms among both treatment groups, with longer disease-free periods in patients who received Goeckerman therapy than those who received newer therapies (22.3 years vs 4.6 months).¹⁴ However, Goeckerman therapy is utilized less frequently than more modern therapies because of the time required for treatment and declining insurance reimbursements for it. Climatotherapy, another older established therapy, involves the temporary or permanent relocation of patients to an environment that is favorable for disease control (grade B level of recommendation). Locations such as the Dead Sea and Canary Islands have been studied and shown to provide both subjective and objective improvement in patients’ psoriasis disease course. Patients had notable improvement in both their psoriasis area and severity index score and quality of life after a 3- to 4-week relocation to these areas.^15,16 Access to climatotherapy and the transient nature of disease relief are apparent limitations of this treatment modality.

Grenz ray is a type of phototherapy that uses longer-wavelength ionizing radiation, which has low penetrance into surrounding tissues and a 95% absorption rate within the first 3 mm of the skin depth. This treatment has been used less frequently since the development of newer alternatives but should still be considered as a second line to UV therapy, especially in cases of recalcitrant disease and palmoplantar psoriasis, and when access to other treatment options is limited. Grenz ray has a grade C level of recommendation due to the paucity of evidence that supports its efficacy. Thus, it is not recommended as first-line therapy for the treatment of moderate to severe psoriasis. Visible light therapy is another treatment option that uses light in the visible wavelength spectrum but predominantly utilizes blue and red light. Psoriatic lesions are sensitive to light therapy because of the elevated levels of naturally occurring photosensitizing agents, called protoporphyrins, in these lesions.¹⁷ Several small studies have shown improvement in psoriatic lesions treated with visible light therapy, with blue light showing greater efficacy in lesional clearance than red light.^18,19

Pulsed dye laser is a phototherapy modality that has shown efficacy in the treatment of nail psoriasis (grade B level of recommendation). One study comparing the effects of tazarotene cream 0.1% with pulsed dye laser and tazarotene cream 0.1% alone showed that patients receiving combination therapy had a greater decrease in nail psoriasis severity index scores, higher scores on the patient’s global assessment of improvement, and higher rates of improvement on the physician global assessment score. A physician global assessment score of 75% improvement or more was seen in patients treated with combination therapy vs monotherapy (5.3% vs 31.6%).²⁰ Intense pulsed light, a type of visible light therapy, also has been used to treat nail psoriasis, with one study showing notable improvement in nail bed and matrix disease and a global improvement in nail psoriasis severity index score after 6 months of biweekly treatment.²¹ However, this treatment has a grade B level of recommendation given the limited number of studies supporting the efficacy of this modality.

Initiation of Phototherapy

Prior to initiating phototherapy, it is important to assess the patient for any personal or family history of skin cancer, as phototherapy carries an increased risk for cutaneous malignancy, especially in patients with a history of skin cancer.^22,23 All patients also should be evaluated for their Fitzpatrick skin type, and the minimal erythema dose should be defined for those initiating UVB treatment. These classifications can be useful for the initial determination of treatment dose and the prevention of treatment-related adverse events (TRAEs). A careful drug history also should be taken before the initiation of phototherapy to avoid photosensitizing reactions. Thiazide diuretics and tetracyclines are 2 such examples of medications commonly associated with photosensitizing reactions.²⁴

Fitzpatrick skin type and/or minimal erythema dose testing also are essential in determining the appropriate initial NB-UVB dose required for treatment initiation (Table 2). Patient response to the initial NB-UVB trial will determine the optimal dosage for subsequent maintenance treatments.

Assessment and Optimization of Phototherapy

After an appropriate starting dosage has been established, patients should be evaluated at each subsequent visit for the degree of treatment response. Excessive erythema (lasting more than 48 hours) or adverse effects, such as itching, stinging, or burning, are indications that the patient should have their dose adjusted back to the last dose without such adverse responses. Because tolerance to treatment develops over time, patients who miss a scheduled dose of NB-UVB phototherapy require their dose to be temporarily lowered. Targeted dosage of UVB phototherapy at a frequency of 2 to 3 times weekly is preferred over treatment 1 to 2 times weekly; however, consideration should be given toward patient preference.²⁶ Dosing may be increased at a rate of 5% to 10% after each treatment, as tolerated, if there is no clearance of skin lesions with the original treatment dose. Patient skin type also is helpful in dictating the maximum phototherapy dose for each patient (Table 3).

Once a patient’s psoriatic lesions have cleared, the patient has the option to taper or indefinitely continue maintenance therapy. The established protocol for patients who choose to taper therapy is treatment twice weekly for 4 weeks, followed by once-weekly treatment for the second month. The maintenance dosage is held constant during the taper. For patients who prefer indefinite maintenance therapy, treatment is administered every 1 to 2 weeks, with a maintenance dosage that is approximately 25% lower than the original maintenance dosage.

Treatment Considerations

Efforts should be made to ensure that the long-term sequalae of phototherapy are minimized (Table 1). Development of cataracts is a recognized consequence of prolonged UVB exposure; therefore, eye protection is recommended during all UVB treatment sessions to reduce the risk for ocular toxicity. Although pregnancy is not a contraindication to phototherapy, except for PUVA, there is a dose-dependent degradation of folate with NB-UVB treatment, so folate supplementation (0.8 mg) is recommended during NB-UVB treatment to prevent development of neural tube defects in fetuses of patients who are pregnant or who may become pregnant.²⁷

Although phototherapy carries the theoretical risk for photocarcinogenesis, multiple studies have shown no increased risk for malignancy with either NB-UVB or BB-UVB phototherapy.^22,23 Regardless, patients who develop new-onset skin cancer while receiving any phototherapeutic treatment should discuss the potential risks and benefits of continued treatment with their physician. Providers should take extra caution prior to initiating treatment, especially in patients with a history of cutaneous malignancy. Because oral PUVA is a systemic therapy, it is associated with a greater risk for photocarcinogenesis than any other modality, particularly in fair-skinned individuals. Patients younger than 10 years; pregnant or nursing patients; and those with a history of lupus, xeroderma pigmentosum, or melanoma should not receive PUVA therapy because of their increased risk for photocarcinogenesis and TRAEs.

The decision to switch patients between different phototherapy modalities during treatment should be individualized to each patient based on factors such as disease severity, quality of life, and treatment burden. Other factors to consider include dosing frequency, treatment cost, and logistical factors, such as proximity to a treatment facility. Physicians should have a detailed discussion about the risks and benefits of continuing therapy for patients who develop new-onset skin cancer during phototherapy.

Final Thoughts

Phototherapy is an effective and safe treatment for patients with psoriasis who have localized and systemic disease. There are several treatment modalities that can be tailored to patient needs and preferences, such as home NB-UVB for patients who are unable or unwilling to undergo office-based treatments. Phototherapy has few absolute contraindications; however, relative contraindications to phototherapy exist. Patients with a history of skin cancer, photosensitivity disorders, and autoimmune diseases (eg, lupus) carry greater risks for adverse events, such as sun-related damage, cancer, and dysplasia. Because these conditions may preclude patients from pursuing phototherapy as a safe and effective approach to treating moderate to severe psoriasis, these patients should be considered for other therapies, such as biologic medications, which may carry a more favorable risk-benefit ratio given that individual’s background.

Psoriasis is a systemic immune-mediated disorder characterized by erythematous, scaly, well-demarcated plaques on the skin that affects approximately 3% of the world’s population.¹ Although topical therapies often are the first-line treatment of mild to moderate psoriasis, approximately 1 in 6 individuals has moderate to severe disease that requires systemic treatment such as biologics or phototherapy.² In patients with localized disease that is refractory to treatment or who have moderate to severe psoriasis requiring systemic treatment, phototherapy should be considered as a potential low-risk treatment option.

In July 2019, the American Academy of Dermatology (AAD) and National Psoriasis Foundation (NPF) released an updated set of guidelines for the use of phototherapy in treating adult patients with psoriasis.³ Since the prior guidelines were released in 2010, there have been numerous studies affirming the efficacy of phototherapy, with several large meta-analyses helping to refine clinical recommendations.^4,5 Each treatment was ranked using Strength of Recommendation Taxonomy, with a score of A, B, or C based on the strength of the evidence supporting the given modality. With the ever-increasing number of treatment options for patients with psoriasis, these guidelines inform dermatologists of the recommendations for the initiation, maintenance, and optimization of phototherapy in the treatment of psoriasis.

The AAD-NPF recommendations discuss the mechanism of action, efficacy, safety, and frequency of adverse events of 10 commonly used phototherapy/photochemotherapy modalities. They also address dosing regimens, the potential to combine phototherapy with other therapies, and the efficacy of treatment modalities for different types of psoriasis.³ The purpose of this discussion is to present these guidelines in a condensed form for prescribers of phototherapy and to review the most clinically significant considerations during each step of treatment. Of note, we only highlight the treatment of adult patients and do not discuss information relevant to pediatric patients with psoriasis.

Choosing a Phototherapy Modality

Phototherapy may be considered for patients with psoriasis that affects more than 3% body surface area or for localized disease refractory to conventional treatments. UV light is believed to provide relief from psoriasis via multiple mechanisms, such as through favorable alterations in cytokine profiles, initiation of apoptosis, and local immunosupression.⁶ There is no single first-line phototherapeutic modality recommended for all patients with psoriasis. Rather, the decision to implement a particular modality should be individualized to the patient, considering factors such as percentage of body surface area affected by disease, quality-of-life assessment, comorbidities, lifestyle, and cost of treatment.

Of the 10 phototherapy modalities reviewed in these guidelines, 4 were ranked by the AAD and NPF as having grade A evidence for efficacy in the treatment of moderate to severe plaque psoriasis. Treatments with a grade A level of recommendation included narrowband UVB (NB-UVB), broadband UVB (BB-UVB), targeted phototherapy (excimer laser and excimer lamp), and oral psoralen plus UVA (PUVA) therapy. Photodynamic therapy for psoriasis was given an A-level recommendation against its use, as it was found to be ineffective with an unfavorable side-effect profile. Treatments with a grade B level of recommendation—nonoral routes of PUVA therapy, pulsed dye laser/intense pulsed light for nail psoriasis only, Goeckerman therapy, and climatotherapy—have sufficient evidence available to support their treatment of moderate to severe psoriasis in some cases. Treatments with a grade C level of recommendation—Grenz ray therapy (also called borderline or ultrasoft therapy) and visible light therapy—have insufficient evidence to support their use in patients with moderate to severe psoriasis (Table 1).

Psoralen plus UVA, which may be used topically (ie, bathwater PUVA) or taken orally, refers to treatment with photosensitizing psoralens. Psoralens are agents that intercalate with DNA and enhance the efficacy of phototherapy.¹⁰ Topical PUVA, with a grade B level of recommendation, is an effective treatment option for patients with localized disease and has been shown to be particularly efficacious in the treatment of palmoplantar pustular psoriasis. Oral PUVA is an effective option for psoriasis with a grade A recommendation, while bathwater PUVA has a grade B level of recommendation for moderate to severe plaque psoriasis. Oral PUVA is associated with greater systemic side effects (both acute and subacute) compared with NB-UVB and also is associated with photocarcinogenesis, particularly squamous cell carcinoma in white patients.¹¹ Other side effects from PUVA include pigmented macules in sun-protected areas (known as PUVA lentigines), which may make evaluation of skin lesions challenging. Because of the increased risk for cancer with oral PUVA, NB-UVB is preferable as a first-line treatment vs PUVA, especially in patients with a history of skin cancer.^12,13

Goeckerman therapy, which involves the synergistic combination of UVB and crude coal tar, is an older treatment that has shown efficacy in the treatment of severe or recalcitrant psoriasis (grade B level of recommendation). One prior case-control study comparing the efficacy of Goeckerman therapy with newer treatments, such as biologic therapies, steroids, and oral immunosuppressants, found a similar reduction in symptoms among both treatment groups, with longer disease-free periods in patients who received Goeckerman therapy than those who received newer therapies (22.3 years vs 4.6 months).¹⁴ However, Goeckerman therapy is utilized less frequently than more modern therapies because of the time required for treatment and declining insurance reimbursements for it. Climatotherapy, another older established therapy, involves the temporary or permanent relocation of patients to an environment that is favorable for disease control (grade B level of recommendation). Locations such as the Dead Sea and Canary Islands have been studied and shown to provide both subjective and objective improvement in patients’ psoriasis disease course. Patients had notable improvement in both their psoriasis area and severity index score and quality of life after a 3- to 4-week relocation to these areas.^15,16 Access to climatotherapy and the transient nature of disease relief are apparent limitations of this treatment modality.

Grenz ray is a type of phototherapy that uses longer-wavelength ionizing radiation, which has low penetrance into surrounding tissues and a 95% absorption rate within the first 3 mm of the skin depth. This treatment has been used less frequently since the development of newer alternatives but should still be considered as a second line to UV therapy, especially in cases of recalcitrant disease and palmoplantar psoriasis, and when access to other treatment options is limited. Grenz ray has a grade C level of recommendation due to the paucity of evidence that supports its efficacy. Thus, it is not recommended as first-line therapy for the treatment of moderate to severe psoriasis. Visible light therapy is another treatment option that uses light in the visible wavelength spectrum but predominantly utilizes blue and red light. Psoriatic lesions are sensitive to light therapy because of the elevated levels of naturally occurring photosensitizing agents, called protoporphyrins, in these lesions.¹⁷ Several small studies have shown improvement in psoriatic lesions treated with visible light therapy, with blue light showing greater efficacy in lesional clearance than red light.^18,19

Pulsed dye laser is a phototherapy modality that has shown efficacy in the treatment of nail psoriasis (grade B level of recommendation). One study comparing the effects of tazarotene cream 0.1% with pulsed dye laser and tazarotene cream 0.1% alone showed that patients receiving combination therapy had a greater decrease in nail psoriasis severity index scores, higher scores on the patient’s global assessment of improvement, and higher rates of improvement on the physician global assessment score. A physician global assessment score of 75% improvement or more was seen in patients treated with combination therapy vs monotherapy (5.3% vs 31.6%).²⁰ Intense pulsed light, a type of visible light therapy, also has been used to treat nail psoriasis, with one study showing notable improvement in nail bed and matrix disease and a global improvement in nail psoriasis severity index score after 6 months of biweekly treatment.²¹ However, this treatment has a grade B level of recommendation given the limited number of studies supporting the efficacy of this modality.

Initiation of Phototherapy

Prior to initiating phototherapy, it is important to assess the patient for any personal or family history of skin cancer, as phototherapy carries an increased risk for cutaneous malignancy, especially in patients with a history of skin cancer.^22,23 All patients also should be evaluated for their Fitzpatrick skin type, and the minimal erythema dose should be defined for those initiating UVB treatment. These classifications can be useful for the initial determination of treatment dose and the prevention of treatment-related adverse events (TRAEs). A careful drug history also should be taken before the initiation of phototherapy to avoid photosensitizing reactions. Thiazide diuretics and tetracyclines are 2 such examples of medications commonly associated with photosensitizing reactions.²⁴

Fitzpatrick skin type and/or minimal erythema dose testing also are essential in determining the appropriate initial NB-UVB dose required for treatment initiation (Table 2). Patient response to the initial NB-UVB trial will determine the optimal dosage for subsequent maintenance treatments.

Assessment and Optimization of Phototherapy

After an appropriate starting dosage has been established, patients should be evaluated at each subsequent visit for the degree of treatment response. Excessive erythema (lasting more than 48 hours) or adverse effects, such as itching, stinging, or burning, are indications that the patient should have their dose adjusted back to the last dose without such adverse responses. Because tolerance to treatment develops over time, patients who miss a scheduled dose of NB-UVB phototherapy require their dose to be temporarily lowered. Targeted dosage of UVB phototherapy at a frequency of 2 to 3 times weekly is preferred over treatment 1 to 2 times weekly; however, consideration should be given toward patient preference.²⁶ Dosing may be increased at a rate of 5% to 10% after each treatment, as tolerated, if there is no clearance of skin lesions with the original treatment dose. Patient skin type also is helpful in dictating the maximum phototherapy dose for each patient (Table 3).

Once a patient’s psoriatic lesions have cleared, the patient has the option to taper or indefinitely continue maintenance therapy. The established protocol for patients who choose to taper therapy is treatment twice weekly for 4 weeks, followed by once-weekly treatment for the second month. The maintenance dosage is held constant during the taper. For patients who prefer indefinite maintenance therapy, treatment is administered every 1 to 2 weeks, with a maintenance dosage that is approximately 25% lower than the original maintenance dosage.

Treatment Considerations

Efforts should be made to ensure that the long-term sequalae of phototherapy are minimized (Table 1). Development of cataracts is a recognized consequence of prolonged UVB exposure; therefore, eye protection is recommended during all UVB treatment sessions to reduce the risk for ocular toxicity. Although pregnancy is not a contraindication to phototherapy, except for PUVA, there is a dose-dependent degradation of folate with NB-UVB treatment, so folate supplementation (0.8 mg) is recommended during NB-UVB treatment to prevent development of neural tube defects in fetuses of patients who are pregnant or who may become pregnant.²⁷

Although phototherapy carries the theoretical risk for photocarcinogenesis, multiple studies have shown no increased risk for malignancy with either NB-UVB or BB-UVB phototherapy.^22,23 Regardless, patients who develop new-onset skin cancer while receiving any phototherapeutic treatment should discuss the potential risks and benefits of continued treatment with their physician. Providers should take extra caution prior to initiating treatment, especially in patients with a history of cutaneous malignancy. Because oral PUVA is a systemic therapy, it is associated with a greater risk for photocarcinogenesis than any other modality, particularly in fair-skinned individuals. Patients younger than 10 years; pregnant or nursing patients; and those with a history of lupus, xeroderma pigmentosum, or melanoma should not receive PUVA therapy because of their increased risk for photocarcinogenesis and TRAEs.

The decision to switch patients between different phototherapy modalities during treatment should be individualized to each patient based on factors such as disease severity, quality of life, and treatment burden. Other factors to consider include dosing frequency, treatment cost, and logistical factors, such as proximity to a treatment facility. Physicians should have a detailed discussion about the risks and benefits of continuing therapy for patients who develop new-onset skin cancer during phototherapy.

Final Thoughts

Phototherapy is an effective and safe treatment for patients with psoriasis who have localized and systemic disease. There are several treatment modalities that can be tailored to patient needs and preferences, such as home NB-UVB for patients who are unable or unwilling to undergo office-based treatments. Phototherapy has few absolute contraindications; however, relative contraindications to phototherapy exist. Patients with a history of skin cancer, photosensitivity disorders, and autoimmune diseases (eg, lupus) carry greater risks for adverse events, such as sun-related damage, cancer, and dysplasia. Because these conditions may preclude patients from pursuing phototherapy as a safe and effective approach to treating moderate to severe psoriasis, these patients should be considered for other therapies, such as biologic medications, which may carry a more favorable risk-benefit ratio given that individual’s background.

Psoriasis is a systemic immune-mediated disorder characterized by erythematous, scaly, well-demarcated plaques on the skin that affects approximately 3% of the world’s population.¹ Although topical therapies often are the first-line treatment of mild to moderate psoriasis, approximately 1 in 6 individuals has moderate to severe disease that requires systemic treatment such as biologics or phototherapy.² In patients with localized disease that is refractory to treatment or who have moderate to severe psoriasis requiring systemic treatment, phototherapy should be considered as a potential low-risk treatment option.

In July 2019, the American Academy of Dermatology (AAD) and National Psoriasis Foundation (NPF) released an updated set of guidelines for the use of phototherapy in treating adult patients with psoriasis.³ Since the prior guidelines were released in 2010, there have been numerous studies affirming the efficacy of phototherapy, with several large meta-analyses helping to refine clinical recommendations.^4,5 Each treatment was ranked using Strength of Recommendation Taxonomy, with a score of A, B, or C based on the strength of the evidence supporting the given modality. With the ever-increasing number of treatment options for patients with psoriasis, these guidelines inform dermatologists of the recommendations for the initiation, maintenance, and optimization of phototherapy in the treatment of psoriasis.

The AAD-NPF recommendations discuss the mechanism of action, efficacy, safety, and frequency of adverse events of 10 commonly used phototherapy/photochemotherapy modalities. They also address dosing regimens, the potential to combine phototherapy with other therapies, and the efficacy of treatment modalities for different types of psoriasis.³ The purpose of this discussion is to present these guidelines in a condensed form for prescribers of phototherapy and to review the most clinically significant considerations during each step of treatment. Of note, we only highlight the treatment of adult patients and do not discuss information relevant to pediatric patients with psoriasis.

Choosing a Phototherapy Modality

Phototherapy may be considered for patients with psoriasis that affects more than 3% body surface area or for localized disease refractory to conventional treatments. UV light is believed to provide relief from psoriasis via multiple mechanisms, such as through favorable alterations in cytokine profiles, initiation of apoptosis, and local immunosupression.⁶ There is no single first-line phototherapeutic modality recommended for all patients with psoriasis. Rather, the decision to implement a particular modality should be individualized to the patient, considering factors such as percentage of body surface area affected by disease, quality-of-life assessment, comorbidities, lifestyle, and cost of treatment.

Of the 10 phototherapy modalities reviewed in these guidelines, 4 were ranked by the AAD and NPF as having grade A evidence for efficacy in the treatment of moderate to severe plaque psoriasis. Treatments with a grade A level of recommendation included narrowband UVB (NB-UVB), broadband UVB (BB-UVB), targeted phototherapy (excimer laser and excimer lamp), and oral psoralen plus UVA (PUVA) therapy. Photodynamic therapy for psoriasis was given an A-level recommendation against its use, as it was found to be ineffective with an unfavorable side-effect profile. Treatments with a grade B level of recommendation—nonoral routes of PUVA therapy, pulsed dye laser/intense pulsed light for nail psoriasis only, Goeckerman therapy, and climatotherapy—have sufficient evidence available to support their treatment of moderate to severe psoriasis in some cases. Treatments with a grade C level of recommendation—Grenz ray therapy (also called borderline or ultrasoft therapy) and visible light therapy—have insufficient evidence to support their use in patients with moderate to severe psoriasis (Table 1).

Psoralen plus UVA, which may be used topically (ie, bathwater PUVA) or taken orally, refers to treatment with photosensitizing psoralens. Psoralens are agents that intercalate with DNA and enhance the efficacy of phototherapy.¹⁰ Topical PUVA, with a grade B level of recommendation, is an effective treatment option for patients with localized disease and has been shown to be particularly efficacious in the treatment of palmoplantar pustular psoriasis. Oral PUVA is an effective option for psoriasis with a grade A recommendation, while bathwater PUVA has a grade B level of recommendation for moderate to severe plaque psoriasis. Oral PUVA is associated with greater systemic side effects (both acute and subacute) compared with NB-UVB and also is associated with photocarcinogenesis, particularly squamous cell carcinoma in white patients.¹¹ Other side effects from PUVA include pigmented macules in sun-protected areas (known as PUVA lentigines), which may make evaluation of skin lesions challenging. Because of the increased risk for cancer with oral PUVA, NB-UVB is preferable as a first-line treatment vs PUVA, especially in patients with a history of skin cancer.^12,13

Goeckerman therapy, which involves the synergistic combination of UVB and crude coal tar, is an older treatment that has shown efficacy in the treatment of severe or recalcitrant psoriasis (grade B level of recommendation). One prior case-control study comparing the efficacy of Goeckerman therapy with newer treatments, such as biologic therapies, steroids, and oral immunosuppressants, found a similar reduction in symptoms among both treatment groups, with longer disease-free periods in patients who received Goeckerman therapy than those who received newer therapies (22.3 years vs 4.6 months).¹⁴ However, Goeckerman therapy is utilized less frequently than more modern therapies because of the time required for treatment and declining insurance reimbursements for it. Climatotherapy, another older established therapy, involves the temporary or permanent relocation of patients to an environment that is favorable for disease control (grade B level of recommendation). Locations such as the Dead Sea and Canary Islands have been studied and shown to provide both subjective and objective improvement in patients’ psoriasis disease course. Patients had notable improvement in both their psoriasis area and severity index score and quality of life after a 3- to 4-week relocation to these areas.^15,16 Access to climatotherapy and the transient nature of disease relief are apparent limitations of this treatment modality.

Grenz ray is a type of phototherapy that uses longer-wavelength ionizing radiation, which has low penetrance into surrounding tissues and a 95% absorption rate within the first 3 mm of the skin depth. This treatment has been used less frequently since the development of newer alternatives but should still be considered as a second line to UV therapy, especially in cases of recalcitrant disease and palmoplantar psoriasis, and when access to other treatment options is limited. Grenz ray has a grade C level of recommendation due to the paucity of evidence that supports its efficacy. Thus, it is not recommended as first-line therapy for the treatment of moderate to severe psoriasis. Visible light therapy is another treatment option that uses light in the visible wavelength spectrum but predominantly utilizes blue and red light. Psoriatic lesions are sensitive to light therapy because of the elevated levels of naturally occurring photosensitizing agents, called protoporphyrins, in these lesions.¹⁷ Several small studies have shown improvement in psoriatic lesions treated with visible light therapy, with blue light showing greater efficacy in lesional clearance than red light.^18,19

Pulsed dye laser is a phototherapy modality that has shown efficacy in the treatment of nail psoriasis (grade B level of recommendation). One study comparing the effects of tazarotene cream 0.1% with pulsed dye laser and tazarotene cream 0.1% alone showed that patients receiving combination therapy had a greater decrease in nail psoriasis severity index scores, higher scores on the patient’s global assessment of improvement, and higher rates of improvement on the physician global assessment score. A physician global assessment score of 75% improvement or more was seen in patients treated with combination therapy vs monotherapy (5.3% vs 31.6%).²⁰ Intense pulsed light, a type of visible light therapy, also has been used to treat nail psoriasis, with one study showing notable improvement in nail bed and matrix disease and a global improvement in nail psoriasis severity index score after 6 months of biweekly treatment.²¹ However, this treatment has a grade B level of recommendation given the limited number of studies supporting the efficacy of this modality.

Initiation of Phototherapy

Prior to initiating phototherapy, it is important to assess the patient for any personal or family history of skin cancer, as phototherapy carries an increased risk for cutaneous malignancy, especially in patients with a history of skin cancer.^22,23 All patients also should be evaluated for their Fitzpatrick skin type, and the minimal erythema dose should be defined for those initiating UVB treatment. These classifications can be useful for the initial determination of treatment dose and the prevention of treatment-related adverse events (TRAEs). A careful drug history also should be taken before the initiation of phototherapy to avoid photosensitizing reactions. Thiazide diuretics and tetracyclines are 2 such examples of medications commonly associated with photosensitizing reactions.²⁴

Fitzpatrick skin type and/or minimal erythema dose testing also are essential in determining the appropriate initial NB-UVB dose required for treatment initiation (Table 2). Patient response to the initial NB-UVB trial will determine the optimal dosage for subsequent maintenance treatments.

Assessment and Optimization of Phototherapy

After an appropriate starting dosage has been established, patients should be evaluated at each subsequent visit for the degree of treatment response. Excessive erythema (lasting more than 48 hours) or adverse effects, such as itching, stinging, or burning, are indications that the patient should have their dose adjusted back to the last dose without such adverse responses. Because tolerance to treatment develops over time, patients who miss a scheduled dose of NB-UVB phototherapy require their dose to be temporarily lowered. Targeted dosage of UVB phototherapy at a frequency of 2 to 3 times weekly is preferred over treatment 1 to 2 times weekly; however, consideration should be given toward patient preference.²⁶ Dosing may be increased at a rate of 5% to 10% after each treatment, as tolerated, if there is no clearance of skin lesions with the original treatment dose. Patient skin type also is helpful in dictating the maximum phototherapy dose for each patient (Table 3).

Once a patient’s psoriatic lesions have cleared, the patient has the option to taper or indefinitely continue maintenance therapy. The established protocol for patients who choose to taper therapy is treatment twice weekly for 4 weeks, followed by once-weekly treatment for the second month. The maintenance dosage is held constant during the taper. For patients who prefer indefinite maintenance therapy, treatment is administered every 1 to 2 weeks, with a maintenance dosage that is approximately 25% lower than the original maintenance dosage.

Treatment Considerations

Efforts should be made to ensure that the long-term sequalae of phototherapy are minimized (Table 1). Development of cataracts is a recognized consequence of prolonged UVB exposure; therefore, eye protection is recommended during all UVB treatment sessions to reduce the risk for ocular toxicity. Although pregnancy is not a contraindication to phototherapy, except for PUVA, there is a dose-dependent degradation of folate with NB-UVB treatment, so folate supplementation (0.8 mg) is recommended during NB-UVB treatment to prevent development of neural tube defects in fetuses of patients who are pregnant or who may become pregnant.²⁷

Although phototherapy carries the theoretical risk for photocarcinogenesis, multiple studies have shown no increased risk for malignancy with either NB-UVB or BB-UVB phototherapy.^22,23 Regardless, patients who develop new-onset skin cancer while receiving any phototherapeutic treatment should discuss the potential risks and benefits of continued treatment with their physician. Providers should take extra caution prior to initiating treatment, especially in patients with a history of cutaneous malignancy. Because oral PUVA is a systemic therapy, it is associated with a greater risk for photocarcinogenesis than any other modality, particularly in fair-skinned individuals. Patients younger than 10 years; pregnant or nursing patients; and those with a history of lupus, xeroderma pigmentosum, or melanoma should not receive PUVA therapy because of their increased risk for photocarcinogenesis and TRAEs.

The decision to switch patients between different phototherapy modalities during treatment should be individualized to each patient based on factors such as disease severity, quality of life, and treatment burden. Other factors to consider include dosing frequency, treatment cost, and logistical factors, such as proximity to a treatment facility. Physicians should have a detailed discussion about the risks and benefits of continuing therapy for patients who develop new-onset skin cancer during phototherapy.

Final Thoughts

Phototherapy is an effective and safe treatment for patients with psoriasis who have localized and systemic disease. There are several treatment modalities that can be tailored to patient needs and preferences, such as home NB-UVB for patients who are unable or unwilling to undergo office-based treatments. Phototherapy has few absolute contraindications; however, relative contraindications to phototherapy exist. Patients with a history of skin cancer, photosensitivity disorders, and autoimmune diseases (eg, lupus) carry greater risks for adverse events, such as sun-related damage, cancer, and dysplasia. Because these conditions may preclude patients from pursuing phototherapy as a safe and effective approach to treating moderate to severe psoriasis, these patients should be considered for other therapies, such as biologic medications, which may carry a more favorable risk-benefit ratio given that individual’s background.

Practice Gap

Cutaneous head and neck reconstruction following Mohs micrographic surgery frequently presents the surgical dilemma of dog-ear formation during wound closure, often necessitating excision of additional tissue to correct the standing cone, which could pose the risk for an undesirable tension vector as well as encroachment upon additional cosmetic units or sensitive anatomic structures such as a free margin. A classic Z-plasty is a transposition flap (by definition, translocation of tissue laterally about a pivot point) that corrects a dog-ear deformity without skin excision by recruiting tissue from the axis of the standing cone and redistributing it along another.

The Technique

A classic Z-plasty is designed with 3 equal limb lengths (<1 cm each) at 60° angles, abutting the pedicle of the rotation or advancement flap. The limbs can extend away from the pedicle of the flap to minimize vascular compromise. In our patient, the theoretical standing cone was located at the lateral aspect of an O to L advancement flap (Figure 1). The 2 identical triangular flaps were elevated (Figure 2A), transposed around the pivot point (Figure 2B), and inset (Figure 3). The standing cone was corrected by redistribution of tissue without excision of additional tissue, resulting in a softer and thinner scar 2 weeks (Figure 4A) and 4 months (Figure 4B) postoperatively.

Practice Implications

This technique can be used to correct cones following primary wound repairs or flaps. The primary advantage of this technique for dog-ear correction is tissue sparing. Disadvantages include more complex surgical planning and longer scar length compared to excisional corrective techniques. Additionally, Z-plasty requires more time to execute compared to simpler techniques.^1,2

Practice Gap

Cutaneous head and neck reconstruction following Mohs micrographic surgery frequently presents the surgical dilemma of dog-ear formation during wound closure, often necessitating excision of additional tissue to correct the standing cone, which could pose the risk for an undesirable tension vector as well as encroachment upon additional cosmetic units or sensitive anatomic structures such as a free margin. A classic Z-plasty is a transposition flap (by definition, translocation of tissue laterally about a pivot point) that corrects a dog-ear deformity without skin excision by recruiting tissue from the axis of the standing cone and redistributing it along another.

The Technique

A classic Z-plasty is designed with 3 equal limb lengths (<1 cm each) at 60° angles, abutting the pedicle of the rotation or advancement flap. The limbs can extend away from the pedicle of the flap to minimize vascular compromise. In our patient, the theoretical standing cone was located at the lateral aspect of an O to L advancement flap (Figure 1). The 2 identical triangular flaps were elevated (Figure 2A), transposed around the pivot point (Figure 2B), and inset (Figure 3). The standing cone was corrected by redistribution of tissue without excision of additional tissue, resulting in a softer and thinner scar 2 weeks (Figure 4A) and 4 months (Figure 4B) postoperatively.

Practice Implications

This technique can be used to correct cones following primary wound repairs or flaps. The primary advantage of this technique for dog-ear correction is tissue sparing. Disadvantages include more complex surgical planning and longer scar length compared to excisional corrective techniques. Additionally, Z-plasty requires more time to execute compared to simpler techniques.^1,2

Practice Gap

Cutaneous head and neck reconstruction following Mohs micrographic surgery frequently presents the surgical dilemma of dog-ear formation during wound closure, often necessitating excision of additional tissue to correct the standing cone, which could pose the risk for an undesirable tension vector as well as encroachment upon additional cosmetic units or sensitive anatomic structures such as a free margin. A classic Z-plasty is a transposition flap (by definition, translocation of tissue laterally about a pivot point) that corrects a dog-ear deformity without skin excision by recruiting tissue from the axis of the standing cone and redistributing it along another.

The Technique

A classic Z-plasty is designed with 3 equal limb lengths (<1 cm each) at 60° angles, abutting the pedicle of the rotation or advancement flap. The limbs can extend away from the pedicle of the flap to minimize vascular compromise. In our patient, the theoretical standing cone was located at the lateral aspect of an O to L advancement flap (Figure 1). The 2 identical triangular flaps were elevated (Figure 2A), transposed around the pivot point (Figure 2B), and inset (Figure 3). The standing cone was corrected by redistribution of tissue without excision of additional tissue, resulting in a softer and thinner scar 2 weeks (Figure 4A) and 4 months (Figure 4B) postoperatively.

Practice Implications

This technique can be used to correct cones following primary wound repairs or flaps. The primary advantage of this technique for dog-ear correction is tissue sparing. Disadvantages include more complex surgical planning and longer scar length compared to excisional corrective techniques. Additionally, Z-plasty requires more time to execute compared to simpler techniques.^1,2

Since the first mobile application (app) was developed in the 1990s, apps have become increasingly integrated into medical practice and training. More than 5.5 million apps were downloadable in 2019,¹ of which more than 300,000 were health related.² In the United States, more than 80% of physicians reported using smartphones for professional purposes in 2016.³ As the complexity of apps and their purpose of use has evolved, regulatory bodies have not adapted adequately to monitor apps that have broad-reaching consequences in medicine.

We review the primary literature on PubMed behind health-related apps that impact dermatologists as well as the government regulation of these apps, with a focus on the 3 most prevalent dermatology-related apps used by dermatology residents in the United States: VisualDx, UpToDate, and Mohs Surgery Appropriate Use Criteria. This prevalence is according to a survey emailed to all dermatology residents in the United States by the American Academy of Dermatology (AAD) in 2019 (unpublished data).

VisualDx

VisualDx, which aims to improve diagnostic accuracy and patient safety, contains peer-reviewed data and more than 32,000 images of dermatologic conditions. The editorial board includes more than 50 physicians. It provides opportunities for continuing medical education credit, is used in more than 2300 medical settings, and costs $399.99 annually for a subscription with partial features. Prior to the launch of the app in 2010, some health science professionals noted that the website version lacked references to primary sources.⁴ The same issue carried over to the app, which has evolved to offer artificial intelligence (AI) analysis of photographed skin lesions. However, there are no peer-reviewed publications showing positive impact of the app on diagnostic skills among dermatology residents or on patient outcomes.

UpToDate

UpToDate is a web-based database created in the early 1990s. A corresponding app was created around 2010. Both internal and independent research has demonstrated improved outcomes, and the app is advertised as the only clinical decision support resource associated with improved outcomes, as shown in more than 80 publications.⁵ UpToDate covers more than 11,800 medical topics and contains more than 35,000 graphics. It cites primary sources and uses a published system for grading recommendation strength and evidence quality. The data are processed and produced by a team of more than 7100 physicians as authors, editors, and reviewers. The platform grants continuing medical education credit and is used by more than 1.9 million clinicians in more than 190 countries. A 1-year subscription for an individual US-based physician costs $559. An observational study assessed UpToDate articles for potential conflicts of interest between authors and their recommendations. Of the 6 articles that met inclusion criteria of discussing management of medical conditions that have controversial or mostly brand-name treatment options, all had conflicts of interest, such as naming drugs from companies with which the authors and/or editors had financial relationships.⁶

Mohs Surgery Appropriate Use Criteria

The Mohs Surgery Appropriate Use Criteria app is a free clinical decision-making tool based on a consensus statement published in 2012 by the AAD, American College of Mohs Surgery, American Society for Dermatologic Surgery Association, and American Society for Mohs Surgery.⁷ It helps guide management of more than 200 dermatologic scenarios. Critique has been made that the criteria are partly based on expert opinion and data largely from the United States and has not been revised to incorporate newer data.⁸ There are no publications regarding the app itself.

Regulation of Health-Related Apps

Health-related apps that are designed for utilization by health care providers can be a valuable tool. However, given their prevalence, cost, and potential impact on patient lives, these apps should be well regulated and researched. The general paucity of peer-reviewed literature demonstrating the utility, safety, quality, and accuracy of health-related apps commonly used by providers is a reflection of insufficient mobile health regulation in the United States.

There are 3 primary government agencies responsible for regulating mobile medical apps: the US Food and Drug Administration (FDA), Federal Trade Commission, and Office for Civil Rights.⁹ The FDA does not regulate all medical devices. Apps intended for use in the diagnosis, cure, mitigation, prevention, or treatment of a disease or condition are considered to be medical devices.¹⁰ The FDA regulates those apps only if they are judged to pose more than minimal risk. Apps that are designed only to provide easy access to information related to health conditions or treatment are considered to be minimal risk but can develop into a different risk level such as by offering AI.¹¹ Although the FDA does update its approach to medical devices, including apps and AI- and machine learning–based software, the rate and direction of update has not kept pace with the rapid evolution of apps.¹² In 2019, the FDA began piloting a precertification program that grants long-term approval to organizations that develop apps instead of reviewing each app product individually.¹³ This decrease in premarket oversight is intended to expedite innovation with the hopeful upside of improving patient outcomes but is inconsistent, with the FDA still reviewing other types of medical devices individually.

For apps that are already in use, the Federal Trade Commission only gets involved in response to deceptive or unfair acts or practices relating to privacy, data security, and false or misleading claims about safety or performance. It may be more beneficial for consumers if those apps had a more stringent initial approval process. The Office for Civil Rights enforces the Health Insurance Portability and Accountability Act when relevant to apps.

Nongovernment agencies also are involved in app regulation. The FDA believes sharing more regulatory responsibility with private industry would promote efficiency.¹⁴ Google does not allow apps that contain false or misleading health claims,¹⁵ and Apple may scrutinize medical apps that could provide inaccurate data or be used for diagnosing or treating patients.¹⁶ Xcertia, a nonprofit organization founded by the American Medical Association and others, develops standards for the security, privacy, content, and operability of health-related apps, but those standards have not been adopted by other parties. Ultimately, nongovernment agencies are not responsible for public health and do not boast the government’s ability to enforce rules or ensure public safety.

Final Thoughts

The AAD survey of US dermatology residents found that the top consideration when choosing apps was up-to-date and accurate information; however, the 3 most prevalent apps among those same respondents did not need government approval and are not required to contain up-to-date data or to improve clinical outcomes, similar to most other health-related apps. This discrepancy is concerning considering the increasing utilization of apps for physician education and health care delivery and the increasing complexity of those apps. In light of these results, the potential decrease in federal premarket regulation suggested by the FDA’s precertification program seems inappropriate. It is important for the government to take responsibility for regulating health-related apps and to find a balance between too much regulation delaying innovation and too little regulation hurting physician training and patient care. It also is important for providers to be aware of the evidence and oversight behind the technologies they use for professional purposes.

Since the first mobile application (app) was developed in the 1990s, apps have become increasingly integrated into medical practice and training. More than 5.5 million apps were downloadable in 2019,¹ of which more than 300,000 were health related.² In the United States, more than 80% of physicians reported using smartphones for professional purposes in 2016.³ As the complexity of apps and their purpose of use has evolved, regulatory bodies have not adapted adequately to monitor apps that have broad-reaching consequences in medicine.

We review the primary literature on PubMed behind health-related apps that impact dermatologists as well as the government regulation of these apps, with a focus on the 3 most prevalent dermatology-related apps used by dermatology residents in the United States: VisualDx, UpToDate, and Mohs Surgery Appropriate Use Criteria. This prevalence is according to a survey emailed to all dermatology residents in the United States by the American Academy of Dermatology (AAD) in 2019 (unpublished data).

VisualDx

VisualDx, which aims to improve diagnostic accuracy and patient safety, contains peer-reviewed data and more than 32,000 images of dermatologic conditions. The editorial board includes more than 50 physicians. It provides opportunities for continuing medical education credit, is used in more than 2300 medical settings, and costs $399.99 annually for a subscription with partial features. Prior to the launch of the app in 2010, some health science professionals noted that the website version lacked references to primary sources.⁴ The same issue carried over to the app, which has evolved to offer artificial intelligence (AI) analysis of photographed skin lesions. However, there are no peer-reviewed publications showing positive impact of the app on diagnostic skills among dermatology residents or on patient outcomes.

UpToDate

UpToDate is a web-based database created in the early 1990s. A corresponding app was created around 2010. Both internal and independent research has demonstrated improved outcomes, and the app is advertised as the only clinical decision support resource associated with improved outcomes, as shown in more than 80 publications.⁵ UpToDate covers more than 11,800 medical topics and contains more than 35,000 graphics. It cites primary sources and uses a published system for grading recommendation strength and evidence quality. The data are processed and produced by a team of more than 7100 physicians as authors, editors, and reviewers. The platform grants continuing medical education credit and is used by more than 1.9 million clinicians in more than 190 countries. A 1-year subscription for an individual US-based physician costs $559. An observational study assessed UpToDate articles for potential conflicts of interest between authors and their recommendations. Of the 6 articles that met inclusion criteria of discussing management of medical conditions that have controversial or mostly brand-name treatment options, all had conflicts of interest, such as naming drugs from companies with which the authors and/or editors had financial relationships.⁶

Mohs Surgery Appropriate Use Criteria

The Mohs Surgery Appropriate Use Criteria app is a free clinical decision-making tool based on a consensus statement published in 2012 by the AAD, American College of Mohs Surgery, American Society for Dermatologic Surgery Association, and American Society for Mohs Surgery.⁷ It helps guide management of more than 200 dermatologic scenarios. Critique has been made that the criteria are partly based on expert opinion and data largely from the United States and has not been revised to incorporate newer data.⁸ There are no publications regarding the app itself.

Regulation of Health-Related Apps

Health-related apps that are designed for utilization by health care providers can be a valuable tool. However, given their prevalence, cost, and potential impact on patient lives, these apps should be well regulated and researched. The general paucity of peer-reviewed literature demonstrating the utility, safety, quality, and accuracy of health-related apps commonly used by providers is a reflection of insufficient mobile health regulation in the United States.

There are 3 primary government agencies responsible for regulating mobile medical apps: the US Food and Drug Administration (FDA), Federal Trade Commission, and Office for Civil Rights.⁹ The FDA does not regulate all medical devices. Apps intended for use in the diagnosis, cure, mitigation, prevention, or treatment of a disease or condition are considered to be medical devices.¹⁰ The FDA regulates those apps only if they are judged to pose more than minimal risk. Apps that are designed only to provide easy access to information related to health conditions or treatment are considered to be minimal risk but can develop into a different risk level such as by offering AI.¹¹ Although the FDA does update its approach to medical devices, including apps and AI- and machine learning–based software, the rate and direction of update has not kept pace with the rapid evolution of apps.¹² In 2019, the FDA began piloting a precertification program that grants long-term approval to organizations that develop apps instead of reviewing each app product individually.¹³ This decrease in premarket oversight is intended to expedite innovation with the hopeful upside of improving patient outcomes but is inconsistent, with the FDA still reviewing other types of medical devices individually.

For apps that are already in use, the Federal Trade Commission only gets involved in response to deceptive or unfair acts or practices relating to privacy, data security, and false or misleading claims about safety or performance. It may be more beneficial for consumers if those apps had a more stringent initial approval process. The Office for Civil Rights enforces the Health Insurance Portability and Accountability Act when relevant to apps.

Nongovernment agencies also are involved in app regulation. The FDA believes sharing more regulatory responsibility with private industry would promote efficiency.¹⁴ Google does not allow apps that contain false or misleading health claims,¹⁵ and Apple may scrutinize medical apps that could provide inaccurate data or be used for diagnosing or treating patients.¹⁶ Xcertia, a nonprofit organization founded by the American Medical Association and others, develops standards for the security, privacy, content, and operability of health-related apps, but those standards have not been adopted by other parties. Ultimately, nongovernment agencies are not responsible for public health and do not boast the government’s ability to enforce rules or ensure public safety.

Final Thoughts

The AAD survey of US dermatology residents found that the top consideration when choosing apps was up-to-date and accurate information; however, the 3 most prevalent apps among those same respondents did not need government approval and are not required to contain up-to-date data or to improve clinical outcomes, similar to most other health-related apps. This discrepancy is concerning considering the increasing utilization of apps for physician education and health care delivery and the increasing complexity of those apps. In light of these results, the potential decrease in federal premarket regulation suggested by the FDA’s precertification program seems inappropriate. It is important for the government to take responsibility for regulating health-related apps and to find a balance between too much regulation delaying innovation and too little regulation hurting physician training and patient care. It also is important for providers to be aware of the evidence and oversight behind the technologies they use for professional purposes.

Since the first mobile application (app) was developed in the 1990s, apps have become increasingly integrated into medical practice and training. More than 5.5 million apps were downloadable in 2019,¹ of which more than 300,000 were health related.² In the United States, more than 80% of physicians reported using smartphones for professional purposes in 2016.³ As the complexity of apps and their purpose of use has evolved, regulatory bodies have not adapted adequately to monitor apps that have broad-reaching consequences in medicine.

We review the primary literature on PubMed behind health-related apps that impact dermatologists as well as the government regulation of these apps, with a focus on the 3 most prevalent dermatology-related apps used by dermatology residents in the United States: VisualDx, UpToDate, and Mohs Surgery Appropriate Use Criteria. This prevalence is according to a survey emailed to all dermatology residents in the United States by the American Academy of Dermatology (AAD) in 2019 (unpublished data).

VisualDx

VisualDx, which aims to improve diagnostic accuracy and patient safety, contains peer-reviewed data and more than 32,000 images of dermatologic conditions. The editorial board includes more than 50 physicians. It provides opportunities for continuing medical education credit, is used in more than 2300 medical settings, and costs $399.99 annually for a subscription with partial features. Prior to the launch of the app in 2010, some health science professionals noted that the website version lacked references to primary sources.⁴ The same issue carried over to the app, which has evolved to offer artificial intelligence (AI) analysis of photographed skin lesions. However, there are no peer-reviewed publications showing positive impact of the app on diagnostic skills among dermatology residents or on patient outcomes.

UpToDate

UpToDate is a web-based database created in the early 1990s. A corresponding app was created around 2010. Both internal and independent research has demonstrated improved outcomes, and the app is advertised as the only clinical decision support resource associated with improved outcomes, as shown in more than 80 publications.⁵ UpToDate covers more than 11,800 medical topics and contains more than 35,000 graphics. It cites primary sources and uses a published system for grading recommendation strength and evidence quality. The data are processed and produced by a team of more than 7100 physicians as authors, editors, and reviewers. The platform grants continuing medical education credit and is used by more than 1.9 million clinicians in more than 190 countries. A 1-year subscription for an individual US-based physician costs $559. An observational study assessed UpToDate articles for potential conflicts of interest between authors and their recommendations. Of the 6 articles that met inclusion criteria of discussing management of medical conditions that have controversial or mostly brand-name treatment options, all had conflicts of interest, such as naming drugs from companies with which the authors and/or editors had financial relationships.⁶

Mohs Surgery Appropriate Use Criteria

The Mohs Surgery Appropriate Use Criteria app is a free clinical decision-making tool based on a consensus statement published in 2012 by the AAD, American College of Mohs Surgery, American Society for Dermatologic Surgery Association, and American Society for Mohs Surgery.⁷ It helps guide management of more than 200 dermatologic scenarios. Critique has been made that the criteria are partly based on expert opinion and data largely from the United States and has not been revised to incorporate newer data.⁸ There are no publications regarding the app itself.

Regulation of Health-Related Apps

Health-related apps that are designed for utilization by health care providers can be a valuable tool. However, given their prevalence, cost, and potential impact on patient lives, these apps should be well regulated and researched. The general paucity of peer-reviewed literature demonstrating the utility, safety, quality, and accuracy of health-related apps commonly used by providers is a reflection of insufficient mobile health regulation in the United States.

There are 3 primary government agencies responsible for regulating mobile medical apps: the US Food and Drug Administration (FDA), Federal Trade Commission, and Office for Civil Rights.⁹ The FDA does not regulate all medical devices. Apps intended for use in the diagnosis, cure, mitigation, prevention, or treatment of a disease or condition are considered to be medical devices.¹⁰ The FDA regulates those apps only if they are judged to pose more than minimal risk. Apps that are designed only to provide easy access to information related to health conditions or treatment are considered to be minimal risk but can develop into a different risk level such as by offering AI.¹¹ Although the FDA does update its approach to medical devices, including apps and AI- and machine learning–based software, the rate and direction of update has not kept pace with the rapid evolution of apps.¹² In 2019, the FDA began piloting a precertification program that grants long-term approval to organizations that develop apps instead of reviewing each app product individually.¹³ This decrease in premarket oversight is intended to expedite innovation with the hopeful upside of improving patient outcomes but is inconsistent, with the FDA still reviewing other types of medical devices individually.

For apps that are already in use, the Federal Trade Commission only gets involved in response to deceptive or unfair acts or practices relating to privacy, data security, and false or misleading claims about safety or performance. It may be more beneficial for consumers if those apps had a more stringent initial approval process. The Office for Civil Rights enforces the Health Insurance Portability and Accountability Act when relevant to apps.

Nongovernment agencies also are involved in app regulation. The FDA believes sharing more regulatory responsibility with private industry would promote efficiency.¹⁴ Google does not allow apps that contain false or misleading health claims,¹⁵ and Apple may scrutinize medical apps that could provide inaccurate data or be used for diagnosing or treating patients.¹⁶ Xcertia, a nonprofit organization founded by the American Medical Association and others, develops standards for the security, privacy, content, and operability of health-related apps, but those standards have not been adopted by other parties. Ultimately, nongovernment agencies are not responsible for public health and do not boast the government’s ability to enforce rules or ensure public safety.

Final Thoughts

The AAD survey of US dermatology residents found that the top consideration when choosing apps was up-to-date and accurate information; however, the 3 most prevalent apps among those same respondents did not need government approval and are not required to contain up-to-date data or to improve clinical outcomes, similar to most other health-related apps. This discrepancy is concerning considering the increasing utilization of apps for physician education and health care delivery and the increasing complexity of those apps. In light of these results, the potential decrease in federal premarket regulation suggested by the FDA’s precertification program seems inappropriate. It is important for the government to take responsibility for regulating health-related apps and to find a balance between too much regulation delaying innovation and too little regulation hurting physician training and patient care. It also is important for providers to be aware of the evidence and oversight behind the technologies they use for professional purposes.

In 2017, lawmakers and insurers in the state of Texas approved the use of telehealth services in times of crisis.¹ During the coronavirus disease 2019 (COVID-19) pandemic, our clinic has used telemedicine to provide remote care to dermatology patients. We posit that the quick introduction and implementation of telemedicine during this time of need will change the way we practice dermatology in the future.

At the University of Texas Medical Branch in Galveston, Texas, we primarily have used 2 forms of telemedicine during the COVID-19 pandemic: live face-to-face video communication (our institution primarily uses FaceTime), and a combination of telephone calls with store-and-forward images. All dermatology services at our institution were converted to telemedicine visits, and in-person office visits were only done if deemed necessary after triage by telemedicine in April and May 2020. This strategy removed the necessity for patients to leave their homes for their appointments, which not only saved them travel costs and time but also reduced the potential spread of COVID-19. Since this time, the clinic has reopened for in-person visits; however, patients still have the option to schedule a telehealth appointment if they prefer. Many patients still select the telehealth option for the above reasons.

Although routine skin checks were not always possible by video and/or store-and-forward images, telemedicine worked very well for follow-up visits, especially isotretinoin follow-ups. During the COVID-19 outbreak, iPLEDGE (https://www.ipledgeprogram.com/iPledgeUI/home.u) rapidly adapted to the use of telemedicine and even began to allow home pregnancy tests to be entered into the iPLEDGE system by health care providers. Isotretinoin follow-ups are especially useful for patients who do not require laboratory monitoring at the visit. Patients are easily evaluated, screened for side effects, and continued on their treatment if no concerns are found during the telemedicine visit. Patients who require laboratory monitoring are still able to schedule tests at our clinics or at free-standing laboratories near their homes without having an in-office dermatology appointment. At-home pregnancy tests are still being utilized as an option for patients electing for telehealth follow-ups. This strategy is both health conscious by protecting the patient from exposure to COVID-19 at a testing center and cost-effective, especially for our uninsured patients, while still meeting the safety check for iPLEDGE.

Additionally, we utilized store-and-forward telemedicine for hospital consultations. If the patient’s condition can easily be diagnosed by viewing unedited clinical images remotely, the clinician can further decrease the risk of COVID-19 spread and exposure by providing the consultation and treatment recommendations by telephone. In cases in which a diagnosis could not be made by reviewing clinical photographs remotely, an in-person visit would be done. We continue to use this strategy for our confirmed COVID-positive hospital consultations to help protect our faculty and residents and decrease the use of personal protective equipment. We propose this model could be instituted for patients admitted to hospitals without access to dermatology consultations. Store-and-forward photographs of worrisome lesions and rashes also can be used to triage visits. For example, a patient with a new-onset keratoacanthoma and a history of nonmelanoma skin cancer contacted our clinic during the pandemic and sent store-and-forward images for review. The patient was triaged by a telemedicine visit and was then brought into the clinic for biopsy based on his clinical photographs and history. Patients also have requested prescriptions for bimatoprost and tretinoin via telehealth, a service that many medical spas and online telehealth companies provide already but was not offered at our practice until now.

Telemedicine also has potentially helped decrease the number of patients going to urgent care clinics for dermatology-related issues. Additionally, we have utilized one provider per day to be the “on-call” dermatologist who would be doing telemedicine appointments for patients with new-onset conditions. This strategy not only minimized possible patient exposure to COVID-19 but also helped preserve resources at urgent care clinics and emergency departments, which currently are inundated with patients. Since we have reopened for in-person visits, we have been unable to sustain an on-call dermatologist for telemedicine but may re-employ this strategy in the future.

The unique experience of practicing medicine during a pandemic has and will affect the way we practice moving forward. The way telemedicine has been quickly and easily implemented by the health care community during the COVID-19 pandemic has taught our dermatologists the value of this method of health care delivery. We will likely continue to use telemedicine after the pandemic has been contained. Telemedicine has the potential to expand access to care to rural and underserved areas, hospitals without on-call dermatologists, and homebound patients. We also may be better able to provide isotretinoin to our patients who have deferred treatment due to difficulty with transportation to the monthly visits. Store-and-forward images could help patients referred to dermatology avoid long wait times for obvious skin cancers that would benefit from early treatment. Telemedicine visits also could potentially improve attendance for patients who forget about their appointment by calling them after they miss their scheduled appointment time and complete a telehealth encounter on the same day instead, which could help recover costs of no-show appointments for clinics.

It is still unclear how private insurance companies will adapt to the new use of telemedicine, but we hope they follow the lead of Medicare, which released a statement on March 6, 2020, supporting the implementation of telehealth services.² Although Medicare has made adjustments to allow for equal reimbursement for telehealth appointments, private insurance companies still vary greatly. Many practices are struggling and some remained open despite shelter-in-place orders, but we propose telemedicine may be a safer alternative for patients and providers during the current health crisis that would keep billable services in place. It is still uncertain whether the laws enacted to make telemedicine accessible during this time will hold after COVID-19 is contained, but we are hopeful that living through the pandemic will bring some positive benefit to our practice and the patients we serve.

In 2017, lawmakers and insurers in the state of Texas approved the use of telehealth services in times of crisis.¹ During the coronavirus disease 2019 (COVID-19) pandemic, our clinic has used telemedicine to provide remote care to dermatology patients. We posit that the quick introduction and implementation of telemedicine during this time of need will change the way we practice dermatology in the future.

At the University of Texas Medical Branch in Galveston, Texas, we primarily have used 2 forms of telemedicine during the COVID-19 pandemic: live face-to-face video communication (our institution primarily uses FaceTime), and a combination of telephone calls with store-and-forward images. All dermatology services at our institution were converted to telemedicine visits, and in-person office visits were only done if deemed necessary after triage by telemedicine in April and May 2020. This strategy removed the necessity for patients to leave their homes for their appointments, which not only saved them travel costs and time but also reduced the potential spread of COVID-19. Since this time, the clinic has reopened for in-person visits; however, patients still have the option to schedule a telehealth appointment if they prefer. Many patients still select the telehealth option for the above reasons.

Although routine skin checks were not always possible by video and/or store-and-forward images, telemedicine worked very well for follow-up visits, especially isotretinoin follow-ups. During the COVID-19 outbreak, iPLEDGE (https://www.ipledgeprogram.com/iPledgeUI/home.u) rapidly adapted to the use of telemedicine and even began to allow home pregnancy tests to be entered into the iPLEDGE system by health care providers. Isotretinoin follow-ups are especially useful for patients who do not require laboratory monitoring at the visit. Patients are easily evaluated, screened for side effects, and continued on their treatment if no concerns are found during the telemedicine visit. Patients who require laboratory monitoring are still able to schedule tests at our clinics or at free-standing laboratories near their homes without having an in-office dermatology appointment. At-home pregnancy tests are still being utilized as an option for patients electing for telehealth follow-ups. This strategy is both health conscious by protecting the patient from exposure to COVID-19 at a testing center and cost-effective, especially for our uninsured patients, while still meeting the safety check for iPLEDGE.

Additionally, we utilized store-and-forward telemedicine for hospital consultations. If the patient’s condition can easily be diagnosed by viewing unedited clinical images remotely, the clinician can further decrease the risk of COVID-19 spread and exposure by providing the consultation and treatment recommendations by telephone. In cases in which a diagnosis could not be made by reviewing clinical photographs remotely, an in-person visit would be done. We continue to use this strategy for our confirmed COVID-positive hospital consultations to help protect our faculty and residents and decrease the use of personal protective equipment. We propose this model could be instituted for patients admitted to hospitals without access to dermatology consultations. Store-and-forward photographs of worrisome lesions and rashes also can be used to triage visits. For example, a patient with a new-onset keratoacanthoma and a history of nonmelanoma skin cancer contacted our clinic during the pandemic and sent store-and-forward images for review. The patient was triaged by a telemedicine visit and was then brought into the clinic for biopsy based on his clinical photographs and history. Patients also have requested prescriptions for bimatoprost and tretinoin via telehealth, a service that many medical spas and online telehealth companies provide already but was not offered at our practice until now.

Telemedicine also has potentially helped decrease the number of patients going to urgent care clinics for dermatology-related issues. Additionally, we have utilized one provider per day to be the “on-call” dermatologist who would be doing telemedicine appointments for patients with new-onset conditions. This strategy not only minimized possible patient exposure to COVID-19 but also helped preserve resources at urgent care clinics and emergency departments, which currently are inundated with patients. Since we have reopened for in-person visits, we have been unable to sustain an on-call dermatologist for telemedicine but may re-employ this strategy in the future.

The unique experience of practicing medicine during a pandemic has and will affect the way we practice moving forward. The way telemedicine has been quickly and easily implemented by the health care community during the COVID-19 pandemic has taught our dermatologists the value of this method of health care delivery. We will likely continue to use telemedicine after the pandemic has been contained. Telemedicine has the potential to expand access to care to rural and underserved areas, hospitals without on-call dermatologists, and homebound patients. We also may be better able to provide isotretinoin to our patients who have deferred treatment due to difficulty with transportation to the monthly visits. Store-and-forward images could help patients referred to dermatology avoid long wait times for obvious skin cancers that would benefit from early treatment. Telemedicine visits also could potentially improve attendance for patients who forget about their appointment by calling them after they miss their scheduled appointment time and complete a telehealth encounter on the same day instead, which could help recover costs of no-show appointments for clinics.

It is still unclear how private insurance companies will adapt to the new use of telemedicine, but we hope they follow the lead of Medicare, which released a statement on March 6, 2020, supporting the implementation of telehealth services.² Although Medicare has made adjustments to allow for equal reimbursement for telehealth appointments, private insurance companies still vary greatly. Many practices are struggling and some remained open despite shelter-in-place orders, but we propose telemedicine may be a safer alternative for patients and providers during the current health crisis that would keep billable services in place. It is still uncertain whether the laws enacted to make telemedicine accessible during this time will hold after COVID-19 is contained, but we are hopeful that living through the pandemic will bring some positive benefit to our practice and the patients we serve.

In 2017, lawmakers and insurers in the state of Texas approved the use of telehealth services in times of crisis.¹ During the coronavirus disease 2019 (COVID-19) pandemic, our clinic has used telemedicine to provide remote care to dermatology patients. We posit that the quick introduction and implementation of telemedicine during this time of need will change the way we practice dermatology in the future.

At the University of Texas Medical Branch in Galveston, Texas, we primarily have used 2 forms of telemedicine during the COVID-19 pandemic: live face-to-face video communication (our institution primarily uses FaceTime), and a combination of telephone calls with store-and-forward images. All dermatology services at our institution were converted to telemedicine visits, and in-person office visits were only done if deemed necessary after triage by telemedicine in April and May 2020. This strategy removed the necessity for patients to leave their homes for their appointments, which not only saved them travel costs and time but also reduced the potential spread of COVID-19. Since this time, the clinic has reopened for in-person visits; however, patients still have the option to schedule a telehealth appointment if they prefer. Many patients still select the telehealth option for the above reasons.

Although routine skin checks were not always possible by video and/or store-and-forward images, telemedicine worked very well for follow-up visits, especially isotretinoin follow-ups. During the COVID-19 outbreak, iPLEDGE (https://www.ipledgeprogram.com/iPledgeUI/home.u) rapidly adapted to the use of telemedicine and even began to allow home pregnancy tests to be entered into the iPLEDGE system by health care providers. Isotretinoin follow-ups are especially useful for patients who do not require laboratory monitoring at the visit. Patients are easily evaluated, screened for side effects, and continued on their treatment if no concerns are found during the telemedicine visit. Patients who require laboratory monitoring are still able to schedule tests at our clinics or at free-standing laboratories near their homes without having an in-office dermatology appointment. At-home pregnancy tests are still being utilized as an option for patients electing for telehealth follow-ups. This strategy is both health conscious by protecting the patient from exposure to COVID-19 at a testing center and cost-effective, especially for our uninsured patients, while still meeting the safety check for iPLEDGE.

Additionally, we utilized store-and-forward telemedicine for hospital consultations. If the patient’s condition can easily be diagnosed by viewing unedited clinical images remotely, the clinician can further decrease the risk of COVID-19 spread and exposure by providing the consultation and treatment recommendations by telephone. In cases in which a diagnosis could not be made by reviewing clinical photographs remotely, an in-person visit would be done. We continue to use this strategy for our confirmed COVID-positive hospital consultations to help protect our faculty and residents and decrease the use of personal protective equipment. We propose this model could be instituted for patients admitted to hospitals without access to dermatology consultations. Store-and-forward photographs of worrisome lesions and rashes also can be used to triage visits. For example, a patient with a new-onset keratoacanthoma and a history of nonmelanoma skin cancer contacted our clinic during the pandemic and sent store-and-forward images for review. The patient was triaged by a telemedicine visit and was then brought into the clinic for biopsy based on his clinical photographs and history. Patients also have requested prescriptions for bimatoprost and tretinoin via telehealth, a service that many medical spas and online telehealth companies provide already but was not offered at our practice until now.

Telemedicine also has potentially helped decrease the number of patients going to urgent care clinics for dermatology-related issues. Additionally, we have utilized one provider per day to be the “on-call” dermatologist who would be doing telemedicine appointments for patients with new-onset conditions. This strategy not only minimized possible patient exposure to COVID-19 but also helped preserve resources at urgent care clinics and emergency departments, which currently are inundated with patients. Since we have reopened for in-person visits, we have been unable to sustain an on-call dermatologist for telemedicine but may re-employ this strategy in the future.

The unique experience of practicing medicine during a pandemic has and will affect the way we practice moving forward. The way telemedicine has been quickly and easily implemented by the health care community during the COVID-19 pandemic has taught our dermatologists the value of this method of health care delivery. We will likely continue to use telemedicine after the pandemic has been contained. Telemedicine has the potential to expand access to care to rural and underserved areas, hospitals without on-call dermatologists, and homebound patients. We also may be better able to provide isotretinoin to our patients who have deferred treatment due to difficulty with transportation to the monthly visits. Store-and-forward images could help patients referred to dermatology avoid long wait times for obvious skin cancers that would benefit from early treatment. Telemedicine visits also could potentially improve attendance for patients who forget about their appointment by calling them after they miss their scheduled appointment time and complete a telehealth encounter on the same day instead, which could help recover costs of no-show appointments for clinics.

It is still unclear how private insurance companies will adapt to the new use of telemedicine, but we hope they follow the lead of Medicare, which released a statement on March 6, 2020, supporting the implementation of telehealth services.² Although Medicare has made adjustments to allow for equal reimbursement for telehealth appointments, private insurance companies still vary greatly. Many practices are struggling and some remained open despite shelter-in-place orders, but we propose telemedicine may be a safer alternative for patients and providers during the current health crisis that would keep billable services in place. It is still uncertain whether the laws enacted to make telemedicine accessible during this time will hold after COVID-19 is contained, but we are hopeful that living through the pandemic will bring some positive benefit to our practice and the patients we serve.

Dermatologists’ offices are not immune from potentially fatal medical events. As a result, it is imperative that dermatologists are well versed in how to manage emergency situations in an outpatient setting. We discuss signs, symptoms, and management of opioid toxicity with an instructive case from our outpatient, hospital-based dermatology clinic.

A 55-year-old woman presented for Mohs micrographic surgery for a large recurrent basal cell carcinoma on the right medial cheek. After informed consent was obtained and the procedure was discussed with the patient, she took one 0.5-mg tablet of clonazepam for perioperative anxiety, which was part of her standard home medication regimen and preoperative administration of clonazepam had been discussed with the treating physician prior to her appointment. During tissue processing, the patient waited alone in the procedure room, with nursing checks every 10 to 15 minutes. Roughly 30 minutes after the initial stage was taken and clear margins were confirmed, the patient was found to be somnolent and unresponsive to voice, light, or touch. Physical examination revealed pupillary constriction, labored breathing, and absent blink reflex. Subsequent examination of the arms, which initially were covered by sleeves, revealed track marks. She was only aroused by a deep sternal rub, which caused her to moan and open her eyes. Her vital signs remained stable, with oxygen saturation greater than 90% and respiratory rate greater than 12 breaths per minute, and a registered nurse remained at her bedside to monitor her clinical status and vitals. Because this event took place in a hospital setting and the patient adequately maintained her airway, respiratory rate, and oxygenation status, the decision was made to closely observe the patient in our clinic. Without additional intervention, the patient gradually regained full awareness, orientation, and mental capacity over the course of 90 minutes. She was ambulatory and conversant at the completion of the procedure, and she declined additional screening for drug abuse or transfer to an acute care facility. She elected for discharge and was accompanied by a family member to drive her home. Later, a search of the state’s prescription monitoring service revealed she had multiple prescriptions from numerous providers for benzodiazepines and opioids. We suspect that her intoxication was the result of ingestion or injection of an opioid medication when she left to visit the restroom unaccompanied, which occurred on at least one known occasion while awaiting tissue processing.

Patients may experience several side effects when using opioid analgesics, most commonly nausea and constipation. When opioids are used long-term, patients are at increased risk for developing fractures, as opioids may decrease bone mineral density by impairing the production of exogenous sex steroid hormones.¹ Respiratory depression also can occur, especially when combined with alcohol and other medications such as benzodiazepines. Lastly, opioid dependence can develop in 1 week of regular use.^1,2

Opioid overdose classically presents with depressed mental status, decreased tidal volume, decreased bowel sounds, miosis, and decreased respiratory rate. Pupillary size may be normal in acute opioid toxicity due to other co-ingested medications or substances. The best predictor of opioid overdose is a decreased respiratory rate, measured as fewer than 12 breaths per minute.¹

If opioid overdose is suspected in the office setting, early intervention is critical. Rapid serum glucose should be obtained if a glucometer is available, as hypoglycemia can be confused with opioid toxicity and is easily correctable. If serum glucose is normal, the provider should notify emergency services. In a hospital setting, a rapid response or code can be initiated. In the office setting, dial 911. If not already in place, noninvasive continuous monitoring of the patient’s pulse, oxygen saturation, and blood pressure is needed.¹

The provider’s primary concern should be ensuring the patient is adequately ventilated and oxygenated. If the patient’s respiratory rate is greater than 12 breaths per minute and oxygen saturation is greater than 90% on room air, as was the case with our patient, observe and reassess the patient frequently. If the oxygen saturation drops to less than 90% but the patient is breathing spontaneously, administer supplemental oxygen followed by naloxone. If the patient is breathing fewer than 12 breaths per minute, the airway can be maintained with the head tilt–chin lift technique while ventilating using a bag valve mask with supplemental oxygen, followed by administration of naloxone.¹

Naloxone is a short-acting opioid antagonist used to treat potentially fatal respiratory depression associated with opioid overdose. It is available in intramuscular (IM), intravenous (IV), and intranasal forms. Intramuscular and IV administration are preferred due to a more rapid onset compared to intranasal. The dosage is 0.04 to 2 mg for IM or IV formulations and 4 mg for the intranasal formulation.^1,3 The anterolateral thigh is the preferred IM injection site. Lower initial doses for the IM and IV forms generally are advisable because of the possibility of naloxone precipitating opioid withdrawal in opioid-dependent patients. Naloxone may be administered every 2 to 3 minutes until emergency personnel arrive. Repeat dosing of naloxone should be given until ventilation is greater than 12 breaths per minute while ensuring oxygen saturation is greater than 90%. If there is an inadequate response after 5 to 10 mg of naloxone administration, reconsider the diagnosis. If there is no response after naloxone administration, continue to provide respiratory support with the bag valve mask and supplemental oxygen. After the administration of naloxone, the patient should be transported to the nearest emergency department regardless of the clinical appearance, as naloxone’s half-life may be shorter than the ingested opioid, requiring further observation in a monitored setting.^1,3

We recommend that dermatologists consider keeping naloxone in their offices. The medication is easily administered and has a relatively long shelf-life of 1 to 2 years, with a 10-mL vial of 0.4 mg/mL solution costing less than $200 in most cases.³ Increasing cases of opioid abuse could lead to more clinical scenarios similar to what we experienced. Proper identification and management of opioid overdose is within the purview of the dermatologist and can be lifesaving.

Dermatologists’ offices are not immune from potentially fatal medical events. As a result, it is imperative that dermatologists are well versed in how to manage emergency situations in an outpatient setting. We discuss signs, symptoms, and management of opioid toxicity with an instructive case from our outpatient, hospital-based dermatology clinic.

A 55-year-old woman presented for Mohs micrographic surgery for a large recurrent basal cell carcinoma on the right medial cheek. After informed consent was obtained and the procedure was discussed with the patient, she took one 0.5-mg tablet of clonazepam for perioperative anxiety, which was part of her standard home medication regimen and preoperative administration of clonazepam had been discussed with the treating physician prior to her appointment. During tissue processing, the patient waited alone in the procedure room, with nursing checks every 10 to 15 minutes. Roughly 30 minutes after the initial stage was taken and clear margins were confirmed, the patient was found to be somnolent and unresponsive to voice, light, or touch. Physical examination revealed pupillary constriction, labored breathing, and absent blink reflex. Subsequent examination of the arms, which initially were covered by sleeves, revealed track marks. She was only aroused by a deep sternal rub, which caused her to moan and open her eyes. Her vital signs remained stable, with oxygen saturation greater than 90% and respiratory rate greater than 12 breaths per minute, and a registered nurse remained at her bedside to monitor her clinical status and vitals. Because this event took place in a hospital setting and the patient adequately maintained her airway, respiratory rate, and oxygenation status, the decision was made to closely observe the patient in our clinic. Without additional intervention, the patient gradually regained full awareness, orientation, and mental capacity over the course of 90 minutes. She was ambulatory and conversant at the completion of the procedure, and she declined additional screening for drug abuse or transfer to an acute care facility. She elected for discharge and was accompanied by a family member to drive her home. Later, a search of the state’s prescription monitoring service revealed she had multiple prescriptions from numerous providers for benzodiazepines and opioids. We suspect that her intoxication was the result of ingestion or injection of an opioid medication when she left to visit the restroom unaccompanied, which occurred on at least one known occasion while awaiting tissue processing.

Patients may experience several side effects when using opioid analgesics, most commonly nausea and constipation. When opioids are used long-term, patients are at increased risk for developing fractures, as opioids may decrease bone mineral density by impairing the production of exogenous sex steroid hormones.¹ Respiratory depression also can occur, especially when combined with alcohol and other medications such as benzodiazepines. Lastly, opioid dependence can develop in 1 week of regular use.^1,2

Opioid overdose classically presents with depressed mental status, decreased tidal volume, decreased bowel sounds, miosis, and decreased respiratory rate. Pupillary size may be normal in acute opioid toxicity due to other co-ingested medications or substances. The best predictor of opioid overdose is a decreased respiratory rate, measured as fewer than 12 breaths per minute.¹

If opioid overdose is suspected in the office setting, early intervention is critical. Rapid serum glucose should be obtained if a glucometer is available, as hypoglycemia can be confused with opioid toxicity and is easily correctable. If serum glucose is normal, the provider should notify emergency services. In a hospital setting, a rapid response or code can be initiated. In the office setting, dial 911. If not already in place, noninvasive continuous monitoring of the patient’s pulse, oxygen saturation, and blood pressure is needed.¹

The provider’s primary concern should be ensuring the patient is adequately ventilated and oxygenated. If the patient’s respiratory rate is greater than 12 breaths per minute and oxygen saturation is greater than 90% on room air, as was the case with our patient, observe and reassess the patient frequently. If the oxygen saturation drops to less than 90% but the patient is breathing spontaneously, administer supplemental oxygen followed by naloxone. If the patient is breathing fewer than 12 breaths per minute, the airway can be maintained with the head tilt–chin lift technique while ventilating using a bag valve mask with supplemental oxygen, followed by administration of naloxone.¹

Naloxone is a short-acting opioid antagonist used to treat potentially fatal respiratory depression associated with opioid overdose. It is available in intramuscular (IM), intravenous (IV), and intranasal forms. Intramuscular and IV administration are preferred due to a more rapid onset compared to intranasal. The dosage is 0.04 to 2 mg for IM or IV formulations and 4 mg for the intranasal formulation.^1,3 The anterolateral thigh is the preferred IM injection site. Lower initial doses for the IM and IV forms generally are advisable because of the possibility of naloxone precipitating opioid withdrawal in opioid-dependent patients. Naloxone may be administered every 2 to 3 minutes until emergency personnel arrive. Repeat dosing of naloxone should be given until ventilation is greater than 12 breaths per minute while ensuring oxygen saturation is greater than 90%. If there is an inadequate response after 5 to 10 mg of naloxone administration, reconsider the diagnosis. If there is no response after naloxone administration, continue to provide respiratory support with the bag valve mask and supplemental oxygen. After the administration of naloxone, the patient should be transported to the nearest emergency department regardless of the clinical appearance, as naloxone’s half-life may be shorter than the ingested opioid, requiring further observation in a monitored setting.^1,3

We recommend that dermatologists consider keeping naloxone in their offices. The medication is easily administered and has a relatively long shelf-life of 1 to 2 years, with a 10-mL vial of 0.4 mg/mL solution costing less than $200 in most cases.³ Increasing cases of opioid abuse could lead to more clinical scenarios similar to what we experienced. Proper identification and management of opioid overdose is within the purview of the dermatologist and can be lifesaving.

Dermatologists’ offices are not immune from potentially fatal medical events. As a result, it is imperative that dermatologists are well versed in how to manage emergency situations in an outpatient setting. We discuss signs, symptoms, and management of opioid toxicity with an instructive case from our outpatient, hospital-based dermatology clinic.

A 55-year-old woman presented for Mohs micrographic surgery for a large recurrent basal cell carcinoma on the right medial cheek. After informed consent was obtained and the procedure was discussed with the patient, she took one 0.5-mg tablet of clonazepam for perioperative anxiety, which was part of her standard home medication regimen and preoperative administration of clonazepam had been discussed with the treating physician prior to her appointment. During tissue processing, the patient waited alone in the procedure room, with nursing checks every 10 to 15 minutes. Roughly 30 minutes after the initial stage was taken and clear margins were confirmed, the patient was found to be somnolent and unresponsive to voice, light, or touch. Physical examination revealed pupillary constriction, labored breathing, and absent blink reflex. Subsequent examination of the arms, which initially were covered by sleeves, revealed track marks. She was only aroused by a deep sternal rub, which caused her to moan and open her eyes. Her vital signs remained stable, with oxygen saturation greater than 90% and respiratory rate greater than 12 breaths per minute, and a registered nurse remained at her bedside to monitor her clinical status and vitals. Because this event took place in a hospital setting and the patient adequately maintained her airway, respiratory rate, and oxygenation status, the decision was made to closely observe the patient in our clinic. Without additional intervention, the patient gradually regained full awareness, orientation, and mental capacity over the course of 90 minutes. She was ambulatory and conversant at the completion of the procedure, and she declined additional screening for drug abuse or transfer to an acute care facility. She elected for discharge and was accompanied by a family member to drive her home. Later, a search of the state’s prescription monitoring service revealed she had multiple prescriptions from numerous providers for benzodiazepines and opioids. We suspect that her intoxication was the result of ingestion or injection of an opioid medication when she left to visit the restroom unaccompanied, which occurred on at least one known occasion while awaiting tissue processing.

Patients may experience several side effects when using opioid analgesics, most commonly nausea and constipation. When opioids are used long-term, patients are at increased risk for developing fractures, as opioids may decrease bone mineral density by impairing the production of exogenous sex steroid hormones.¹ Respiratory depression also can occur, especially when combined with alcohol and other medications such as benzodiazepines. Lastly, opioid dependence can develop in 1 week of regular use.^1,2

Opioid overdose classically presents with depressed mental status, decreased tidal volume, decreased bowel sounds, miosis, and decreased respiratory rate. Pupillary size may be normal in acute opioid toxicity due to other co-ingested medications or substances. The best predictor of opioid overdose is a decreased respiratory rate, measured as fewer than 12 breaths per minute.¹

If opioid overdose is suspected in the office setting, early intervention is critical. Rapid serum glucose should be obtained if a glucometer is available, as hypoglycemia can be confused with opioid toxicity and is easily correctable. If serum glucose is normal, the provider should notify emergency services. In a hospital setting, a rapid response or code can be initiated. In the office setting, dial 911. If not already in place, noninvasive continuous monitoring of the patient’s pulse, oxygen saturation, and blood pressure is needed.¹

The provider’s primary concern should be ensuring the patient is adequately ventilated and oxygenated. If the patient’s respiratory rate is greater than 12 breaths per minute and oxygen saturation is greater than 90% on room air, as was the case with our patient, observe and reassess the patient frequently. If the oxygen saturation drops to less than 90% but the patient is breathing spontaneously, administer supplemental oxygen followed by naloxone. If the patient is breathing fewer than 12 breaths per minute, the airway can be maintained with the head tilt–chin lift technique while ventilating using a bag valve mask with supplemental oxygen, followed by administration of naloxone.¹

Naloxone is a short-acting opioid antagonist used to treat potentially fatal respiratory depression associated with opioid overdose. It is available in intramuscular (IM), intravenous (IV), and intranasal forms. Intramuscular and IV administration are preferred due to a more rapid onset compared to intranasal. The dosage is 0.04 to 2 mg for IM or IV formulations and 4 mg for the intranasal formulation.^1,3 The anterolateral thigh is the preferred IM injection site. Lower initial doses for the IM and IV forms generally are advisable because of the possibility of naloxone precipitating opioid withdrawal in opioid-dependent patients. Naloxone may be administered every 2 to 3 minutes until emergency personnel arrive. Repeat dosing of naloxone should be given until ventilation is greater than 12 breaths per minute while ensuring oxygen saturation is greater than 90%. If there is an inadequate response after 5 to 10 mg of naloxone administration, reconsider the diagnosis. If there is no response after naloxone administration, continue to provide respiratory support with the bag valve mask and supplemental oxygen. After the administration of naloxone, the patient should be transported to the nearest emergency department regardless of the clinical appearance, as naloxone’s half-life may be shorter than the ingested opioid, requiring further observation in a monitored setting.^1,3

We recommend that dermatologists consider keeping naloxone in their offices. The medication is easily administered and has a relatively long shelf-life of 1 to 2 years, with a 10-mL vial of 0.4 mg/mL solution costing less than $200 in most cases.³ Increasing cases of opioid abuse could lead to more clinical scenarios similar to what we experienced. Proper identification and management of opioid overdose is within the purview of the dermatologist and can be lifesaving.

Sometimes regrettable yet increasingly common, tattoos are an ancient art form used in modern times as a mark of artistic and cultural expression. Allergic contact dermatitis (ACD) to tattoo ink is rare, but the popularity of tattoos makes ACD an increasingly recognized occurrence. In a retrospective study of 38,543 patch-tested patients, only 29 (0.08%) had tattoo-related ACD, with the majority of patients being female and young adults. The most common contact allergy was to paraphenylenediamine (PPD), which occurred in 22 (76%) patients.¹ In this article, we will walk you through the rainbow of tattoo ACD, covering hypersensitivity reactions to both temporary and permanent tattoo inks.

Temporary Tattoo Inks

Henna is the most common temporary tattoo ink. Derived from the plant Lawsonia inermis, henna is an orange dye that has been used in many parts of the world, particularly in Islamic and Hindu cultures, to dye skin, hair, and fabrics. Application of henna tattoos is common for weddings and other celebrations, and brides may wear elaborate henna patterns. To create these tattoos, henna powder is mixed with water and sometimes essential oils and is then applied to the skin for several hours. After application, the henna pigment lawsone (2-hydroxy-1,4-naphthoquinone) interacts with keratin and leaves a red-orange stain on the skin²; longer application time leads to a deeper color. Most traditional cutaneous henna designs fade in 2 to 6 weeks, but some last longer. Red henna generally is considered safe with low incidence of contact allergy. What is referred to as black henna usually is red henna mixed with PPD, a black dye, which is added to deepen the color. Paraphenylenediamine is highly sensitizing; patients can become sensitized to the PPD in the tattoo itself.² One study confirmed the presence of PPD in black henna tattoos, with chemical analysis of common preparations revealing concentrations ranging from less than 1% to 30%.² Patients who undergo patch testing for tattoo reactions often are strongly positive to PPD and have concomitant reactions to azo dyes, black rubber, and anesthetics. Other aromatic amines including aminophenols have been identified in black henna tattoo ink, and these chemicals also may contribute to ACD.³ Less common sources of contact allergy from temporary black henna tattoos include resorcinol,⁴ para-tertiary butylphenol formaldehyde resin,⁵ and fragrance.⁶

Clinically, ACD to PPD in temporary tattoos presents 1 to 3 days after application if the patient is already sensitized or 4 to 14 days if the patient is sensitized by the tattoo ink.² Most patients notice erythema, edema, vesicles, papules, and/or bullae, but other less common reactions including generalized dermatitis, systemic symptoms, urticaria, and pustules have been described.² Postinflammatory hypopigmentation or hyperpigmentation also can occur.

Because of the sensitizing nature of black henna tattoos, consumers are turning to natural temporary tattoos. Jagua temporary tattoos, with pigment derived from the sap of fruit from the Genipa americana tree, have been associated with ACD.⁷ This black dye is applied and washed off in a similar fashion to henna tattoos. Importantly, a recent analysis of jagua dye identified no PPD. In one case, a patient who developed ACD to a jagua tattoo was patch tested to components of the dye and had a positive reaction to genipin, a component of the fruit extract.⁷ Thus, jagua tattoos often are marketed as safe but are an emerging source of contact dermatitis to temporary tattoos.

Permanent Tattoo Inks

Permanent tattoos are created by injecting small amounts of ink into the dermis. As the name suggests, these tattoos are permanent. Tattoos are common; nearly one-third of Americans have at least 1 tattoo.¹ Historically, tattoos were created using black pigment composed of amorphous carbon or black iron oxides.^8,9 Metallic pigments (eg, mercury, chromium, cobalt, cadmium) were once used to add color to tattoos, but these metals are now only rarely used; in fact, a 2019 study of tattoo ink components identified 44 distinct pigments in 1416 permanent inks, with an average of 3 pigments per ink.⁸ Of the 44 pigments, 10 had metallic components including iron, barium, zinc, copper, molybdenum, and titanium. The remaining 34 pigments contained carbon, azo, diketopyrrolopyrrole, quinacridone, anthraquinone, dioxazine (purple), or quinophthalone (yellow) dyes. The authors noted that nearly one-quarter of the tattoo pigments identified in their study had been reported as contact allergens.⁸

Typically, reactions to permanent tattoo inks manifest as an eczematous dermatitis occurring weeks to years after tattoo application.^9,10 The dermatitis usually is locally confined to the tattoo and may be limited to particular colors; occasionally, a new tattoo reaction may trigger concurrent inflammation in older tattoos. Many tattoo reactions occur as a response to red pigment but also have occurred with other tattoo ink components.⁹ Many researchers have speculated as to whether the reaction is related to the ink component itself or from the photochemical breakdown of the ink by exposure to UV radiation and/or laser therapy.⁹

Red Pigment
Red ink is the most common color reported to cause tattoo hypersensitivity reactions. Historically, red tattoo pigments include mercuric sulfide (vermilion, cinnabar), scarlet lake, cadmium red, carmine, and cochineal,¹¹ but today’s tattoo inks primarily are composed of other pigments, such as quinacridone and azo dyes.¹² Several cases of red tattoo ink hypersensitivity reactions exist in the literature, many without completion of patch tests or without positive patch tests to relevant red pigments.^11-15

Black Pigment
In general, reactions to permanent black tattoo ink are rare; however, a few case reports exist. Black pigment can be created with India ink (carbon), logwood (chrome), iron oxide, and titanium.^16,17 Shellac can be used as a binding agent in tattoo ink; there is at least one report of a reaction to black tattoo ink with a positive patch test to shellac and the original black ink.¹⁸

Azo Pigments
Azo pigments frequently are used in modern tattoos due to their vibrant colors. One case of hypersensitivity to azo pigment involved an eczematous ulcerated plaque overlying yellow, red, and green ink in a recently applied tattoo. Patch testing with the inks originally used in the tattoo was negative. The authors noted that the 3 problematic ink colors all contained pigment yellow 65—an azo pigment—and attributed the reaction to this dye.²² In another azo reaction, a patient had erythema and pruritus overlying a tattoo applied 1 month prior. Patch testing was positive for aminoazobenzene, an azo pigment that was present in the orange ink of the tattoo.²³

Management of Tattoo Hypersensitivity Reactions

Hypersensitivity reactions to temporary tattoos are just that—temporary. Topical steroids and time generally will allow these reactions to resolve. In the setting of vigorous reactions, patients may develop postinflammatory hypopigmentation or hyperpigmentation that may last for months. Unfortunately, bullous tattoo reactions can lead to scarring and keloid formation, requiring more aggressive therapy.

Management of reactions to permanent tattoos is more challenging. High-potency topical steroids under occlusion or intralesional corticosteroid injections may aid in treating pruritus or discomfort. For severe reactions, oral corticosteroids may be required. Patients also may consider laser tattoo removal; however, providers should be aware that there have been rare reports of systemic urticarial reactions from this procedure.^24,25 Obviously limited by location and size, excision also may be offered.

Patch Testing for Tattoo Ink Contact Allergy

When patients present for evaluation and management of tattoo ACD, it is important to also consider other causes, including granulomatous tattoo reaction, pseudolymphoma, and lichenoid tattoo reaction. A biopsy can be helpful if the diagnosis is in question.

Patch testing for contact allergy to temporary tattoo inks should include PPD, fragrance, aminophenols, resorcinol, para-tertiary butylphenol formaldehyde, and essential oils. Jagua currently is not available for commercial purchase but also should be considered if the patient has the original product or in research settings. If the individual tattoo ingredients can be identified, they also should be tested. In this scenario, recall reactions may occur; testing with the tattoo paste should be avoided if the prior reaction was severe. Importantly, patients with a PPD allergy should be counseled to avoid hair dyes that contain PPD. Many patients who are sensitized to PPD have strong reactions on patch testing and are at risk for severe reactions if PPD or PPD-related compounds are encountered in hair dye.

Patch testing for ACD to permanent tattoos is complex. In most cases, patch testing is of limited utility because many of the chemicals that have been reported to cause ACD are not commercially available. Additionally, a 2014 study of 90 patients with chronic tattoo reactions found that the majority had negative patch testing to the European baseline series (66%), disperse dyes (87%), and tattoo inks (87%–92%). The investigators theorized that the allergens causing tattoo reactions are formed by haptenization of “parent” chemicals in the dermis, meaning application of chemicals present in the original tattoo ink may not identify the relevant allergen.²⁶ If patch testing is performed, it is most ideal if individual pigment ingredients can be identified. Allergens to be considered for testing include azo dyes, aromatic amines, iron oxide, barium, zinc, copper, molybdenum, titanium, gold sodium thiosulfate, nickel sulfate, carbon, shellac, diketopyrrolopyrrole, quinacridone, anthraquinone, dioxazine (purple), quinophthalone (yellow) dyes, mercuric sulfide (vermilion, cinnabar), scarlet lake, cadmium red, carmine, and cochineal, many of which are not commercially available for purchase.

Final Interpretation

As tattoos become increasingly trendy, tattoo ACD should be recognized by the astute dermatologist. The most common allergen associated with tattoo ACD is PPD, but other potential allergens include azo dyes and newer pigments. Unlike tattoos of the past, today’s inks are unlikely to contain toxic metals. Diagnosing ACD caused by permanent tattoo inks requires a high degree of suspicion, as patch testing may be of limited utility.

Sometimes regrettable yet increasingly common, tattoos are an ancient art form used in modern times as a mark of artistic and cultural expression. Allergic contact dermatitis (ACD) to tattoo ink is rare, but the popularity of tattoos makes ACD an increasingly recognized occurrence. In a retrospective study of 38,543 patch-tested patients, only 29 (0.08%) had tattoo-related ACD, with the majority of patients being female and young adults. The most common contact allergy was to paraphenylenediamine (PPD), which occurred in 22 (76%) patients.¹ In this article, we will walk you through the rainbow of tattoo ACD, covering hypersensitivity reactions to both temporary and permanent tattoo inks.

Temporary Tattoo Inks

Henna is the most common temporary tattoo ink. Derived from the plant Lawsonia inermis, henna is an orange dye that has been used in many parts of the world, particularly in Islamic and Hindu cultures, to dye skin, hair, and fabrics. Application of henna tattoos is common for weddings and other celebrations, and brides may wear elaborate henna patterns. To create these tattoos, henna powder is mixed with water and sometimes essential oils and is then applied to the skin for several hours. After application, the henna pigment lawsone (2-hydroxy-1,4-naphthoquinone) interacts with keratin and leaves a red-orange stain on the skin²; longer application time leads to a deeper color. Most traditional cutaneous henna designs fade in 2 to 6 weeks, but some last longer. Red henna generally is considered safe with low incidence of contact allergy. What is referred to as black henna usually is red henna mixed with PPD, a black dye, which is added to deepen the color. Paraphenylenediamine is highly sensitizing; patients can become sensitized to the PPD in the tattoo itself.² One study confirmed the presence of PPD in black henna tattoos, with chemical analysis of common preparations revealing concentrations ranging from less than 1% to 30%.² Patients who undergo patch testing for tattoo reactions often are strongly positive to PPD and have concomitant reactions to azo dyes, black rubber, and anesthetics. Other aromatic amines including aminophenols have been identified in black henna tattoo ink, and these chemicals also may contribute to ACD.³ Less common sources of contact allergy from temporary black henna tattoos include resorcinol,⁴ para-tertiary butylphenol formaldehyde resin,⁵ and fragrance.⁶

Clinically, ACD to PPD in temporary tattoos presents 1 to 3 days after application if the patient is already sensitized or 4 to 14 days if the patient is sensitized by the tattoo ink.² Most patients notice erythema, edema, vesicles, papules, and/or bullae, but other less common reactions including generalized dermatitis, systemic symptoms, urticaria, and pustules have been described.² Postinflammatory hypopigmentation or hyperpigmentation also can occur.

Because of the sensitizing nature of black henna tattoos, consumers are turning to natural temporary tattoos. Jagua temporary tattoos, with pigment derived from the sap of fruit from the Genipa americana tree, have been associated with ACD.⁷ This black dye is applied and washed off in a similar fashion to henna tattoos. Importantly, a recent analysis of jagua dye identified no PPD. In one case, a patient who developed ACD to a jagua tattoo was patch tested to components of the dye and had a positive reaction to genipin, a component of the fruit extract.⁷ Thus, jagua tattoos often are marketed as safe but are an emerging source of contact dermatitis to temporary tattoos.

Permanent Tattoo Inks

Permanent tattoos are created by injecting small amounts of ink into the dermis. As the name suggests, these tattoos are permanent. Tattoos are common; nearly one-third of Americans have at least 1 tattoo.¹ Historically, tattoos were created using black pigment composed of amorphous carbon or black iron oxides.^8,9 Metallic pigments (eg, mercury, chromium, cobalt, cadmium) were once used to add color to tattoos, but these metals are now only rarely used; in fact, a 2019 study of tattoo ink components identified 44 distinct pigments in 1416 permanent inks, with an average of 3 pigments per ink.⁸ Of the 44 pigments, 10 had metallic components including iron, barium, zinc, copper, molybdenum, and titanium. The remaining 34 pigments contained carbon, azo, diketopyrrolopyrrole, quinacridone, anthraquinone, dioxazine (purple), or quinophthalone (yellow) dyes. The authors noted that nearly one-quarter of the tattoo pigments identified in their study had been reported as contact allergens.⁸

Typically, reactions to permanent tattoo inks manifest as an eczematous dermatitis occurring weeks to years after tattoo application.^9,10 The dermatitis usually is locally confined to the tattoo and may be limited to particular colors; occasionally, a new tattoo reaction may trigger concurrent inflammation in older tattoos. Many tattoo reactions occur as a response to red pigment but also have occurred with other tattoo ink components.⁹ Many researchers have speculated as to whether the reaction is related to the ink component itself or from the photochemical breakdown of the ink by exposure to UV radiation and/or laser therapy.⁹

Red Pigment
Red ink is the most common color reported to cause tattoo hypersensitivity reactions. Historically, red tattoo pigments include mercuric sulfide (vermilion, cinnabar), scarlet lake, cadmium red, carmine, and cochineal,¹¹ but today’s tattoo inks primarily are composed of other pigments, such as quinacridone and azo dyes.¹² Several cases of red tattoo ink hypersensitivity reactions exist in the literature, many without completion of patch tests or without positive patch tests to relevant red pigments.^11-15

Black Pigment
In general, reactions to permanent black tattoo ink are rare; however, a few case reports exist. Black pigment can be created with India ink (carbon), logwood (chrome), iron oxide, and titanium.^16,17 Shellac can be used as a binding agent in tattoo ink; there is at least one report of a reaction to black tattoo ink with a positive patch test to shellac and the original black ink.¹⁸

Azo Pigments
Azo pigments frequently are used in modern tattoos due to their vibrant colors. One case of hypersensitivity to azo pigment involved an eczematous ulcerated plaque overlying yellow, red, and green ink in a recently applied tattoo. Patch testing with the inks originally used in the tattoo was negative. The authors noted that the 3 problematic ink colors all contained pigment yellow 65—an azo pigment—and attributed the reaction to this dye.²² In another azo reaction, a patient had erythema and pruritus overlying a tattoo applied 1 month prior. Patch testing was positive for aminoazobenzene, an azo pigment that was present in the orange ink of the tattoo.²³

Management of Tattoo Hypersensitivity Reactions

Hypersensitivity reactions to temporary tattoos are just that—temporary. Topical steroids and time generally will allow these reactions to resolve. In the setting of vigorous reactions, patients may develop postinflammatory hypopigmentation or hyperpigmentation that may last for months. Unfortunately, bullous tattoo reactions can lead to scarring and keloid formation, requiring more aggressive therapy.

Management of reactions to permanent tattoos is more challenging. High-potency topical steroids under occlusion or intralesional corticosteroid injections may aid in treating pruritus or discomfort. For severe reactions, oral corticosteroids may be required. Patients also may consider laser tattoo removal; however, providers should be aware that there have been rare reports of systemic urticarial reactions from this procedure.^24,25 Obviously limited by location and size, excision also may be offered.

Patch Testing for Tattoo Ink Contact Allergy

When patients present for evaluation and management of tattoo ACD, it is important to also consider other causes, including granulomatous tattoo reaction, pseudolymphoma, and lichenoid tattoo reaction. A biopsy can be helpful if the diagnosis is in question.

Patch testing for contact allergy to temporary tattoo inks should include PPD, fragrance, aminophenols, resorcinol, para-tertiary butylphenol formaldehyde, and essential oils. Jagua currently is not available for commercial purchase but also should be considered if the patient has the original product or in research settings. If the individual tattoo ingredients can be identified, they also should be tested. In this scenario, recall reactions may occur; testing with the tattoo paste should be avoided if the prior reaction was severe. Importantly, patients with a PPD allergy should be counseled to avoid hair dyes that contain PPD. Many patients who are sensitized to PPD have strong reactions on patch testing and are at risk for severe reactions if PPD or PPD-related compounds are encountered in hair dye.

Patch testing for ACD to permanent tattoos is complex. In most cases, patch testing is of limited utility because many of the chemicals that have been reported to cause ACD are not commercially available. Additionally, a 2014 study of 90 patients with chronic tattoo reactions found that the majority had negative patch testing to the European baseline series (66%), disperse dyes (87%), and tattoo inks (87%–92%). The investigators theorized that the allergens causing tattoo reactions are formed by haptenization of “parent” chemicals in the dermis, meaning application of chemicals present in the original tattoo ink may not identify the relevant allergen.²⁶ If patch testing is performed, it is most ideal if individual pigment ingredients can be identified. Allergens to be considered for testing include azo dyes, aromatic amines, iron oxide, barium, zinc, copper, molybdenum, titanium, gold sodium thiosulfate, nickel sulfate, carbon, shellac, diketopyrrolopyrrole, quinacridone, anthraquinone, dioxazine (purple), quinophthalone (yellow) dyes, mercuric sulfide (vermilion, cinnabar), scarlet lake, cadmium red, carmine, and cochineal, many of which are not commercially available for purchase.

Final Interpretation

As tattoos become increasingly trendy, tattoo ACD should be recognized by the astute dermatologist. The most common allergen associated with tattoo ACD is PPD, but other potential allergens include azo dyes and newer pigments. Unlike tattoos of the past, today’s inks are unlikely to contain toxic metals. Diagnosing ACD caused by permanent tattoo inks requires a high degree of suspicion, as patch testing may be of limited utility.

Sometimes regrettable yet increasingly common, tattoos are an ancient art form used in modern times as a mark of artistic and cultural expression. Allergic contact dermatitis (ACD) to tattoo ink is rare, but the popularity of tattoos makes ACD an increasingly recognized occurrence. In a retrospective study of 38,543 patch-tested patients, only 29 (0.08%) had tattoo-related ACD, with the majority of patients being female and young adults. The most common contact allergy was to paraphenylenediamine (PPD), which occurred in 22 (76%) patients.¹ In this article, we will walk you through the rainbow of tattoo ACD, covering hypersensitivity reactions to both temporary and permanent tattoo inks.

Temporary Tattoo Inks

Henna is the most common temporary tattoo ink. Derived from the plant Lawsonia inermis, henna is an orange dye that has been used in many parts of the world, particularly in Islamic and Hindu cultures, to dye skin, hair, and fabrics. Application of henna tattoos is common for weddings and other celebrations, and brides may wear elaborate henna patterns. To create these tattoos, henna powder is mixed with water and sometimes essential oils and is then applied to the skin for several hours. After application, the henna pigment lawsone (2-hydroxy-1,4-naphthoquinone) interacts with keratin and leaves a red-orange stain on the skin²; longer application time leads to a deeper color. Most traditional cutaneous henna designs fade in 2 to 6 weeks, but some last longer. Red henna generally is considered safe with low incidence of contact allergy. What is referred to as black henna usually is red henna mixed with PPD, a black dye, which is added to deepen the color. Paraphenylenediamine is highly sensitizing; patients can become sensitized to the PPD in the tattoo itself.² One study confirmed the presence of PPD in black henna tattoos, with chemical analysis of common preparations revealing concentrations ranging from less than 1% to 30%.² Patients who undergo patch testing for tattoo reactions often are strongly positive to PPD and have concomitant reactions to azo dyes, black rubber, and anesthetics. Other aromatic amines including aminophenols have been identified in black henna tattoo ink, and these chemicals also may contribute to ACD.³ Less common sources of contact allergy from temporary black henna tattoos include resorcinol,⁴ para-tertiary butylphenol formaldehyde resin,⁵ and fragrance.⁶

Clinically, ACD to PPD in temporary tattoos presents 1 to 3 days after application if the patient is already sensitized or 4 to 14 days if the patient is sensitized by the tattoo ink.² Most patients notice erythema, edema, vesicles, papules, and/or bullae, but other less common reactions including generalized dermatitis, systemic symptoms, urticaria, and pustules have been described.² Postinflammatory hypopigmentation or hyperpigmentation also can occur.

Because of the sensitizing nature of black henna tattoos, consumers are turning to natural temporary tattoos. Jagua temporary tattoos, with pigment derived from the sap of fruit from the Genipa americana tree, have been associated with ACD.⁷ This black dye is applied and washed off in a similar fashion to henna tattoos. Importantly, a recent analysis of jagua dye identified no PPD. In one case, a patient who developed ACD to a jagua tattoo was patch tested to components of the dye and had a positive reaction to genipin, a component of the fruit extract.⁷ Thus, jagua tattoos often are marketed as safe but are an emerging source of contact dermatitis to temporary tattoos.

Permanent Tattoo Inks

Permanent tattoos are created by injecting small amounts of ink into the dermis. As the name suggests, these tattoos are permanent. Tattoos are common; nearly one-third of Americans have at least 1 tattoo.¹ Historically, tattoos were created using black pigment composed of amorphous carbon or black iron oxides.^8,9 Metallic pigments (eg, mercury, chromium, cobalt, cadmium) were once used to add color to tattoos, but these metals are now only rarely used; in fact, a 2019 study of tattoo ink components identified 44 distinct pigments in 1416 permanent inks, with an average of 3 pigments per ink.⁸ Of the 44 pigments, 10 had metallic components including iron, barium, zinc, copper, molybdenum, and titanium. The remaining 34 pigments contained carbon, azo, diketopyrrolopyrrole, quinacridone, anthraquinone, dioxazine (purple), or quinophthalone (yellow) dyes. The authors noted that nearly one-quarter of the tattoo pigments identified in their study had been reported as contact allergens.⁸

Typically, reactions to permanent tattoo inks manifest as an eczematous dermatitis occurring weeks to years after tattoo application.^9,10 The dermatitis usually is locally confined to the tattoo and may be limited to particular colors; occasionally, a new tattoo reaction may trigger concurrent inflammation in older tattoos. Many tattoo reactions occur as a response to red pigment but also have occurred with other tattoo ink components.⁹ Many researchers have speculated as to whether the reaction is related to the ink component itself or from the photochemical breakdown of the ink by exposure to UV radiation and/or laser therapy.⁹

Red Pigment
Red ink is the most common color reported to cause tattoo hypersensitivity reactions. Historically, red tattoo pigments include mercuric sulfide (vermilion, cinnabar), scarlet lake, cadmium red, carmine, and cochineal,¹¹ but today’s tattoo inks primarily are composed of other pigments, such as quinacridone and azo dyes.¹² Several cases of red tattoo ink hypersensitivity reactions exist in the literature, many without completion of patch tests or without positive patch tests to relevant red pigments.^11-15

Black Pigment
In general, reactions to permanent black tattoo ink are rare; however, a few case reports exist. Black pigment can be created with India ink (carbon), logwood (chrome), iron oxide, and titanium.^16,17 Shellac can be used as a binding agent in tattoo ink; there is at least one report of a reaction to black tattoo ink with a positive patch test to shellac and the original black ink.¹⁸

Azo Pigments
Azo pigments frequently are used in modern tattoos due to their vibrant colors. One case of hypersensitivity to azo pigment involved an eczematous ulcerated plaque overlying yellow, red, and green ink in a recently applied tattoo. Patch testing with the inks originally used in the tattoo was negative. The authors noted that the 3 problematic ink colors all contained pigment yellow 65—an azo pigment—and attributed the reaction to this dye.²² In another azo reaction, a patient had erythema and pruritus overlying a tattoo applied 1 month prior. Patch testing was positive for aminoazobenzene, an azo pigment that was present in the orange ink of the tattoo.²³

Management of Tattoo Hypersensitivity Reactions

Hypersensitivity reactions to temporary tattoos are just that—temporary. Topical steroids and time generally will allow these reactions to resolve. In the setting of vigorous reactions, patients may develop postinflammatory hypopigmentation or hyperpigmentation that may last for months. Unfortunately, bullous tattoo reactions can lead to scarring and keloid formation, requiring more aggressive therapy.

Management of reactions to permanent tattoos is more challenging. High-potency topical steroids under occlusion or intralesional corticosteroid injections may aid in treating pruritus or discomfort. For severe reactions, oral corticosteroids may be required. Patients also may consider laser tattoo removal; however, providers should be aware that there have been rare reports of systemic urticarial reactions from this procedure.^24,25 Obviously limited by location and size, excision also may be offered.

Patch Testing for Tattoo Ink Contact Allergy

When patients present for evaluation and management of tattoo ACD, it is important to also consider other causes, including granulomatous tattoo reaction, pseudolymphoma, and lichenoid tattoo reaction. A biopsy can be helpful if the diagnosis is in question.

Patch testing for contact allergy to temporary tattoo inks should include PPD, fragrance, aminophenols, resorcinol, para-tertiary butylphenol formaldehyde, and essential oils. Jagua currently is not available for commercial purchase but also should be considered if the patient has the original product or in research settings. If the individual tattoo ingredients can be identified, they also should be tested. In this scenario, recall reactions may occur; testing with the tattoo paste should be avoided if the prior reaction was severe. Importantly, patients with a PPD allergy should be counseled to avoid hair dyes that contain PPD. Many patients who are sensitized to PPD have strong reactions on patch testing and are at risk for severe reactions if PPD or PPD-related compounds are encountered in hair dye.

Patch testing for ACD to permanent tattoos is complex. In most cases, patch testing is of limited utility because many of the chemicals that have been reported to cause ACD are not commercially available. Additionally, a 2014 study of 90 patients with chronic tattoo reactions found that the majority had negative patch testing to the European baseline series (66%), disperse dyes (87%), and tattoo inks (87%–92%). The investigators theorized that the allergens causing tattoo reactions are formed by haptenization of “parent” chemicals in the dermis, meaning application of chemicals present in the original tattoo ink may not identify the relevant allergen.²⁶ If patch testing is performed, it is most ideal if individual pigment ingredients can be identified. Allergens to be considered for testing include azo dyes, aromatic amines, iron oxide, barium, zinc, copper, molybdenum, titanium, gold sodium thiosulfate, nickel sulfate, carbon, shellac, diketopyrrolopyrrole, quinacridone, anthraquinone, dioxazine (purple), quinophthalone (yellow) dyes, mercuric sulfide (vermilion, cinnabar), scarlet lake, cadmium red, carmine, and cochineal, many of which are not commercially available for purchase.

Final Interpretation

As tattoos become increasingly trendy, tattoo ACD should be recognized by the astute dermatologist. The most common allergen associated with tattoo ACD is PPD, but other potential allergens include azo dyes and newer pigments. Unlike tattoos of the past, today’s inks are unlikely to contain toxic metals. Diagnosing ACD caused by permanent tattoo inks requires a high degree of suspicion, as patch testing may be of limited utility.

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.

As hospitalists and other physicians at the University of Texas at Austin considered how to treat COVID-19 patients in the early weeks of the pandemic, one question they had to consider was: What about convalescent plasma?

All they had to go on were small case series in Ebola, SARS, and MERS and a few small, nonrandomized COVID-19 studies showing a possible benefit and minimal risk, but the evidence was only “toward the middle or bottom” of the evidence pyramid, said Johanna Busch, MD, of the department of internal medicine at Dell Medical Center at the university.

The center’s COVID-19 committee asked a few of its members – infectious disease and internal medicine physicians – to analyze the literature and other factors. In the end, the committee – which meets regularly and also includes pulmonology–critical care experts, nursing experts, and others – recommended using convalescent plasma because of the evidence and the available supply. But in subsequent meetings, as the pandemic surged in the South and the supply dwindled, the committee changed its recommendation for convalescent plasma to more limited use, she said during the virtual annual meeting of the Society of Hospital Medicine.

Dell’s experience with the therapy is one example of how the center had to quickly develop protocols for managing a pandemic with essentially no solid evidence for treatment and a system that had never been challenged before to the same degree.

“It’s all about teamwork,” said W. Michael Brode, MD, of the department of internal medicine at Dell. “The interprofessional team members know their roles and have shared expectations because they have a common understanding of the protocol.” It’s okay to deviate from the protocol, he said, as long as the language exists to communicate these deviations.

“Maybe the approach is more important than the actual content,” he said.

What Dr. Brode and Dr. Busch described was in large part a fine-tuning of communication – being available to communicate in real time and being aware of when certain specialists should be contacted – for instance, to determine at what oxygenation level internal medicine staff should get in touch with the pulmonary–critical care team.

Dr. Brode said that the groundwork is laid for productive meetings, with agendas announced ahead of time and readings assigned and presenters ready with near-finished products at meeting time, “with a clear path for operationalizing it.”

“We don’t want people kind of riffing off the top of their heads,” he said.

Committee members are encouraged to be as specific as possible when giving input into COVID-19 care decisions, he said.

“We’re so used to dealing with uncertainty, but that doesn’t really help when we’re trying to make tough decisions,” Dr. Brode said. They might be asked, “What are you going to write in your consult note template?” or “It’s 1:00 a.m. and your intern’s panicked and calling you – what are you going to tell them to do over the phone?”

The recommendations have to go into writing and are incorporated into the electronic medical record, a process that required some workarounds, he said. He also noted that the committee learned early on that they should assume that no one reads the e-mails – especially after being off for a period of time – so they likely won’t digest updates on an email-by-email basis.

“We quickly learned,” Dr. Brode said, “that this information needs to live on a Web site or [be] linked to the most up-to-date version in a cloud-sharing platform.”

In a question-and-answer discussion, session viewers expressed enthusiasm for the presenters’ one-page summary of protocols – much more, they said, and it could feel overwhelming.

Dr. Busch and Dr. Brode were asked how standardized order sets for COVID patients could be justified without comparison to a control group that didn’t use the standard order set.

Dr. Busch responded that, while there was no controlled trial, the order sets they use have evolved based on experience.

“At the beginning, we were following every inflammatory marker known to mankind, and then we realized as we gained more experience with COVID and COVID patients that some of those markers were not really informing any of our clinical decisions,” she said. “Obviously, as literature comes out we may reevaluate what goes into that standard order set and how frequently we follow labs.”

Dr. Brode said the context – a pandemic – has to be considered.

“In an ideal world, we could show that the intervention is superior through a randomized fashion with a control group, but really our thought process behind it is just, what is the default?” he said. “I looked at the order sets [as] not that they’re going to be dictating care, but it’s really like the guardrails of what’s reasonable. And when you’re in the middle of a surge, what is usually reasonable and easiest is what is going to be done.”

Dr. Busch and Dr. Brode reported no relevant financial relationships.

As hospitalists and other physicians at the University of Texas at Austin considered how to treat COVID-19 patients in the early weeks of the pandemic, one question they had to consider was: What about convalescent plasma?

All they had to go on were small case series in Ebola, SARS, and MERS and a few small, nonrandomized COVID-19 studies showing a possible benefit and minimal risk, but the evidence was only “toward the middle or bottom” of the evidence pyramid, said Johanna Busch, MD, of the department of internal medicine at Dell Medical Center at the university.

The center’s COVID-19 committee asked a few of its members – infectious disease and internal medicine physicians – to analyze the literature and other factors. In the end, the committee – which meets regularly and also includes pulmonology–critical care experts, nursing experts, and others – recommended using convalescent plasma because of the evidence and the available supply. But in subsequent meetings, as the pandemic surged in the South and the supply dwindled, the committee changed its recommendation for convalescent plasma to more limited use, she said during the virtual annual meeting of the Society of Hospital Medicine.

Dell’s experience with the therapy is one example of how the center had to quickly develop protocols for managing a pandemic with essentially no solid evidence for treatment and a system that had never been challenged before to the same degree.

“It’s all about teamwork,” said W. Michael Brode, MD, of the department of internal medicine at Dell. “The interprofessional team members know their roles and have shared expectations because they have a common understanding of the protocol.” It’s okay to deviate from the protocol, he said, as long as the language exists to communicate these deviations.

“Maybe the approach is more important than the actual content,” he said.

What Dr. Brode and Dr. Busch described was in large part a fine-tuning of communication – being available to communicate in real time and being aware of when certain specialists should be contacted – for instance, to determine at what oxygenation level internal medicine staff should get in touch with the pulmonary–critical care team.

Dr. Brode said that the groundwork is laid for productive meetings, with agendas announced ahead of time and readings assigned and presenters ready with near-finished products at meeting time, “with a clear path for operationalizing it.”

“We don’t want people kind of riffing off the top of their heads,” he said.

Committee members are encouraged to be as specific as possible when giving input into COVID-19 care decisions, he said.

“We’re so used to dealing with uncertainty, but that doesn’t really help when we’re trying to make tough decisions,” Dr. Brode said. They might be asked, “What are you going to write in your consult note template?” or “It’s 1:00 a.m. and your intern’s panicked and calling you – what are you going to tell them to do over the phone?”

The recommendations have to go into writing and are incorporated into the electronic medical record, a process that required some workarounds, he said. He also noted that the committee learned early on that they should assume that no one reads the e-mails – especially after being off for a period of time – so they likely won’t digest updates on an email-by-email basis.

“We quickly learned,” Dr. Brode said, “that this information needs to live on a Web site or [be] linked to the most up-to-date version in a cloud-sharing platform.”

In a question-and-answer discussion, session viewers expressed enthusiasm for the presenters’ one-page summary of protocols – much more, they said, and it could feel overwhelming.

Dr. Busch and Dr. Brode were asked how standardized order sets for COVID patients could be justified without comparison to a control group that didn’t use the standard order set.

Dr. Busch responded that, while there was no controlled trial, the order sets they use have evolved based on experience.

“At the beginning, we were following every inflammatory marker known to mankind, and then we realized as we gained more experience with COVID and COVID patients that some of those markers were not really informing any of our clinical decisions,” she said. “Obviously, as literature comes out we may reevaluate what goes into that standard order set and how frequently we follow labs.”

Dr. Brode said the context – a pandemic – has to be considered.

“In an ideal world, we could show that the intervention is superior through a randomized fashion with a control group, but really our thought process behind it is just, what is the default?” he said. “I looked at the order sets [as] not that they’re going to be dictating care, but it’s really like the guardrails of what’s reasonable. And when you’re in the middle of a surge, what is usually reasonable and easiest is what is going to be done.”

Dr. Busch and Dr. Brode reported no relevant financial relationships.

As hospitalists and other physicians at the University of Texas at Austin considered how to treat COVID-19 patients in the early weeks of the pandemic, one question they had to consider was: What about convalescent plasma?

All they had to go on were small case series in Ebola, SARS, and MERS and a few small, nonrandomized COVID-19 studies showing a possible benefit and minimal risk, but the evidence was only “toward the middle or bottom” of the evidence pyramid, said Johanna Busch, MD, of the department of internal medicine at Dell Medical Center at the university.

The center’s COVID-19 committee asked a few of its members – infectious disease and internal medicine physicians – to analyze the literature and other factors. In the end, the committee – which meets regularly and also includes pulmonology–critical care experts, nursing experts, and others – recommended using convalescent plasma because of the evidence and the available supply. But in subsequent meetings, as the pandemic surged in the South and the supply dwindled, the committee changed its recommendation for convalescent plasma to more limited use, she said during the virtual annual meeting of the Society of Hospital Medicine.

Dell’s experience with the therapy is one example of how the center had to quickly develop protocols for managing a pandemic with essentially no solid evidence for treatment and a system that had never been challenged before to the same degree.

“It’s all about teamwork,” said W. Michael Brode, MD, of the department of internal medicine at Dell. “The interprofessional team members know their roles and have shared expectations because they have a common understanding of the protocol.” It’s okay to deviate from the protocol, he said, as long as the language exists to communicate these deviations.

“Maybe the approach is more important than the actual content,” he said.

What Dr. Brode and Dr. Busch described was in large part a fine-tuning of communication – being available to communicate in real time and being aware of when certain specialists should be contacted – for instance, to determine at what oxygenation level internal medicine staff should get in touch with the pulmonary–critical care team.

Dr. Brode said that the groundwork is laid for productive meetings, with agendas announced ahead of time and readings assigned and presenters ready with near-finished products at meeting time, “with a clear path for operationalizing it.”

“We don’t want people kind of riffing off the top of their heads,” he said.

Committee members are encouraged to be as specific as possible when giving input into COVID-19 care decisions, he said.

“We’re so used to dealing with uncertainty, but that doesn’t really help when we’re trying to make tough decisions,” Dr. Brode said. They might be asked, “What are you going to write in your consult note template?” or “It’s 1:00 a.m. and your intern’s panicked and calling you – what are you going to tell them to do over the phone?”

The recommendations have to go into writing and are incorporated into the electronic medical record, a process that required some workarounds, he said. He also noted that the committee learned early on that they should assume that no one reads the e-mails – especially after being off for a period of time – so they likely won’t digest updates on an email-by-email basis.

“We quickly learned,” Dr. Brode said, “that this information needs to live on a Web site or [be] linked to the most up-to-date version in a cloud-sharing platform.”

In a question-and-answer discussion, session viewers expressed enthusiasm for the presenters’ one-page summary of protocols – much more, they said, and it could feel overwhelming.

Dr. Busch and Dr. Brode were asked how standardized order sets for COVID patients could be justified without comparison to a control group that didn’t use the standard order set.

Dr. Busch responded that, while there was no controlled trial, the order sets they use have evolved based on experience.

“At the beginning, we were following every inflammatory marker known to mankind, and then we realized as we gained more experience with COVID and COVID patients that some of those markers were not really informing any of our clinical decisions,” she said. “Obviously, as literature comes out we may reevaluate what goes into that standard order set and how frequently we follow labs.”

Dr. Brode said the context – a pandemic – has to be considered.

“In an ideal world, we could show that the intervention is superior through a randomized fashion with a control group, but really our thought process behind it is just, what is the default?” he said. “I looked at the order sets [as] not that they’re going to be dictating care, but it’s really like the guardrails of what’s reasonable. And when you’re in the middle of a surge, what is usually reasonable and easiest is what is going to be done.”

Dr. Busch and Dr. Brode reported no relevant financial relationships.

Elotuzumab-based maintenance therapy may improve the posttransplant response for multiple myeloma (MM), according to the results of a small retrospective study at a single institution.

In addition, the therapies appear to be safely administered even to older patients because of the low rate of adverse effects, as indicated in a report published online in Blood Cells, Molecules and Diseases.

The researchers retrospectively evaluated the outcomes of seven MM patients who were started on elotuzumab-based maintenance (elotuzumab/lenalidomide/dexamethasone, elotuzumab/bortezomib/dexamethasone, or elotuzumab/bortezomib/methylprednisolone) following transplant, according to Xin Wang, MD, of the UMass Memorial Medical Center, Worcester, and colleagues.

The median age was 68 years (ranging from 56 years to 81 years) at the time of transplant, and median lines of induction therapy was 2; three patients (42.9%) had high-risk cytogenetics and five (71.4%) had stage II or greater disease at diagnosis.
 

Promising elotuzumab results

At a median follow-up of 24 months, five patients (71.4%) had improvement in their quality of response. Among all patients, there was a combined complete response (CR) or very good partial response (VGPR) rate increase from 57.1% to 100% (CR = 3, VGPR = 4). VGPR was defined by the researchers as an absence of abnormal immunofixation and soft tissue plasmacytoma without bone marrow biopsy.

All patients were alive without relapse or progression at the time of the final analysis. In terms of adverse effects, grade 3-4 events were observed in three (42.9%) of the patients. None of the patients discontinued the treatment because of intolerance, according to the researchers.

“Our study demonstrates that elotuzumab-based maintenance may deepen response post transplant in MM and can be safely administered even in older patients. Given its unique action and rare side effects, further studies of elotuzumab in the post-transplant setting are warranted,” the researchers concluded.

The study had no outside funding and the researchers reported that they had no disclosures.

[email protected]

SOURCE: Wang X et al. Blood Cells Mol Dis. 2020 Jul 28. doi: 10.1016/j.bcmd.2020.102482.

Elotuzumab-based maintenance therapy may improve the posttransplant response for multiple myeloma (MM), according to the results of a small retrospective study at a single institution.

In addition, the therapies appear to be safely administered even to older patients because of the low rate of adverse effects, as indicated in a report published online in Blood Cells, Molecules and Diseases.

The researchers retrospectively evaluated the outcomes of seven MM patients who were started on elotuzumab-based maintenance (elotuzumab/lenalidomide/dexamethasone, elotuzumab/bortezomib/dexamethasone, or elotuzumab/bortezomib/methylprednisolone) following transplant, according to Xin Wang, MD, of the UMass Memorial Medical Center, Worcester, and colleagues.

The median age was 68 years (ranging from 56 years to 81 years) at the time of transplant, and median lines of induction therapy was 2; three patients (42.9%) had high-risk cytogenetics and five (71.4%) had stage II or greater disease at diagnosis.
 

Promising elotuzumab results

At a median follow-up of 24 months, five patients (71.4%) had improvement in their quality of response. Among all patients, there was a combined complete response (CR) or very good partial response (VGPR) rate increase from 57.1% to 100% (CR = 3, VGPR = 4). VGPR was defined by the researchers as an absence of abnormal immunofixation and soft tissue plasmacytoma without bone marrow biopsy.

All patients were alive without relapse or progression at the time of the final analysis. In terms of adverse effects, grade 3-4 events were observed in three (42.9%) of the patients. None of the patients discontinued the treatment because of intolerance, according to the researchers.

“Our study demonstrates that elotuzumab-based maintenance may deepen response post transplant in MM and can be safely administered even in older patients. Given its unique action and rare side effects, further studies of elotuzumab in the post-transplant setting are warranted,” the researchers concluded.

The study had no outside funding and the researchers reported that they had no disclosures.

[email protected]

SOURCE: Wang X et al. Blood Cells Mol Dis. 2020 Jul 28. doi: 10.1016/j.bcmd.2020.102482.

Elotuzumab-based maintenance therapy may improve the posttransplant response for multiple myeloma (MM), according to the results of a small retrospective study at a single institution.

In addition, the therapies appear to be safely administered even to older patients because of the low rate of adverse effects, as indicated in a report published online in Blood Cells, Molecules and Diseases.

The researchers retrospectively evaluated the outcomes of seven MM patients who were started on elotuzumab-based maintenance (elotuzumab/lenalidomide/dexamethasone, elotuzumab/bortezomib/dexamethasone, or elotuzumab/bortezomib/methylprednisolone) following transplant, according to Xin Wang, MD, of the UMass Memorial Medical Center, Worcester, and colleagues.

The median age was 68 years (ranging from 56 years to 81 years) at the time of transplant, and median lines of induction therapy was 2; three patients (42.9%) had high-risk cytogenetics and five (71.4%) had stage II or greater disease at diagnosis.
 

Promising elotuzumab results

At a median follow-up of 24 months, five patients (71.4%) had improvement in their quality of response. Among all patients, there was a combined complete response (CR) or very good partial response (VGPR) rate increase from 57.1% to 100% (CR = 3, VGPR = 4). VGPR was defined by the researchers as an absence of abnormal immunofixation and soft tissue plasmacytoma without bone marrow biopsy.

All patients were alive without relapse or progression at the time of the final analysis. In terms of adverse effects, grade 3-4 events were observed in three (42.9%) of the patients. None of the patients discontinued the treatment because of intolerance, according to the researchers.

“Our study demonstrates that elotuzumab-based maintenance may deepen response post transplant in MM and can be safely administered even in older patients. Given its unique action and rare side effects, further studies of elotuzumab in the post-transplant setting are warranted,” the researchers concluded.

The study had no outside funding and the researchers reported that they had no disclosures.

[email protected]

SOURCE: Wang X et al. Blood Cells Mol Dis. 2020 Jul 28. doi: 10.1016/j.bcmd.2020.102482.

A new analysis from Michigan’s largest health system provides sobering verification of the risks for QT interval prolongation in COVID-19 patients treated with hydroxychloroquine and azithromycin (HCQ/AZM).

One in five patients (21%) had a corrected QT (QTc) interval of at least 500 msec, a value that increases the risk for torsade de pointes in the general population and at which cardiovascular leaders have suggested withholding HCQ/AZM in COVID-19 patients.

“One of the most striking findings was when we looked at the other drugs being administered to these patients; 61% were being administered drugs that had QT-prolonging effects concomitantly with the HCQ and AZM therapy. So they were inadvertently doubling down on the QT-prolonging effects of these drugs,” senior author David E. Haines, MD, director of the Heart Rhythm Center at William Beaumont Hospital, Royal Oak, Mich., said in an interview.

A total of 34 medications overlapped with HCQ/AZM therapy are known or suspected to increase the risk for torsade de pointes, a potentially life-threatening ventricular tachycardia. The most common of these were propofol coadministered in 123 patients, ondansetron in 114, dexmedetomidine in 54, haloperidol in 44, amiodarone in 43, and tramadol in 26.

“This speaks to the medical complexity of this patient population, but also suggests inadequate awareness of the QT-prolonging effects of many common medications,” the researchers say.

The study was published Aug. 5 in JACC Clinical Electrophysiology.

Both hydroxychloroquine and azithromycin increase the risk for QTc-interval prolongation by blocking the KCHN2-encoded hERG potassium channel. Several reports have linked the drugs to a triggering of QT prolongation in patients with COVID-19.

For the present study, Dr. Haines and colleagues examined data from 586 consecutive patients admitted with COVID-19 to the Beaumont Hospitals in Royal Oak and Troy, Mich., between March 13 and April 6. A baseline QTc interval was measured with 12-lead ECG prior to treatment initiation with hydroxychloroquine 400 mg twice daily for two doses, then 200 mg twice daily for 4 days, and azithromycin 500 mg once followed by 250 mg daily for 4 days.

Because of limited availability at the time, lead II ECG telemetry monitoring over the 5-day course of HCQ/AZM was recommended only in patients with baseline QTc intervals of at least 440 msec.

Patients without an interpretable baseline ECG or available telemetry/ECG monitoring for at least 1 day were also excluded, leaving 415 patients (mean age, 64 years; 45% female) in the study population. More than half (52%) were Black, 52% had hypertension, 30% had diabetes, and 14% had cancer.

As seen in previous studies, the QTc interval increased progressively and significantly after the administration of HCQ/AZM, from 443 msec to 473 msec.

The average time to maximum QTc was 2.9 days in a subset of 135 patients with QTc measurements prior to starting therapy and on days 1 through 5.

In multivariate analysis, independent predictors of a potentially hazardous QTc interval of at least 500 msec were:

• Age older than 65 years (odds ratio, 3.0; 95% confidence interval, 1.62-5.54).
• History of  (OR, 4.65; 95% CI, 2.01-10.74).
• Admission  of at least 1.5 mg/dL (OR, 2.22; 95% CI, 1.28-3.84).
• Peak troponin I level above 0.04 mg/mL (OR, 3.89; 95% CI, 2.22-6.83).
• Body mass index below 30 kg/m² (OR for a BMI of 30 kg/m² or higher, 0.45; 95% CI, 0.26-0.78).

Concomitant use of drugs with known risk for torsade de pointes was a significant risk factor in univariate analysis (OR, 1.73; P = .036), but fell out in the multivariate model.

No patients experienced high-grade arrhythmias during the study. In all, 112 of the 586 patients died during hospitalization, including 85 (21%) of the 415 study patients.

The change in QTc interval from baseline was greater in patients who died. Despite this, the only independent predictor of mortality was older age. One possible explanation is that the decision to monitor patients with baseline QTc intervals of at least 440 msec may have skewed the study population toward people with moderate or slightly long QTc intervals prior to the initiation of HCQ/AZM, Dr. Haines suggested. Monitoring and treatment duration were short, and clinicians also likely adjusted medications when excess QTc prolongation was observed.

Although it’s been months since data collection was completed in April, and the paper was written in record-breaking time, the study “is still very relevant because the drug is still out there,” observed Dr. Haines. “Even though it may not be used in as widespread a fashion as it had been when we first submitted the paper, it is still being used routinely by many hospitals and many practitioners.”

The use of hydroxychloroquine is “going through the roof” because of COVID-19, commented Dhanunjaya Lakkireddy, MD, medical director for the Kansas City Heart Rhythm Institute, HCA Midwest Health, Overland Park, Kan., who was not involved in the study.

“This study is very relevant, and I’m glad they shared their experience, and it’s pretty consistent with the data presented by other people. The question of whether hydroxychloroquine helps people with COVID is up for debate, but there is more evidence today that it is not as helpful as it was 3 months ago,” said Dr. Lakkireddy, who is also chair of the American College of Cardiology Electrophysiology Council.

He expressed concern for patients who may be taking HCQ with other medications that have QT-prolonging effects, and for the lack of long-term protocols in place for the drug.

In the coming weeks, however, the ACC and rheumatology leaders will be publishing an expert consensus statement that addresses key issues, such as how to best to use HCQ, maintenance HCQ, electrolyte monitoring, the optimal timing of electrocardiography and cardiac magnetic imaging, and symptoms to look for if cardiac involvement is suspected, Dr. Lakkireddy said.

Asked whether HCQ and AZM should be used in COVID-19 patients, Dr. Haines said in an interview that the “QT-prolonging effects are real, the arrhythmogenic potential is real, and the benefit to patients is nil or marginal. So I think that use of these drugs is appropriate and reasonable if it is done in a setting of a controlled trial, and I support that. But the routine use of these drugs probably is not warranted based on the data that we have available.”

Still, hydroxychloroquine continues to be dragged into the spotlight in recent days as an effective treatment for COVID-19, despite discredited research and the U.S. Food and Drug Administration’s June 15 revocation of its emergency-use authorization to allow use of HCQ and chloroquine to treat certain hospitalized COVID-19 patients.

“The unfortunate politicization of this issue has really muddied the waters because the general public doesn’t know what to believe or who to believe. The fact that treatment for a disease as serious as COVID should be modulated by political affiliation is just crazy to me,” said Dr. Haines. “We should be using the best science and taking careful observations, and whatever the recommendations derived from that should be uniformly adopted by everybody, irrespective of your political affiliation.”

Dr. Haines has received honoraria from Biosense Webster, Farapulse, and Sagentia, and is a consultant for Affera, Boston Scientific, Integer, Medtronic, Philips Healthcare, and Zoll. Dr. Lakkireddy has served as a consultant to Abbott, Biosense Webster, Biotronik, Boston Scientific, and Medtronic. 

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

A new analysis from Michigan’s largest health system provides sobering verification of the risks for QT interval prolongation in COVID-19 patients treated with hydroxychloroquine and azithromycin (HCQ/AZM).

One in five patients (21%) had a corrected QT (QTc) interval of at least 500 msec, a value that increases the risk for torsade de pointes in the general population and at which cardiovascular leaders have suggested withholding HCQ/AZM in COVID-19 patients.

“One of the most striking findings was when we looked at the other drugs being administered to these patients; 61% were being administered drugs that had QT-prolonging effects concomitantly with the HCQ and AZM therapy. So they were inadvertently doubling down on the QT-prolonging effects of these drugs,” senior author David E. Haines, MD, director of the Heart Rhythm Center at William Beaumont Hospital, Royal Oak, Mich., said in an interview.

A total of 34 medications overlapped with HCQ/AZM therapy are known or suspected to increase the risk for torsade de pointes, a potentially life-threatening ventricular tachycardia. The most common of these were propofol coadministered in 123 patients, ondansetron in 114, dexmedetomidine in 54, haloperidol in 44, amiodarone in 43, and tramadol in 26.

“This speaks to the medical complexity of this patient population, but also suggests inadequate awareness of the QT-prolonging effects of many common medications,” the researchers say.

The study was published Aug. 5 in JACC Clinical Electrophysiology.

Both hydroxychloroquine and azithromycin increase the risk for QTc-interval prolongation by blocking the KCHN2-encoded hERG potassium channel. Several reports have linked the drugs to a triggering of QT prolongation in patients with COVID-19.

For the present study, Dr. Haines and colleagues examined data from 586 consecutive patients admitted with COVID-19 to the Beaumont Hospitals in Royal Oak and Troy, Mich., between March 13 and April 6. A baseline QTc interval was measured with 12-lead ECG prior to treatment initiation with hydroxychloroquine 400 mg twice daily for two doses, then 200 mg twice daily for 4 days, and azithromycin 500 mg once followed by 250 mg daily for 4 days.

Because of limited availability at the time, lead II ECG telemetry monitoring over the 5-day course of HCQ/AZM was recommended only in patients with baseline QTc intervals of at least 440 msec.

Patients without an interpretable baseline ECG or available telemetry/ECG monitoring for at least 1 day were also excluded, leaving 415 patients (mean age, 64 years; 45% female) in the study population. More than half (52%) were Black, 52% had hypertension, 30% had diabetes, and 14% had cancer.

As seen in previous studies, the QTc interval increased progressively and significantly after the administration of HCQ/AZM, from 443 msec to 473 msec.

The average time to maximum QTc was 2.9 days in a subset of 135 patients with QTc measurements prior to starting therapy and on days 1 through 5.

In multivariate analysis, independent predictors of a potentially hazardous QTc interval of at least 500 msec were:

• Age older than 65 years (odds ratio, 3.0; 95% confidence interval, 1.62-5.54).
• History of  (OR, 4.65; 95% CI, 2.01-10.74).
• Admission  of at least 1.5 mg/dL (OR, 2.22; 95% CI, 1.28-3.84).
• Peak troponin I level above 0.04 mg/mL (OR, 3.89; 95% CI, 2.22-6.83).
• Body mass index below 30 kg/m² (OR for a BMI of 30 kg/m² or higher, 0.45; 95% CI, 0.26-0.78).

Concomitant use of drugs with known risk for torsade de pointes was a significant risk factor in univariate analysis (OR, 1.73; P = .036), but fell out in the multivariate model.

No patients experienced high-grade arrhythmias during the study. In all, 112 of the 586 patients died during hospitalization, including 85 (21%) of the 415 study patients.

The change in QTc interval from baseline was greater in patients who died. Despite this, the only independent predictor of mortality was older age. One possible explanation is that the decision to monitor patients with baseline QTc intervals of at least 440 msec may have skewed the study population toward people with moderate or slightly long QTc intervals prior to the initiation of HCQ/AZM, Dr. Haines suggested. Monitoring and treatment duration were short, and clinicians also likely adjusted medications when excess QTc prolongation was observed.

Although it’s been months since data collection was completed in April, and the paper was written in record-breaking time, the study “is still very relevant because the drug is still out there,” observed Dr. Haines. “Even though it may not be used in as widespread a fashion as it had been when we first submitted the paper, it is still being used routinely by many hospitals and many practitioners.”

The use of hydroxychloroquine is “going through the roof” because of COVID-19, commented Dhanunjaya Lakkireddy, MD, medical director for the Kansas City Heart Rhythm Institute, HCA Midwest Health, Overland Park, Kan., who was not involved in the study.

“This study is very relevant, and I’m glad they shared their experience, and it’s pretty consistent with the data presented by other people. The question of whether hydroxychloroquine helps people with COVID is up for debate, but there is more evidence today that it is not as helpful as it was 3 months ago,” said Dr. Lakkireddy, who is also chair of the American College of Cardiology Electrophysiology Council.

He expressed concern for patients who may be taking HCQ with other medications that have QT-prolonging effects, and for the lack of long-term protocols in place for the drug.

In the coming weeks, however, the ACC and rheumatology leaders will be publishing an expert consensus statement that addresses key issues, such as how to best to use HCQ, maintenance HCQ, electrolyte monitoring, the optimal timing of electrocardiography and cardiac magnetic imaging, and symptoms to look for if cardiac involvement is suspected, Dr. Lakkireddy said.

Asked whether HCQ and AZM should be used in COVID-19 patients, Dr. Haines said in an interview that the “QT-prolonging effects are real, the arrhythmogenic potential is real, and the benefit to patients is nil or marginal. So I think that use of these drugs is appropriate and reasonable if it is done in a setting of a controlled trial, and I support that. But the routine use of these drugs probably is not warranted based on the data that we have available.”

Still, hydroxychloroquine continues to be dragged into the spotlight in recent days as an effective treatment for COVID-19, despite discredited research and the U.S. Food and Drug Administration’s June 15 revocation of its emergency-use authorization to allow use of HCQ and chloroquine to treat certain hospitalized COVID-19 patients.

“The unfortunate politicization of this issue has really muddied the waters because the general public doesn’t know what to believe or who to believe. The fact that treatment for a disease as serious as COVID should be modulated by political affiliation is just crazy to me,” said Dr. Haines. “We should be using the best science and taking careful observations, and whatever the recommendations derived from that should be uniformly adopted by everybody, irrespective of your political affiliation.”

Dr. Haines has received honoraria from Biosense Webster, Farapulse, and Sagentia, and is a consultant for Affera, Boston Scientific, Integer, Medtronic, Philips Healthcare, and Zoll. Dr. Lakkireddy has served as a consultant to Abbott, Biosense Webster, Biotronik, Boston Scientific, and Medtronic. 

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

A new analysis from Michigan’s largest health system provides sobering verification of the risks for QT interval prolongation in COVID-19 patients treated with hydroxychloroquine and azithromycin (HCQ/AZM).

One in five patients (21%) had a corrected QT (QTc) interval of at least 500 msec, a value that increases the risk for torsade de pointes in the general population and at which cardiovascular leaders have suggested withholding HCQ/AZM in COVID-19 patients.

“One of the most striking findings was when we looked at the other drugs being administered to these patients; 61% were being administered drugs that had QT-prolonging effects concomitantly with the HCQ and AZM therapy. So they were inadvertently doubling down on the QT-prolonging effects of these drugs,” senior author David E. Haines, MD, director of the Heart Rhythm Center at William Beaumont Hospital, Royal Oak, Mich., said in an interview.

A total of 34 medications overlapped with HCQ/AZM therapy are known or suspected to increase the risk for torsade de pointes, a potentially life-threatening ventricular tachycardia. The most common of these were propofol coadministered in 123 patients, ondansetron in 114, dexmedetomidine in 54, haloperidol in 44, amiodarone in 43, and tramadol in 26.

“This speaks to the medical complexity of this patient population, but also suggests inadequate awareness of the QT-prolonging effects of many common medications,” the researchers say.

The study was published Aug. 5 in JACC Clinical Electrophysiology.

Both hydroxychloroquine and azithromycin increase the risk for QTc-interval prolongation by blocking the KCHN2-encoded hERG potassium channel. Several reports have linked the drugs to a triggering of QT prolongation in patients with COVID-19.

For the present study, Dr. Haines and colleagues examined data from 586 consecutive patients admitted with COVID-19 to the Beaumont Hospitals in Royal Oak and Troy, Mich., between March 13 and April 6. A baseline QTc interval was measured with 12-lead ECG prior to treatment initiation with hydroxychloroquine 400 mg twice daily for two doses, then 200 mg twice daily for 4 days, and azithromycin 500 mg once followed by 250 mg daily for 4 days.

Because of limited availability at the time, lead II ECG telemetry monitoring over the 5-day course of HCQ/AZM was recommended only in patients with baseline QTc intervals of at least 440 msec.

Patients without an interpretable baseline ECG or available telemetry/ECG monitoring for at least 1 day were also excluded, leaving 415 patients (mean age, 64 years; 45% female) in the study population. More than half (52%) were Black, 52% had hypertension, 30% had diabetes, and 14% had cancer.

As seen in previous studies, the QTc interval increased progressively and significantly after the administration of HCQ/AZM, from 443 msec to 473 msec.

The average time to maximum QTc was 2.9 days in a subset of 135 patients with QTc measurements prior to starting therapy and on days 1 through 5.

In multivariate analysis, independent predictors of a potentially hazardous QTc interval of at least 500 msec were:

• Age older than 65 years (odds ratio, 3.0; 95% confidence interval, 1.62-5.54).
• History of  (OR, 4.65; 95% CI, 2.01-10.74).
• Admission  of at least 1.5 mg/dL (OR, 2.22; 95% CI, 1.28-3.84).
• Peak troponin I level above 0.04 mg/mL (OR, 3.89; 95% CI, 2.22-6.83).
• Body mass index below 30 kg/m² (OR for a BMI of 30 kg/m² or higher, 0.45; 95% CI, 0.26-0.78).

Concomitant use of drugs with known risk for torsade de pointes was a significant risk factor in univariate analysis (OR, 1.73; P = .036), but fell out in the multivariate model.

No patients experienced high-grade arrhythmias during the study. In all, 112 of the 586 patients died during hospitalization, including 85 (21%) of the 415 study patients.

The change in QTc interval from baseline was greater in patients who died. Despite this, the only independent predictor of mortality was older age. One possible explanation is that the decision to monitor patients with baseline QTc intervals of at least 440 msec may have skewed the study population toward people with moderate or slightly long QTc intervals prior to the initiation of HCQ/AZM, Dr. Haines suggested. Monitoring and treatment duration were short, and clinicians also likely adjusted medications when excess QTc prolongation was observed.

Although it’s been months since data collection was completed in April, and the paper was written in record-breaking time, the study “is still very relevant because the drug is still out there,” observed Dr. Haines. “Even though it may not be used in as widespread a fashion as it had been when we first submitted the paper, it is still being used routinely by many hospitals and many practitioners.”

The use of hydroxychloroquine is “going through the roof” because of COVID-19, commented Dhanunjaya Lakkireddy, MD, medical director for the Kansas City Heart Rhythm Institute, HCA Midwest Health, Overland Park, Kan., who was not involved in the study.

“This study is very relevant, and I’m glad they shared their experience, and it’s pretty consistent with the data presented by other people. The question of whether hydroxychloroquine helps people with COVID is up for debate, but there is more evidence today that it is not as helpful as it was 3 months ago,” said Dr. Lakkireddy, who is also chair of the American College of Cardiology Electrophysiology Council.

He expressed concern for patients who may be taking HCQ with other medications that have QT-prolonging effects, and for the lack of long-term protocols in place for the drug.

In the coming weeks, however, the ACC and rheumatology leaders will be publishing an expert consensus statement that addresses key issues, such as how to best to use HCQ, maintenance HCQ, electrolyte monitoring, the optimal timing of electrocardiography and cardiac magnetic imaging, and symptoms to look for if cardiac involvement is suspected, Dr. Lakkireddy said.

Asked whether HCQ and AZM should be used in COVID-19 patients, Dr. Haines said in an interview that the “QT-prolonging effects are real, the arrhythmogenic potential is real, and the benefit to patients is nil or marginal. So I think that use of these drugs is appropriate and reasonable if it is done in a setting of a controlled trial, and I support that. But the routine use of these drugs probably is not warranted based on the data that we have available.”

Still, hydroxychloroquine continues to be dragged into the spotlight in recent days as an effective treatment for COVID-19, despite discredited research and the U.S. Food and Drug Administration’s June 15 revocation of its emergency-use authorization to allow use of HCQ and chloroquine to treat certain hospitalized COVID-19 patients.

“The unfortunate politicization of this issue has really muddied the waters because the general public doesn’t know what to believe or who to believe. The fact that treatment for a disease as serious as COVID should be modulated by political affiliation is just crazy to me,” said Dr. Haines. “We should be using the best science and taking careful observations, and whatever the recommendations derived from that should be uniformly adopted by everybody, irrespective of your political affiliation.”

Dr. Haines has received honoraria from Biosense Webster, Farapulse, and Sagentia, and is a consultant for Affera, Boston Scientific, Integer, Medtronic, Philips Healthcare, and Zoll. Dr. Lakkireddy has served as a consultant to Abbott, Biosense Webster, Biotronik, Boston Scientific, and Medtronic. 

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